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LA RANOLAZINA UN NUOVO FARMACO CON UNAZIONE DI CLASSE / RANOLAZINE, A NEW DRUG WITH A CLASS ACTION Lazione antiaritmica – The Anti-Arrhythmic Action Stefano.

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Presentation on theme: "LA RANOLAZINA UN NUOVO FARMACO CON UNAZIONE DI CLASSE / RANOLAZINE, A NEW DRUG WITH A CLASS ACTION Lazione antiaritmica – The Anti-Arrhythmic Action Stefano."— Presentation transcript:

1 LA RANOLAZINA UN NUOVO FARMACO CON UNAZIONE DI CLASSE / RANOLAZINE, A NEW DRUG WITH A CLASS ACTION Lazione antiaritmica – The Anti-Arrhythmic Action Stefano Fumagalli SOD Cardiologia e Medicina Geriatrica AOU Careggi e Università di Firenze

2 Tail Current (Normalized) Ranolazine Concentration ( M/L) I Kr – rapidly activating component of delayed rectifier current 26 Ranolazine Concentration ( M/L) I Na late normalized current 26 Late I Na – late sodium current Normalized current Late I Ca – late calcium current 26 Ranolazine Concentration 2-6 M/L: therapeutic range Inhibition of I Kr by ranolazine prolongs APD, and its effect to inhibit late I Na and late I Ca,L abbreviates APD Antzelevitch C, 2004 Canine ventricular myocytes

3 Effects of ranolazine on epicardial and M cell Action Potential Duration – APD 50/90 : 50/90% repolarization Ranolazine Concentration ( M/L) APD 50 (ms) K + Concentration: 4 mM/L Antzelevitch C, 2004 APD 90 (ms) Control Ranolazine Concentration ( M/L) Control * : P<0.05 vs Control M cell (N=5) Epicardial cell (N=4) M cell (N=5) Epicardial cell (N=5)

4 Rapid pacing 2-4 different waveforms Rapid pacing Persisting VF DC Shock VF + Ranolazine 10 M VF interruption (12+6 s) Progressive reduction of waveforms Isolated Rat Hearts (N=8) Morita N, 2011

5 VF Ranolazine 10 M VF interruption m Isolated Rat Hearts (N=8) Morita N, 2011 Pseudo-ECG Micro- Electrode EADs H 2 O 2 (0.1 mM) Multifocal activation VF H 2 O 2 (0.1 mM) EADs Ranolazine stop VF min

6 Number of Foci per 100 ms 1 second H 2 O 2 (0.1 mM) VF termination (SR) Ranolazine 10 M Morita N, 2011 VFSR Time course of the reduction in the number of foci after ranolazine perfusion.

7 Incidence of PACs (%) Termination of PACs (%) VehicleRanolazineVehicleRanolazine Iso-induced PACs Ca 2+ -induced PACs Sossalla S, 2010 Termination of PACs (%)

8 Late I Na integral (msA/F) Baseline Peak I Na (A/F) Sinus rhythmAtrial Fibrillation Frequency (Hz) * : P<0.05 vs Vehicle * / #: P<0.05 vs Vehicle / Baseline * : P<0.05 vs SR Sossalla S, 2010

9 Effective refractory period (ms) Time (min) Right ventricle Right Atrium Vehicle Ranolazine Vehicle Ranolazine * : P<0.05 vs Baseline +57 Ranolazine 50 mg (2mL) - Intra-pericardial injection N=7 - closed-chest anesthetized pigs N=6 - closed-chest anesthetized pigs Carvas M, J Cardiovasc Pharmacol 2010

10 * : P<0.05 vs Baseline Carvas M, J Cardiovasc Pharmacol 2010 Ranolazine 50 mg (2mL) - Intra-pericardial injection Intensity (mA) Time (min) Right Atrium 5 29 Atrial Fibrillation Threshold N=6 - closed-chest anesthetized pigs Intensity (mA) Right ventricle Ventricular Fibrillation Threshold

11 ControlRano (5 M) Chronic Amio Chronic Amio & Rano ControlRano (5 M) Chronic Amio Chronic Amio & Rano ERP APD 90 * : P<0.01 vs APD 75 ERP APD 75 AtriaVentricle ERP: effective refractory period APD 75/90 : action potential duration at 75/90% of repolarizaion PRR: post-repolarization refractoriness Sicouri S, Circ Arrhythm Electrophysiol 2010

12 ControlRano (5 M) Chronic Amio Chronic Amio & Rano ControlRano (5 M) Chronic Amio Chronic Amio & Rano V max : maximum rate of rise of action potential upstroke DTE: diastolic threshold of excitation * : P<0.05 vs Control & Ranolazine * : P<0.001 vs Control; : P<0.01 vs Amiodarone & Ranolazine Right Atrial preparations Sicouri S, Circ Arrhythm Electrophysiol 2010

13 CRano (5 M) WODron & Ran Dron (10 M) CRano (5 M) Dron & Ran Dron (10 M) CRano (5 M) WODron & Ran Dron (10 M) The shortest CL with 1:1 activation (ms) ERP and APD 70 (ms) V max (% of Control) V max (% of Control at 5000 ms CL) Atria ERP APD 70 Atria Ventricle Atria Ventricle Pulmonary veins * : P<0.05 vs Control #: P<0.05 vs ERP * : P<0.05 vs Control Burashnikov A, 2010 Canine preparations

14 ACh (1 M/L) Rano (5 M/L) Dron & Ran Dron (10 M/L) Induction of persistent AF (%) Burashnikov A, 2010 N=10N=7N=6N=10 ACh (1 M/L) Rano (5 M/L) Dron & Ran Dron (10 M/L) Termination of persistent AF (%) N=10N=5N=6N=10 Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated Persistent AF in the Isolated Canine Coronary-Perfused Right Atria

15 Incidence (%) Duration (s) SotalolLidoRanoControlSotalolLidoRanoControl P<0.05 P=0.01 P<0.05 Ventricular arrhythmias VT episodes Lido: Lidocaine Rano: Ranolazine Dogs (N=20 per group) - 5 proximal LAD occlusion; 5 reperfusion Kloner RA, J Cardiovasc Pharmacol Ther 2010 First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model

16 Scirica BM, 2007 Incidence (%) Supraventricular Arrhythmias p=0.08 AFSVT>3 b>4 b>8 b Ventricular Tachycardia P<0.001 Bradycardia <45 bpm Pause >3 s P<0.001 P=0.01 Placebo N= Age: 63 years Ranolazine N= Age: 63 years Continuous ECG monitoring duration: 6.8 days

17 Incidence (%) Hours from randomization 2.3% 3.4% 3.1% 4.7% RR=0.67 p=0.008 RR=0.65 p<0.001 RR=0.63 p<0.001 Placebo – 8.3% N= Age: 63 years Ranolazine – 5.3% N= Age: 63 years P<0.001 Scirica BM, 2007 Incidence of VT >8 beats Continuous ECG monitoring duration: 6.8 days

18 Hospital admission 30 day Mortality Atrial fibrillation P=NS P=0.035 P=NS (%) Post-CABG events Ranolazine – 1000 mg bid age: 67 years; LVEF: 58%; n=182 Amiodarone – 200 mg bid age: 65 years; LVEF: 55%; n=211 Ranolazine versus Amiodarone for atrial fibrillation prophylaxis following coronary bypass surgery Murdock D et al, ACC, 60 th Annual Scientific Sessions, 2011

19 Conclusioni La ranolazina sembra caratterizzata da un importante effetto antiaritmico … … dovuto non solo allinterazione con la corrente tardiva del sodio, ma al blocco di più canali cellulari Questo meccanismo dazione rende la molecola molto vicina allamiodarone in termini di efficacia Il miocardio atriale sembrerebbe più sensibile alle azioni della ranolazina, anche se alcuni dati pre-clinici e clinici sembrano confermare lefficacia del farmaco anche nei confronti delle aritmie ventricolari Lutilizzo della ranolazina in associazione con amiodarone e dronedarone potrebbe portare ad una vera e propria sinergia clinica, permettendo la riduzione delle dosi degli anti-aritmici e diminuendo lincidenza di eventi avversi

20 Chinidina Flecainide Propafenone Classe IC Amiodarone Sotalolo Classe III Amiodarone vs. Classe I Amiodarone vs. Sotalolo NS P=0.002 P=0.02 NS P<0.001 P=0.004 P<0.001 NS OR Effetti collaterali – Abbandono dello studio entro 12 mesi Lafuente-Lafuente C, Arch Int Med P=0.005 NNH 9 17§ 27 NNH: number needed to harm §: solo eventi pro-aritmici

21 The major conclusion of this study is that the late Na current blocking drug ranolazine demonstrates efficacy against both pacing-induced re-entrant VF and spontaneous oxidative multifocal VF The suppression of multifocal VF is associated with a progressive reduction in the number of foci This finding supports the hypothesis that multifocal VF requires the constant generation of new interacting foci to maintain themselves such that when the rate of production of new foci falls below a critical level, VF terminates This is analogous to re-entrant VF, in which a critical mass is required to ensure that the rate of formation of new wavelets exceeds the rate of wavelet extinction Although H 2 O 2 is an artificial means of inducing oxidative stress, there are many known triggers … stress in the heart, such as aging, heart failure, and ischemia–reperfusion, … all conditions associated with increased risk of VF Morita N, 2011

22 The results show that permanent AF is associated with altered expression and function of Na + channels Late I Na was significantly greater as well as Nav1.1 expression Ranolazine reduced peak and late I Na in SR, but it preferentially blocked late over peak I Na in AF Ranolazine restores the physiological relationship between peak and late I Na and consequently suppresses known pro- arrhythmogenic mechanisms in vitro Ranolazine reduced Ca 2+ - and Iso-induced PACs and caused a concentration-dependent and reversible negative inotropic effect associated with an improved diastolic tension Sossalla S, 2010

23 Amiodarone action includes inhibition of a number of cardiac ionic currents (I Kr, I Ks, I Na, late I Na, I to, I Ca-L, I Ca-T, I K1, I K(ACh), I K(ATP) ) as well as - and -adrenoceptor– blocking activity Ranolazine has been shown to have a pharmacological profile similar to that of chronic amiodarone … (and) causes inhibition of I Na, I Kr, and I Ca Both agents have rapid unbinding kinetics from the Na + channel Unlike amiodarone, which is an inactivated-state blocker of cardiac Na + channels, ranolazine is an activated-state blocker The actions of amiodarone & ranolazine to produce potent block of the Na + channels in the atria are similar to that of class IC antiarrhythmic agents. However, the effects of the combination are largely restricted to the atrial myocardium The potentiation by ranolazine of the anti-AF effects amiodarone may permit the use of a lower dose of amiodarone Sicouri S, Circ Arrhythm Electrophysiol 2010


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