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`iifiachment 1f: Cogy oiga ’1;
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`PSasma brain Bairiurs‘iic pepiéde as a pmgnosfic indicatth in pafiems with primary puimofiar}:
`hypertensmn
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`"’rar‘xgplanwtimz Q? emdothefihal progeniim‘ ceEEE mm the king to alieviaie guimonary hypertengioz‘a in
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`é‘University of
`
`
`© URBAN & VOGEL 2005
`
`
`
`N-_.__u,—V—~.\J._.V,__~u._,~
`
`l i
`
`i l
`
`l i i l i i l l l l i '
`
`l r l g i
`
`NeueTherapieoptionen in der Behandlung der
`pulmonalarteriellen Hypertonie
`Hossein Ardeschir Ghofrani, Robert Voswinckel, Frank Reichenberger, Friedrich Grimminger,
`Werner Seegerl
`
`Zusammenfassung
`Trotz aller Fortschritte in derTherapie der pulmonalarteriellen
`Hypertonie gibt es bisher keine Aussicht auf Heilung dieser
`schwerwiegenden Erkrankung. Mit der Einfiihrung effektiver
`und nonparenteraler Medikamente (2.8. orale Endothelin-Re-
`zeptor-Antagonisten [ERA], inhalative Prostanoide) haben sich
`jedoch die Lebensqualitat, die kérperliche Belastbarkeit und
`die Prognose der Patienten in den letzten Jahren erheblich ver—
`bessern lassen. Die Anwendbarkeit dieser Medikamente ist
`aber durch die z.T'. gravierenden Nebenwirkungen und/oder
`aufwendigenApplikationsformeneingeschranktDb selektive
`ERA aufgrund ihrer Spezifitat flir den A-Rezeptor Vorteile ge-
`geniiber dem nichtselektiven ERA Bosentan im Hinbiick auf
`Nebenwirkungen, aber auch in Bezug auf die Effektivitéit ha—
`ben, wird erst nach Auswertung der derzeit laufenden zuias-
`sungsrelevanten Studien mitAmbrisentan und Sitaxsentan zu
`eruieren sein. lnhaliertes Treprostinil konnte aufgrund seiner
`hohen Selektivitiit fijr die pulmonale Zirkulation sowie auf—
`Schliisselwiirter: Pulmonale Hypertonie - Vasodilatative Therapie - Stickstoffmonoxid - Prostacyclin - Endothelinant—
`agonist - Phosphodiesteraseinhibitoren - Kombinationstherapien
`
`grund der langeren Wirkung einen Vorteil gegeniiber dem be-
`reits zugelassenen inhalierten Iloprost haben. Bisher stehen
`jedoch noch Ergebnisse einer kontrollierten randomisierten
`Studie aus, die die Wirksamkeit dieserTherapie in der chroni-
`schen Anwendung dokumentieren. Der selektive Phospho-
`diesterase-s-(PDE5-)lnhibitor Sildenafil ist im Vergleich zu den
`vorgenannten Substanzen bereits am nachsten zur klinischen
`Zulassung. Sildenafil erwies sich bei verschiedenen Formen
`der pulmonalen Hypertonie als starker pulmonal selektiver
`Vasodilatator. Die Ergebnisse der Phase-lll-Studie zurAnwen-
`dung von Sildenafil bei pulmonalarterieller Hypertonie besti-
`tigen die hervorragende Wirksamkeit dieses Medikaments bei
`exzellenterVertraglichkeit. Kombinationstherapien stellen bei
`alien noch zu erwartenden Fortschritten in der Entwicklung
`einzelner Substanzen die aussichtsreichste zukijnftige Thera-
`pieoption dar. Kontrollierte Studien zur Uberpriifung dieser
`Option, unter Beriicksichtigung verschiedener Medikamen-
`tenkombinationen, befinden sich bereits in Planung.
`
`Herz 2005;30:296—302
`D0110.1007/500059—005-2695-4
`
`Emerging Therapies for the Treatment of Pulmonary Arterial Hypertension
`Abstract
`the analysis of pivotal trials recently carried out with ambris-
`entan and sitaxsentan. Inhaled treprostinil can potentially
`have benefits over the already approved inhaled iloprost,re-
`lated to its higher pulmonary selectivity as well as to the ion-
`ger biological half-life. However,this has yet to be proven in
`long-term randomized controlled trials. In comparisontothe
`previously mentioned substances, the selective phosphodi-
`esterase-5 (PDE5) inhibitor sildenafil approached approval
`closest as new therapy for pulmonary arterial hypertension
`Oral siidenafil has proven its efficacy as a selective pulmO'
`nary vasodilator in various forms of pulmonary hypertension-
`The results Of the pivotal phase lll trial have confirmed the
`
`Besides all progress in the therapy of pulmonary arterial hy-
`pertension over the past years, there is still no cure for this
`devastating disease By introducing effective and nonparen—
`teral medications (e.g., oral endothelin receptor antagonists
`[ERAS], inhaled prostanoids), quality of life,exercise tolerance
`and prognosis of patients have substantially improved. How—
`ever, applicability of these therapies can be hampered by se-
`rious side effects and/or the necessity for elaborate applica-
`tion techniques.Whether selective ERAS — due to their speci-
`ficity for the A-type receptor — have potential benefits over
`the nonselective ERA bosentan remains to be answered by
`
`
`‘Medizinische Klinik und Poliklinik ll, University Giessen Lung Center
`(UGLC), Justus~Liebig-Universitat Gieisen.
`
`296
`
`WATSON LABORATORIES, INC. , lPR2017-01622, p.50 of 74
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`Herz30-2005‘Nr.4 ©Urban8iVogE
`
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`
`.
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`l
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`WATSON LABORATORIES, INC. , IPR2017-01622, p. 50 of 74
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`

`
`
`on'iereity of ééilEEEEEQWQMJLSEWEQ
`>>>>“Doetgfien‘e7777
`iteééfiééhewii
`EL‘ibr‘ary:
`‘
`
`I) ohofrant H7X,et all. PuFmonale Hyper ome—neue Aspe e cFerTherapIe
`
`strong efficacy and excellent tolerability of this substance.
`Combination therapies, despite all progress seen for single
`agents, can‘be regarded as the most promising therapeutic
`
`approach for the future. However, controlled randomized tri-
`als that are currently under consideration have to confirm
`this notion.
`
`Key Words: Pulmonary‘hypertension -Vasodilative therapy - Nitric oxide ~ Prostacyclin - Endothelin antagonist -
`Phosphodiesterase inhibitors - Combination therapies
`
`3 l l l
`
`1
`
`dem genannten Artikel auch schon auf inhaliertes Ilop-
`rost (Ventavis®) eingegangen wurde, sei diese Thera—
`pieforrn hier noch einmal kurz erwahnt, da sie zur Er-
`lauterung der neuen Therapie rnit inhaliertem Trepros—
`tinil den theoretischen und klinischen Hintergrund
`liefert.
`
`lnhalatives lloprost
`Die Inhalation aerosolierter Prostanoide umgeht Wir-
`
`kungsvoll einen GroBteil der Nachteile der Infusions-
`therapie: Durch die alveolare Deposition des Wirkstoffs
`wird eine pulmonal und intrapulmonal selektive Wir-
`kung erzielt. Die Therapie der pulmonalen Hypertonie
`mit wiederholten Inhalationen des lang Wirksarnen
`Prostacyclinanalogons lloprost hat in einer multizentri-
`schen, randomisierten, plazebokontrollierten Studie ih-
`re Effektivitat bei gleichzeitig guter Sicherheit bewiesen
`[1]. In der mit lloprost behandelten Gruppe zeigte sich
`sowohl eine signifikante Verbesserung der 6-min-Geh-
`strecke (als MaBstab der Belastbarkeit) als auch der
`NYHA—Klasse (New York Heart Association) im Ver—
`gleich zur plazebobehandelten Gruppe. Dieser zulasv
`sungsrelevanten Studie waren bereits mehrere, nicht
`kontrollierte Studien an Patienten rnit verschiedenen
`
`Formen der pulmonalen Hypertonie vorausgegangen
`[2-4]. 1m Wesentlichen konnte die Phase—ULStudie
`hierbei die friiheren positiven Erfahrungen bestatigen.
`Nachteile dieser Therapie sind jedoch neben der auf-
`wendigen Aerosoltechnologie die relativ kurze Wirk-
`dauer der einzelnen Gabe (60—90 min) mit der Notwen-
`digkeit haufiger Inhalationen (sechs- bis neunrnal tag-
`lich) und die therapeutische Pause wahrend der Nacht.
`
`InhaliertesTreprostinil
`Treprostinil ist ein lang wirksames Prostacyclinanalo-
`gon, welches aufgrund seiner langen Plasmahalbwerts—
`zeit und chemischen Stabilitat in Lbsung potentielle
`Vorteile gegeniiber Epoprostenol bietet und somit zu-
`nachst als Substitut fiir die Infusionsbehandlung ent—
`wickelt wurde. Zur Vermeidung katheterassoziierter
`
`I ll
`
`l l
`
`l
`i
`
`Einleitung
`[m Beitrag von Hoeper in diesem Heft wurde bereits
`ausffihrlich auf die leitliniengerechte Therapie der pul-
`' monalarteriellen Hypertonie (PAH) eingegangen. Leit-
`liniengerecht bedeutet in diesem Fall die Be-zugnahme
`auf zugelassene Medikamente oder Substanzen, die
`aufgrund einer eindeutigen Publikationslage Eingang
`in die evidenzbasierten Therapieempfehlungen gefun—
`3
`l den haben. Inhalt dieses Beitrags wird die Darstellung
`i neuer. z.T. noch in Entwicklung befindlicher Therapie-
`l
`anséitze sein, die in naher Zukunft Eingang in die Thera—
`l pieleitlinien finden konnen oder die bereits aufgrund
`l
`eines eindeutigen Wirksamkeitsnachweises im sog.
`,,off—label use“ zum Einsatz kommen. Im Einzelnen
`
`[ werden wir aufdie Therapie Init inhalierten Prostano-
`
`iden, selektiven Endothelin—A-Rezeptor—Antagonisten
`(Sitaxsentan und Ambrisentan) sowie Phosphodieste—
`rase—S-(PDE5-)Hemmern (hier insbesondere Sildena-
`fil) eingehen. Des Weiteren werden Kombinationsthe-
`rapien als moglicher zukiinftiger Therapiestandard dis-
`K
`‘i kutiert.
`:
`
`Vasoaktive Therapie
`l
`‘ Angriffspunkte einer vasoaktiven Therapie sind die po—
`1‘
`tentiell reversiblen Komponenten der GefaBobstruk-
`l
`lion. Prinzipiell bestehen zwei Moglichkeiten, durch
`K pharmakologische Intervention den Gefanuerschnitt
`!
`Zu erweitern:
`' Aufhebung eines dauerhaft erhohten Vasotonus durch
`Relaxation der glatten GefaBmuskulatur (unmittelba-
`l
`rer Effekt von Vasodilatatoren);
`l
`'Beeinflussung des strukturellen GefaBurnbaus (vas-
`[
`kulares Remodeling) durch Nutzung von antiin-
`,
`flammatorischen und antiproliferativen Wirkstoffen.
`l‘
`Eine Vielzahl vasodilatativer Agenzien ist in der Be-
`(
`2
`handlung der chronischen pulmonalen Hypertonie kli-
`nisch getestet worden. Bezfiglich der Anwendung von
`l
`[ Calciumantagonisten, Prostanoiden und nichtselekti—
`’
`V911 Endothelinantagonisten sei nochrnals auf den Arti-
`
`kElVonHoeperindiesemHefthingewiesen. Obwohlin
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`ibrary
`Ghofrani HA, et al. Pulmonale Hypertonie — neue Aspekte derTherapie
`
`Komplikationen wird die Treprostinilinfusion subkutan
`fiber eine (der Insulindauertherapie entnommene) Spe—
`zialkaniile infundiert. Die zulassungsrelevante Studie
`zu diesem Therapieprinzip hat eine Wirksamkeit bei
`der Behandlung von Patienten mit PAH erbracht [5].
`Nachteil dieser Behandlungsform ist jedoch, dass es bei
`bis zu 80% der Patienten zu Schmerzen an der Injekti—
`onsstelle kommt, welche eine dauerhafte Therapie er-
`schweren. Erste Untersuchungen aus GieBen haben
`den Wirksamkeitsnachweis von inhaliertem Treprosti-
`nil zur effektiven Senkung des pulmonalen GefiiBwi—
`derstands (PVR) erbracht [6]. In dieser ersten Untersu-
`Chung wurde bei 17 Patienten mit schwerer prékapil-
`léirer pulmonaler Hypertonie inhaliertes Treprostinil
`(15 [lg/Inhalation) verabreicht. Dies ffihrte zu einer
`starken pulmonal selektiven Druck- und Widerstands-
`senkung mit einer Gesamtwirkdauer von > 180 min. Im
`direkten Vergleich mit inhaliertem Iloprost zeigte inha-
`lierles Trepros