ΠΡΟΣΤΑΝΟΕΙΔΗ: ΕΦΑΡΜΟΓΗ ΚΑΙ ΡΟΛΟΣ ΣΤΗΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ ΣΗΜΕΡΑ

1. ΠΡΟΣΤΑΝΟΕΙΔΗ: ΕΦΑΡΜΟΓΗ ΚΑΙ ΡΟΛΟΣ ΣΤΗΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ ΣΗΜΕΡΑ Γεωργία Γ. Πίτσιου, MD, PhD Πνευμονολόγος- Εντατικολόγος Μονάδα Αναπνευστικής Ανεπάρκειας ΑΠΘ

2. ACCF/AHA 2009 EXPERT CONSENSUS DOCUMENT ON PULMONARY HYPERTENSION JACC April 2009

3. J Am CollCardiol. 2009 Jun 30;54(1 Suppl)

4. The discovery of prostacyclin (1976) A young woman, bedbound with severe PH, responded to intravenous epoprostenol with a fail in pulmonary vascular resistance, improved oxygenation, and a rise in exercise tolerance. For 13 months, continuous infusion of epoprostenol has enabled her to live independently at home Higenbottam et al. Lancet 1984; 1(8385):1046-7 An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation Nature, 1976

5. Prostacyclin analogues:Chemical structures and plasma half-lives COOH COOH O CH3 OH OH OH OH PGI2 (t½= 2 min)1 Iloprost (t½= ~30 min)2 COOH COO* O O Na+ CH3 HO OH OH OH Treprostinil (t½= ~240 min)3 Beraprost (t½= ~30 min)2 PGI2, prostacyclin; t1/2, half-life 1. Clapp et al. Am J Respir Cell Mol Biol. 2002;26:194-201; 2. Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; 3. Remodulin® (treprostinil) US prescribing information; United Therapeutics Corp. January 2010

6. Importance of prostacyclin in PAH pathophysiology Anti-proliferation Vasodilatation Anti-thrombosis AC, adenylyl cyclase; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; IP; prostaglandin receptor; P, arachidonic acid; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; PGH2, prostaglandin H2; PGI2, prostacyclin; PPAR, peroxisome proliferator-activated receptor 1. Humbert et al. N Engl J Med. 2004;351:1425-1436; 2. Ghofrani et al. J Am Coll Cardiol. 2004;43:68S-72S; 3. Mitchell et al. Exp Physiol. 2007;93:141-147

7. Mubarak KK. Respir Med 2010

8. Treprostinil (Remodulin®) Iloprost (Ventavis®) Epoprostenol (Flolan®) Treprostinil (Remodulin®) Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled

9. Pharmacological effects of prostacyclin HOOC O OH OH Prostacyclin Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; Zardi et al. Int Immunopharmacol. 2005;5:437-459; Ghofrani et al. J Am Coll Cardiol. 2004;43:68S-72S; Humbert et al. J Am Coll Cardiol. 2004;43:13S-24S

10. Haemodynamic effects of systemically applied prostanoids Prostacyclin + Pulmonary vasodilatation(mins) Systemic vasodilatation Positive inotropic effects - PVR  SAP  - - Cardiac output  Pulmonary vasodilatation(weeks) Arterial baroreflex (mins) Neurohormonal activation(weeks) PVR, pulmonary vascular resistance; SAP, systemic arterial pressure as measured with the method of Riva Rocci. +: positive effect; –: negative effect Adapted from Gomberg-Maitland M. EurRespir J 2008;31:891-901

11. Instability of epoprostenol 100 Epoprostenol Tyrode’s solution pH 7.7 80 Washed human platelets(2x108 ml-1) • Unstable at physiological temperatures and pH2 • Light sensitive2 • Hydrolysed to 6-oxo-PGF1α2 • Elimination half-life of approximately 3 minutes2 60 % Control 40 20 10 20 30 Incubation time (min) Decay of prostacyclin at 37°C in vitro1 Data are mean ±standard error PGF, prostaglandin F 1. Adapted from Whittle BJR; 1983. Actions of prostacyclin and thromboxanes: Products of the arachidonic acid cascade. In: Hormones and cell regulation, Volume 7. Eds Dumont, J.E., Nunez, J., Denton, R.M. Elsevier Biomedical Press; Amsterdam, pp 3-23; 2. Flolan® (epoprostenol sodium) Summary of Product Characteristics, GlaxoSmithKline. March 2006

12. What are the facts about practicalities of Flolan administration Practicalities Short half-life (3-5 minutes) Continuous IV infusion - Permanent tunneled subclavian catheter Drug preparation and change-over crucial Mixed with buffer Drug must be stored refrigerated Post change flushing 12hour dosing un-cooled, 24 hour dosing if cooled Continuous infusion Patient education / Specialized nurses Complications Total infections: 0.19 patients/year1 Catheter related sepsis: 0.1-0.4 per patient/year2 1. Sitbon et al 2002 JACC 40:7807-88 2.Hoeper et al, Am J Respir Crit Care Med 165.:209–1216, 2002.

13. I.V. Εποπροστενόλη

14. * Conventional treatment consisted of oral anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen. All patients received anticoagulants except for one in the treatment group

15. IV epoprostenol long-term observational study: Survival rates Mc Laughlin1 Sitbon2 100 1.0 IV epoprostenol (n=178) 0.8 (n=162) 80 0.6 60 Survival (%) Cumulative survival 0.4 40 Historical controls** (n=135) 0.2 Predicted survival (NIH)* 20 0.0 0 6 12 18 24 30 36 0 12 24 36 48 60 72 84 96 108 120 Time (months) Time (months) 178 129 85 57 36 21 7 3 1 n 135 59 34 20 11 4 2 2 1 * Survival was predicted according to the equation derived from NIH registry 3 ** Historical control: patients were followed up at the centre 1. McLaughlin W et alCirculation 2002; 106: 1477–1482 2. Sitbon O et alJ Am Coll Cardiol 2002; 40: 780–799 NIH: National Institutes for Health

16. IV epoprostenol: NYHA FC is predictive of survival 100 80 60 40 20 0 12 24 36 48 60 72 84 96 108 PAH patients in NYHA FC III at baseline have a higher survival rate when treated with IV epoprostenol compared with those in NYHA FC IV at baseline McLaughlin 20021 Sitbon 20022 100 80 NYHA FC III NYHA FC III 60 Survival (%) p=0.001 40 NYHA FC IV NYHA FC IV 20 0 0 12 24 36 48 60 72 84 Time on epoprostenol (months) Time on epoprostenol (months) 120 92 65 46 31 17 6 2 1 N n 10 58 37 20 11 5 4 1 1 162 33 95 70 48 30 20 1. McLaughlin W et alCirculation 2002; 106: 1477–1482 2. Sitbon O et al J Am Coll Cardiol 2002; 40: 780–799

17. Adverse events with IV epoprostenol from SmPC *Associated with the delivery system for epoprostenol Very common – 10%; common – 1% and <10%; uncommon – 0.1% and <1%; rare – 0.01% and <0.1%; very rare –<0.01% 1. Flolan® Summary of Product Characteristics

19. Ενημέρωση ασθενή • Αναλυτική ενημέρωση για στάδιο της νόσου και εξελικτική πορεία • Περιγραφή θεραπείας-Προετοιμασίας (καθετήρας, φορητή αντλία, φάρμακο, παρενέργειες) • Απόλυτη συναίνεση, Διάθεση και πιστή τήρηση οδηγιών • Ψυχολογική Υποστήριξη

20. FLOLAN : IV infusion 24 hours, daily. A central line & a PUMP (200g) FLOLAN administration

21. Εκπαίδευσηστο χειρισμό τουκεντρικού φλεβικού καθετήραντρικοί Φλεβικοί καθετήρες

22. Εκπαίδευση Φορητή αντλία χορήγησης

23. Initiation and long-term dose adaptation1of IV Flolan infusion Initiation: Flow rate is adjusted under medical supervision1 Begin treatment at 1 ng/kg/min Increase by increments of 1 ng/kg/min every 12 to 24 hours up to 10 ng/kg Increase by increments of 1 ng/kg/min every 15 days up to 16 ng/kg • Dose reduction • Reduce when clinical signs of overdoseor excessive elevation of cardiac outputare evident • Decrease gradually in stages of 2 ng/kg/min • Dose increase • According to PAH symptom exacerbation in trials, mean monthly increase is 1 ng/kg/min • However, increase must be tailored toeach individual Patient follow up should be assessed early, within 3 months of therapy initiation,8regularly and systematically 1. Flolan SpC. 8. Sitbon et al. J American Coll Cardiol 2002.

24. Prostacyclin analogues:Chemical structures and plasma half-lives COOH COOH O CH3 OH OH OH OH PGI2 (t½= 2 min)1 Iloprost (t½= ~30 min)2 COOH COO* O O Na+ CH3 HO OH OH OH Treprostinil (t½= ~240 min)3 Beraprost (t½= ~30 min)2 PGI2, prostacyclin; t1/2, half-life 1. Clapp et al. Am J Respir Cell Mol Biol. 2002;26:194-201; 2. Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; 3. Remodulin® (treprostinil) US prescribing information; United Therapeutics Corp. January 2010

25. Modifications to the prostacyclin side chain for increased stability Treprostinil O COOH Stability HOOC Beraprost CH3 O OH OH OH Iloprost CH3 Prostacyclin CH3 OH

26. Treprostinil background • Prostacyclin analogue • Pharmacology: vasodilatation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation1 • Approved for SC infusion for idiopathic and heritable PAH in patients with NYHA class III severity of disease to improve exercise tolerance and symptoms of the disease1 • Metabolised bythe liver2 • Treprostinil metabolites mainly excreted via kidneys1 IPAH, idiopathic pulmonary arterial hypertension; NYHA, New York Heart Association; SC, subcutaneous 1. Remodulin® (treprostinil sodium) Summary of Product Characteristics, United Therapeutics Europe Ltd. April 2010; 2. Skoro-Sajer et al. Vasc Health Risk Manag. 2008;4:507-513

27. Treprostinil PK data: Dose proportionality • In patients with PAH, increasing SC or IV treprostinil dose increases plasma concentrations in linear fashion, irrespective of route of administration • Conclusion: Treprostinil plasma concentrations follow predictable relationship to treprostinil dose Route of treprostinil administration IV SC 20,000 16,000 n=47 12,000 Treprostinil plasma concentration (pg/ml) 8,000 4,000 0 10 20 30 40 50 60 70 80 100 110 120 130 0 90 Treprostinil dose (ng/kg/min) IV, intravenous; PAH, pulmonary arterial hypertension; PK, pharmacokinetics; SC, subcutaneous McSwain et al. J Clin Pharmacol. 2008;48:19-25

28. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertensionA double-blind, randomized, placebo-controlled trial Simonneau et al. Am J Respir Crit Care Med. 2002;165:800–804

30. Safety profile and tolerability • 18 patients (8%) in treprostinil group discontinued treatment due to intolerable abdominal infusion site pain vs 1 patient in placebo group ns, non-significant; SC, subcutaneous Adapted from Simonneau et al. Am J Respir Crit Care Med. 2002;165:800-804

31. Long-term survival profile in IPAH patients 91% 82% 69% 56% Observed vs predicted survival 100 90 80 76% 72% Observed survival 70 60 46% Survival (%) 50 38% 40 Predicted survival 30 20 10 0 0.0 4.5 1.0 2.0 3.0 4.0 0.5 1.5 2.5 3.5 At risk (n) 10 231 149 82 332 Time (years) Observed survival in 332 SC treprostinil-treated IPAH patients (with baseline haemodynamic parameters available) vs predicted survival by the National Institutes of Health equation IPAH, idiopathic pulmonary arterial hypertension; SC, subcutaneous Adapted from Barst et al. Eur Respir J. 2006;28:1195-1203

32. REMODULIN®Μορφή / ΠεριεκτικότηταΔιάλυμα για έγχυση 1 mg/ml (φιαλίδιο 20ml)Διάλυμα για έγχυση 2.5 mg/ml (φιαλίδιο 20ml)Διάλυμα για έγχυση 5 mg/ml (φιαλίδιο 20ml)Διάλυμα για έγχυση 10 mg/ml (φιαλίδιο 20ml) • Πολλαπλές συγκεντρώσεις • Tailoring dose /συμπτωματολογία • Εξατομικευμένη χορήγηση

33. Infusion pump comparison Treprostinil reservoir should be changed at least every 72 hours5 Change of reservoir is not associated with change of site. IV, intravenous; SC, subcutaneous CADD-MS is a trademark and CADD-Legacy is a registered trademark of Smiths Medical System 1. http://www.smiths-medical.com/catalog/ambulatory-pumps-sets/cadd-ambulatory-infusion-pumps/cadd-ms/cadd-ms-3-ambulatory.html. Accessed May 2010; 2; http://www.smiths-medical.com/catalog/ambulatory-pumps-sets/cadd-ambulatory-infusion-pumps/cadd-legacy/cadd-legacy-1-pump.html. Accessed May 2010; 3. http://www.firstbiomed.com/catalog_page_print.aspx?equip_id=77&id=13&key=equip_mfg_id&link=c. Accessed May 2010; 4. http://www.infucare.ch/cronoFIVE.htm. Accessed May 2010; 5. Treprostinil Summary of Product Characteristics. United Therapeutics, April 2010

34. ΤΟΠΟΘΕΤΗΣΗ ΑΝΤΛΙΑΣ Το REMODULIN χορηγείται μέσω συνεχούς υποδόριας έγχυσης Διαμέσου ενός υποδόριου καθετήρα, με χρήση μιας μικρής φορητής αντλίας 24ωρης έγχυσης Πολλαπλές επιλογές σημείων έγχυσης Για περιπατητικούς ασθενείς Χωρίς να απαιτούνται άσηπτες συνθήκες Σέβεται την αυτονομία του ασθενή

35. ΒΗΜΑΤΑ ΧΟΡΗΓΗΣΗΣ 2 1 • 3 4

37. Infusion site reaction and pain • In the pivotal study and long-term follow up: • 83%1 and 81%2 of patients experienced some level of infusion site reaction • 85%1 and 92%2 of patients reported some degree of infusion site pain • 8%1 and 23%2 of patients discontinued therapy because of site pain (70% of these within the first year)2 • Rate of discontinuation due to infusion site pain markedly reduced through education, strong nursing support and proactive pain management3 1. Simonneau et al. Am J Respir Crit Care Med. 2002;165:800-804; 2. Barst et al. Eur Respir J. 2006;28:1195-1203; 3. Lang et al. Chest. 2006;129:1636-1643

38. Πόνος στο σημείο της έγχυσης • Συνήθως υποχωρεί μετά από 3-5 ημέρες • Μπορεί να διαχειριστεί αποτελεσματικά και μπορεί να μειωθεί με τη μακροχρόνια θεραπεία • Το σημείο της έγχυσης να αλλάζει μια φορά κάθε 3-4 εβδομάδες: γεγονός το οποίο μπορεί να βοηθήσει στην ελαχιστοποίηση εμφάνισης του πόνου

39. Site pain care:Possible pharmacological approaches • Hot / cold packs • Oral and topical analgesics • Anti-inflammatory creams • Oral and topical antihistamines • Corticosteroids • Anti-depressants • Systemic analgesics (eg NSAIDs, GABA analogues or opioids) GABA, gamma-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug

40. Recommended dosing for treprostinil • Initial infusion rate: 1.25 ng/kg/min (0.625 ng/kg/min if poorly tolerated) • Increase infusion rate in increments of 1.25 ng/kg/min per week for first 4 weeks and then 2.5 ng/kg/min per week • Adjust dose on individual basis in order to achieve maintenance dose at which symptoms improve and which is tolerated by the patient • Efficacy only maintained in pivotal 12-week trials with dose increases on average of 3–4 times/month • Aim of treatment: Establish dose at which PAH symptoms are improved, whilst minimising excessive pharmacological effects of treprostinil • Adverse events (eg flushing, headache, jaw pain, hypotension, nausea, vomiting and diarrhoea) are generally dose-dependent • They may disappear with continued treatment • Infusion rate may be reduced to diminish intensity if persistent / intolerable PAH, pulmonary arterial hypertension United Therapeutics Europe Ltd. Remodulin (treprostinil) summary of product characteristics. April 2010

41. Relationship between rate of dose titration and incidence of site pain • Study assessed effect of treprostinil infusion rate on incidence of site pain • 23 patients with PAH randomised to slow or fast dose escalation groups • Treprostinil dose at week 12 • Slow escalation group: 12.9 ±2.7 ng/kg/min • Rapid escalation group: 20.3 ±5.8 ng/kg/min 25 58% experienced site pain 20 p=0.04 15 82% experienced site pain Dose (ng/kg/min) 10 Rapid dose escalation Slow dose escalation 5 0 0 8 12 2 6 10 4 Time (week) • Rapid titration associated with lower incidence of infusion site pain • Lack of treprostinil dose dependence of infusion site pain PAH, pulmonary arterial hypertension Skoro-Sajer et al. Clin Pharmacokinet. 2008;47:611-618

42. 1ηεβδομαδα ΓΡΗΓΟΡΗ ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ 14ng/kg/min 1ος μήνας 22ng/kg/min 28ng/kg/min

43. Περιστατικό • Γυναίκα 54 ετών, ΙΠΑΥ • Σε τριπλή θεραπεία με συνδυασμό • Tb Sildenafil 25 mg(1X3), tbTracleer 125 mg(1X2), • amp Ventavis(1X6), tbLasix 40 (1X2), LTOT (3lit/min) • Επανειλημμένες εισαγωγές με δεξιά καρδιακή ανεπάρκεια • 6MWT: 100m • NYHA IV • RHC: mPAP 54mmHg, CI 2 Lt/min/m2, RAP 15mmHg

44. A/α θώρακος

45. Έναρξη τρεπροστινίλης sc(Remodulin) • Σταδιακή ↑της δόσης κατά 1,25 ng/kg/min έως 30 ng/kg/min

46. 6 μήνες μετά • Υπό tb Tracleer 125 (1X2), tb Viagra 25(1X3) και Remodulin (30ng/kg/min ) • Σε 6ΜWΤ: 386 m SpO2: 94%→87% (υπό ρινική κάνουλα 3lit/min) • NHYA III • Τελική έκβαση: Η ασθενής κατέληξε περίπου 18 μήνες μετά την έναρξη τρεπροστινίληςαπό συγκοπικό επεισόδιο

48. Aιμοδυναμική επίδραση της εισπνεόμενης ιλοπρόστης σε σοβαρή πνευμονική υπέρτασηOlschewski et al. Ann Intern Med 1996

49. ΕΙΣΠΝΕΟΜΕΝΗ ΙΛΟΠΡΟΣΤΗ (ILOPROST) PPH-CTD-CTEPH N = 203 NYHA : III-IV Iloprost = 2.5 or 5 µg 6-9/d Combined primary end-point(NYHA FC + 6MWT) • Εκλεκτική αγγειοδιαστολή της πνευμονικής κυκλοφορίας • Ανεπιθύμητες δράσεις ξηρός βήχας ήπιες συστηματικές • Χρήση ειδικού νεφελοποιητή • Βραχεία διάρκεια δράσης 6-9 (- 12) εισπνοές /ημέρα Διακοπή κατά τη διάρκεια της νύχτας Olschewski H, Simonneau G,Galie N et al. AIR study N Engl J Med 2002