ΝΕΟΤΕΡΑ ΚΑΙ ΜΕΛΛΟΝΤΙΚΑ ΑΝΤΙΑΡΡΥΘΜΙΚΑ ΦΑΡΜΑΚΑ (ΑΑΦ-AAD)

Transcription

1 ΝΕΟΤΕΡΑ ΚΑΙ ΜΕΛΛΟΝΤΙΚΑ ΑΝΤΙΑΡΡΥΘΜΙΚΑ ΦΑΡΜΑΚΑ (ΑΑΦ-AAD) ΣΤΕΛΙΟΣ ΠΑΡΑΣΚΕΥΑÏΔΗΣ ΔΙΕΥΘΥΝΤΗΣ ΕΣΥ Α Καρδιολογική Κλινική ΑΠΘ, Νοσοκομείο ΑΧΕΠΑ, Θεσσαλονίκη

2 NO CONFLICT OF INTEREST

3 1985 selectivity and effectiveness no adverse effects, both cardiac and non-cardiac no clinically significant adverse interactions (pharmacokinetic and pharmacodynamic) with other drugs used in patients with cardiac problems orally and intravenously. Orally administered drugs should have little or no first-pass metabolism reasonably long half-life to allow less frequent dosing relatively little between and within patient variability in pharmacokinetic parameters good correlation between its effectiveness and its plasma concentrations

4 ACTION POTENTIALS AND ARRHYTHMIOGENESIS EAD DAD

5 AAD -Vaughan Williams - classification

6 Novel AAD

7 Budiodarone- amiodarone analogue 2 small studies (n=6, n=72) in pts with pacemaker and atrial arrhythmias Budiodarone vs placebo significant reduction in the total AF burden

8 Celivarone Celivarone is a noniodinated benzofuran derivative 2 studies (n=153, n=486) for VT, VF in ICD recipients 2 studies for AF, AFL (n=673, n=150) No diference than than placebo in all above studies Celivarone was well tolerated and had an acceptable safety profile Due to disappointing clinical data to date, it is not currently approved for use in humans.

9 DRONEDARONE ANDROMEDA and PALLAS: No safety (double risk of death, stroke, HF ) in pts with structural heart disease.hepatotoxicity

10 Dofetilide (class ΙΙΙ) safe and effective in patients with left ventricular dysfunction and CAD TDP risk in loading phase: inpatient 3 days monitoring approved in North America for AF limited clinical experience in ventricular arrhythmia it may be an alternative AAD for pts with VT/VF events refractory to amiodarone and/or sotalol therapy

11 Azimilide (class III) Ikr, Iks blocker APD, ERP in atria and ventricles SHIELD trial RCT, n= 633, secondary prevention ICD pts primary endpoint of all-cause shocks plus symptomatic VTs terminated by ATP was significantly reduced in azimilide group ALIVE trial RCT, n=3,717, recent MI, EF: 15%- 35%. F/U: 1 year No significant differences in all-cause, cardiac, or arrhythmic mortality between the azimilide and placebo groups Not yet approved for use in North America or Europe.

12 RANOLAZINE (IB class) ATRIUM VENTRICLE APD: action potential duration, DAD: delayed after depolarization EAD: early after depolarization, ERP: effective refractory period, Ikr: delayed rectifier potassium current, INaL: late inward sodium current, INaP: peak inward sodium current, TDR: transmural dispersion of repolarization.

13 Ranolazine for AF monotherapy adjunctive

14 Ranolazine for the prevention or treatment of post-cardiothothoracic surgery (CTS) AF

15 RANOLAZINE. MERLIN-TIMI 36 TRIAL n=6500, ranolazine or placebo in addition to standard therapy Ranolazine: antiarrhythmic effect in the first week after admission for acute coronary syndrome NS-VT(>8 BEATS) placebo ranolazine, Scirica BM et al, Circulation 2007;116:

16 Ranolazine Implantable Cardioverter- Defibrillator Trial (RAID)-NCT Randomized,double-blind placebo control, F/U:2 yrs, n=1440, high-risk ICD/CRT-D pts ranolazine did not significantly reduce the incidence of the primary composite outcome of VT/VF or death. Zareba W et al, ΗRS 2017

17 2018 n= 7500, 14 studies (3 clinical trials, 2 observational studies, 8 case reports, 1 case series). Ranolazine seems to have a beneficial role in ventricular arrhythmias in different clinical settings

18 AAD for AF CARDIOVERSION (ESC 2016)

19 Vernakalant mixed voltage- and frequency K+ and Na+ channels blocker with atria-selective action with minimal effects on ventricular repolarization Not approved from FDA

20 AF Different types of AF (paroxysmal, persistent, chronic ) present distinct forms of atrial remodeling It is very unlikely that one single molecular target can cover all pathological abnormalities

21 mechanisms of ΑF

22 Ιncreased diastolic sarcoplasmic reticulum Ca 2+-leak in AF

23 2017

24 Nifekalant (ΙΙΙ) pure potassium channel blocker IKuR Νifekalant vs amiodarone (Laboratory studies) no negative inotropic effects, no effect on cardiac conduction and hemodynamic status DFT (defibrillation threshold)

25 CONCLUSION systematic reviews and meta analyses: Αmiodarone, lidocaine, and nifekalant therapies equally improve survival to hospital admission compared with placebo However, none of these antiarrhythmic drugs improved long term outcomes (post discharge)

26 AAD for BRUGADA Syndrome no randomized clinical studies in Brugada syndrome Quinidine, Isoproterenol : in storm(i indication) Bepridil :Ca+ blocker Anti-arrhythmic (IIa) Cilostazol Phosphodiesterase inhibitor (IIb ) antiplatelet, claudication

27 Future Antiarrhythmic Targets intracellular calcium gap junctions sodium calcium exchange adenosine triphosphate (ATP)-sensitive potassium channel blockade

28 Intracellular Calcium calcium homeostasis: SERCA2a: sarcoplasmic reticulum (SR) calcium ATPase RyR2: ryanodine receptor CPVT : leaky RyR2, resulting in delayed afterdepolarizations and polymorphic VT Flecainide : targets RyR2, suppress VT events in patients with CPVT in conjunction with beta-blockers

29 gap junctions Connexin 43 gap junction protein responsible for cell cell coupling in ventricular myocardium function: impaired in acute ischemia and acidosis Rotigaptide (peptide, experimental studies) prevents dephosphorylation of connexin 43 and improves conduction across gap junctions reducing dispersion of refractorines possibly antifibrotic property

30 sodium calcium exchange (NCX) key role in intracellular Ca removal in the cardiomyocyte cell membrane protein 1Ca+ 3 Na+ Increased expression or activity of NCX has been associated with impaired cardiac contractility and an increased risk of arrhythmias in heart failure KBR-7943 and SEA-0400 drugs

31 Adenosine triphosphate (ATP)-sensitive potassium channel blockade Myocardial ischemia : cardiac cell membrane ATP extracellular K+, APD ventricular proarrhythmia Glibenclamide : ATP sensitive potassium channel inhibitor Attenuates reductions in action potential duration in models of ischemia Suppress PVCs and VF Agents HMR-1883, HMR and HMR-1402

32 2016

33 GENE THERAPY HISTORY 1973 DNA transfer from one organism to another 1995 successfully treatment with retroviral gene therapy for ADA-SCID (adenosine deaminase deficiency- severe combined immunodeficiency) 2012 first gene therapy drug approval (EC) Glyberas (alipogene tiparvovec) is an adeno-associated virus (AAV-1) engineered to express lipoprotein lipase in the muscle for the treatment of lipoprotein lipase deficiency 2015 Imlygic (talimogenelaherparepvec), an oncolytic herpes simplex virus 1 to treat melanoma

34 CUPID study phase I, II (HF) first trial of cardiac gene transfer in humans an AAV1(adeno-virus) vector was used to deliver SERCA2 cdna to pts with advanced heart failure via percutaneous intracoronary delivery SERCA2 is central to controlling the flow of calcium ions between the sarcoplasmic reticulum and cytoplasm, and so has an important role in regulating myocardial contractility reduction in hospitalization and major clinical events Zsebo, K. et al. Circ. Res. 2014;114: Gene therapy for heart rhythm disorders is currently being evaluated in preclinical stages

35 Gene therapy for AF biological b-blocker

36 Gene therapy for AF

37 Gene therapy for VT

38 Gene therapy for pacing

39 Οne-size-fits-most approach Precicion-medicine approach Medication-oriented therapy Patient-centered therapy

40 ΣΥΜΠΕΡΑΣΜΑΤΑ To ιδεώδες αντιαρρυθμικό δεν έχει βρεθεί Κατανόηση μηχανισμού αρρυθμιών Εξατομίκευση Γονιδιακή θεραπεία μέλλον?

41 EYXAΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ

42