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Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension

Irene M. Lang, Sean P. Gaine
European Respiratory Review 2015 24: 630-641; DOI: 10.1183/16000617.0067-2015
Irene M. Lang
1Division of Cardiology, Medical University of Vienna, Vienna, Austria
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  • For correspondence: irene.lang@meduniwien.ac.at
Sean P. Gaine
2National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
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  • FIGURE 1
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    FIGURE 1

    Involvement of the endothelin, nitric oxide and prostacyclin (PGI2) pathways in the pathogenesis of pulmonary arterial hypertension [1–14]. DP1, EP2, EP4, EP1 and FP are not functionally expressed in the pulmonary artery and do not contribute to vessel tone in the pulmonary artery. In the endothelin pathway the effects of endothelin (ET)-1 are mediated via the ETA and ETB receptors. Receptor binding leads to activation of phospholipase-C and mobilisation of calcium, resulting in vasoconstriction. Selective and dual endothelin receptor antagonists (ERAs) inhibit this pathway. In the pulmonary artery the prostanoid receptors IP, EP3 and TP regulate vessel tone. The prostacyclin pathway involves prostacyclin binding to the IP receptor, which belongs to a family of prostanoid target receptors. Prostanoid binding to the IP receptor induces adenylate cyclase activity, cAMP production and ultimately reduction of Ca2+ concentrations, and leads to vasodilation. TP binding activates phospholipase C, mediating mobilisation of calcium and vasoconstriction. EP3 receptor binding leads to a decrease in cAMP, which blocks vasodilation. Prostacyclin analogues activate this pathway (EP3 pathway). The nitric oxide (NO) pathway involves the production of cGMP, which leads to inhibition of calcium entry, resulting in vasodilation. Phosphodiesterase type 5 inhibitors (PDE-5i) and soluble guanylate cyclase (sGC) stimulators activate this pathway [2–5, 7–14]. #: prostacyclin analogues activate at least one prostanoid receptor in addition to IP. Reproduced and modified from [1], with permission from the publisher.

  • FIGURE 2
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    FIGURE 2

    Chemical structures of drugs that bind to the prostacyclin pathway. a) Prostacyclin; b) beraprost sodium; c) iloprost; d) treprostinil; and e) selexipag.

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    FIGURE 3

    Drugs that target the prostacyclin pathway. a) Routes of administration, and b) target receptors and adverse events [3, 16, 19, 20]. Key tissues associated with known adverse effects are listed. #: approved only by the US Food and Drug Administration; ¶: approved only in Japan and South Korea; +: approved only in New Zealand; §: this pump is an innovation that is not yet widely available.

Tables

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  • TABLE 1

    Evidence-based monotherapy treatment algorithm for drugs that target the prostacyclin pathway

    RecommendationEvidencePAH severity
    WHO FC IIWHO FC IIIWHO FC IV
    Recommended  (class I)Data derived from multiple randomised clinical trials or meta-analyses, or from a single randomised clinical trial or large nonrandomised studiesSelexipag oral#Epoprostenol i.v.¶; iloprost inhaled+; treprostinil s.c. and inhaled§; selexipag oral#Epoprostenol i.v.
    Should be considered  (class IIa)Consensus of opinion of the experts and/or small studies, retrospective studies and registriesIloprost i.v.+; treprostinil i.v.§
    May be considered  (class IIb)Data derived from a single randomised clinical trial or large nonrandomised studiesBeraprost oralƒ; treprostinil oralIloprost inhaled and i.v.; treprostinil s.c., i.v. and inhaled
    • Recommendation IA for prostanoid use in sequential combination therapy for inadequate clinical response at maximal therapy [3]. WHO: World Health Organization; FC: functional class. #: not approved at the time of publication; ¶: approved for continuous i.v. administration for pulmonary arterial hypertension (PAH) WHO FC III–IV by the US Food and Drug Administration (FDA) in 1995; +: approved for aerosol administration for PAH WHO FC III in the European Union and Australia in 2003, and PAH WHO FC III–IV by the FDA in 2004; §: approved for s.c. administration for PAH WHO FC II–IV by the FDA and Health Canada in 2002; ƒ: approved for oral administration for idiopathic PAH in Japan in 1995 [36]. Information from [15, 16].

  • TABLE 2

    Key randomised controlled clinical trials of drugs that target the prostacyclin pathway

    First author [ref.]Year (trial acronym)Background therapyDrugPatients nDurationPrimary end-pointPrimary end-point met?
    Epoprostenol#
     Rubin [37]1990Nonei.v. epoprostenol248 weeksChange in total pulmonary resistanceYes
     Barst [38]1996Nonei.v. epoprostenol8112 weeksChange in 6MWDYes
     Badesch [39]2000Nonei.v. epoprostenol11112 weeksChange in 6MWDYes
     Badesch [40]2009Nonei.v. epoprostenol1023 yearsSurvivalNo
     Humbert [41]2004 (BREATHE-2)Nonei.v. epoprostenol with bosentan or placebo3316 weeksChange in total pulmonary resistanceNo
     Simonneau [42]2008 (PACES)i.v. epoprostenolSildenafil or placebo26716 weeksChange in 6MWDYes
    Iloprost¶
     Olschewski [43]2002NoneInhaled iloprost or placebo20312 weeksComposite ≥10% increase in 6MWD and improvement in WHO FCYes
     Hoeper [44]2006 (COMBI)BosentanInhaled iloprost4012 weeksChange in 6MWDNo
     McLaughlin [45]2006BosentanInhaled iloprost6712 weeksChange in 6MWD and WHO FCYes
    Treprostinil+
     Simonneau [46]2002Nones.c. treprostinil or placebo47012 weeksChange in 6MWDYes
     Jing [47]2013 (FREEDOM-M)NoneOral treprostinil or placebo34912 weeksChange in 6MWDYes
     Tapson [48]2012 (FREEDOM-C)ERA, PDE-5i or bothOral treprostinil or placebo35016 weeksChange in 6MWDNo
     Tapson [49]2013 (FREEDOM-C2)ERA, PDE-5i or bothOral treprostinil or placebo31016 weeksChange in 6MWDNo
     McLaughlin [50]2010 (TRIUMPH-I)Bosentan or sildenafilInhaled treprostinil or placebo23512 weeksChange in 6MWD 10–60 min after inhalationYes
    Beraprost§
     Galiè [51]2002 (ALPHABET)NoneOral beraprost or placebo13012 weeksChange in 6MWDYes
     Barst [52]2003NoneOral beraprost or placebo11612 monthsDifference in disease progressionYes
    Selexipag
     McLaughlin [53]2015 (GRIPHON)None, ERA, PDE-5i or bothOral selexipagƒ11563 yearsTime to first morbidity or mortality eventYes
    • 6MWD: 6-min walking distance; WHO: World Health Organization; FC: functional class; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase type 5 inhibitor.  #: approved for continuous i.v. administration for pulmonary arterial hypertension (PAH) WHO FC III–IV by the US Food and Drug Administration (FDA) in 1995; ¶: approved for aerosol administration for PAH WHO FC III in the European Union and Australia in 2003, and PAH WHO FC III–IV by the FDA in 2004; +: approved for s.c. administration for PAH WHO FC II–IV by the FDA and Health Canada in 2002; §: approved for oral administration for idiopathic PAH in Japan in 1995 [36]; ƒ: not approved at time of publication.

Additional Files

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    • S.P. Gaine
    • I.M. Lang
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Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension
Irene M. Lang, Sean P. Gaine
European Respiratory Review Dec 2015, 24 (138) 630-641; DOI: 10.1183/16000617.0067-2015

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Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension
Irene M. Lang, Sean P. Gaine
European Respiratory Review Dec 2015, 24 (138) 630-641; DOI: 10.1183/16000617.0067-2015
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  • Article
    • Abstract
    • Abstract
    • Introduction
    • The prostacyclin pathway in PAH
    • Prostacyclin therapy for PAH
    • Established prostacyclin analogues
    • Unmet needs and future strategies
    • Development of new oral therapies to target the prostacyclin pathway
    • Conclusion
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