Tecadenoson (CVT-510)

Termination of paroxysmal supraventricular tachycardia by tecadenoson (CVT-510), a novel A1-adenosine receptor agonist

Objectives: The aim of this study was to evaluate tecadenoson safety and efficacy during conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. Background: Tecadenoson (CVT-510), a novel adenosine receptor (Ado R) agonist, selectively activates the A1 Ado R and prolongs atrioventricular (AV) nodal conduction at doses lower than those required to cause A2 Ado R-mediated coronary and peripheral vasodilation. Unlike adenosine, which non-selectively activates all four Ado R subtypes and produces unwanted effects, tecadenoson appears to terminate AV node-dependent supraventricular tachycardias without hypotension and bronchoconstriction. Methods: In this open-label, multicenter, dose escalation study, tecadenoson was administered to 37 patients (AV node re-entrant tachycardia, n = 29; AV re-entrant tachycardia, n = 8) with inducible PSVT sustained for > or =1 min during an electrophysiology study. Seven regimens (0.3 to 15 microg/kg) of up to two identical tecadenoson intravenous bolus doses were administered. Results: After the first or second bolus, PSVT converted to sustained sinus rhythm for > or =5 min in 86.5% (32/37) of the patients, with 91% (29/32) of the conversions occurring after the first bolus (most within 30 s), coincident with anterograde conduction block in the AV node. No effects on sinus cycle length (SCL) or systolic blood pressure were observed. The atrial-His (AH), but not the His-ventricular (HV) interval was prolonged up to 5 min after the final tecadenoson bolus, returning to baseline by 10 min. Tecadenoson was generally well tolerated. Conclusions: In this study, tecadenoson rapidly terminated sustained PSVT by depressing AV nodal conduction without causing hypotension. After sinus rhythm restoration, there was minimal AH interval prolongation without HV interval or SCL prolongation.

CVT-510: a selective A1 adenosine receptor agonist

Adenosine is an endogenous nucleoside that has potent antiarrhythmic effects on paroxysmal supraventricular tachycardia (PSVT) due to its negative dromotropic effects on the atrioventricular node. In addition to its electrophysiologic effects, adenosine has important effects on vascular smooth muscle cells, inflammatory cells, the central nervous system, and the kidney. Four known adenosine receptor subtypes (A1, A2A, A2B, and A3) mediate the pleiotropic effects of adenosine in humans. These receptors are coupled to a wide range of second messenger cascades. Activation of the A1 adenosine receptor accounts for the negative chronotropic and dromotropic effects of adenosine, whereas A2A, A2B and A3 adenosine receptor activation are responsible for such effects as coronary vasodilation, bronchospasm, inhibition of platelet aggregation, and neuronal stimulation. Elucidation of the specific properties of each of the adenosine receptor subtypes has led to the development of selective ligands as potential therapeutic agents. CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, was developed as a selective A1 adenosine receptor agonist that specifically targets the atrioventricular node for termination of PSVT. Preliminary clinical trials have shown that CVT-510 is effective in terminating PSVT and eliminating many of the undesirable adverse effects of adenosine. CVT-510 is also being explored as a potential agent for controlling the ventricular rate of atrial fibrillation and flutter.

CVT-510 (CV Therapeutics)

CVT-510, the lead compound from a series of selective adenosine A1 receptor agonists, is being developed by CV Therapeutics for the potential treatment of supraventricular tachycardias and atrial arrhythmias [224364], [299365]. Phase II trialsfor atrial fibrillation commenced in December 1999 [349469], while a phase III trial for paroxysmal supraventricular tachycardia (PSVT) began in June 2001; this multicenter, randomized, double-blind, placebo-controlled trial, was to determine the safety and efficacy of CVT-510 in the conversion of PS VT to normal sinus rhythm [414190]. Analysts at Morgan Stanley predicted in December 2001, that the product would befiled with the FDA in 2004 and be launched onto the US market in 2005, with revenues of US $25 million, rising to US $83 million in 2006 [435233].

Noninvasive Assessment of Atrioventricular Nodal Function: Effect of Rate-Control Drugs during Atrial Fibrillation

Background: During atrial fibrillation (AF), conventional electrophysiological techniques for assessment of refractory period or conduction velocity of the atrioventricular (AV) node cannot be used. We aimed at evaluating changes in AV nodal properties during administration of tecadenoson and esmolol using a novel ECG-based method.
Methods: Fourteen patients (age 58 ± 8 years, 10 men) with AF were randomly assigned to either 75 or 300 μg intravenous tecadenoson. After tecadenoson wash-out, patients received esmolol continuously (100 μg/kg per min for 10 mins, then 50 μg/kg per min for 50 mins). Atrial fibrillatory rate (AFR) and heart rate (HR) were assessed in 15-min segments. Using the novel method, we assessed the absolute refractory periods of the slow and fast pathways (aRPs and aRPf) of the AV node to produce an estimate of the functional refractory period.
Results: During esmolol infusion, AFR and HR were significantly decreased and the absolute refractory period was significantly prolonged in both pathways (aRPs: 387 ± 73 vs 409 ± 62 ms, P < 0.05; aRPf: 490 ± 80 vs 529 ± 58 ms, P < 0.05). During both tecadenoson doses, HR decreased significantly and AFR was unchanged. Both aRPs and aRPf were prolonged for a 75 μg dose (aRPs: 322 ± 97 vs 476 ± 75 ms, P < 0.05; aRPf: 456 ± 102 vs 512 ± 55 ms, P < 0.05) whereas a trend toward prolongation was observed for a 300 μg dose.
Conclusions: The estimated parameters reflect expected changes in AV nodal properties, i.e., slower conduction through the AV node for tecadenoson and prolongation of the AV node refractory period for esmolol. Thus, the proposed approach may be used to assess drug effects on the AV node in AF patients.

Beta-blockade and A1-adenosine receptor agonist effects on atrial fibrillatory rate and atrioventricular conduction in patients with atrial fibrillation

Aims: Reduced irregularity of RR intervals in permanent atrial fibrillation (AF) has been associated with poor outcome. It is not fully understood, however, whether modification of atrioventricular (AV) conduction using rate-control drugs affects RR variability and irregularity measures. We aimed at assessing whether atrial fibrillatory rate (AFR) and variability and irregularity of the ventricular rate are modified by a selective A1-adenosine receptor agonist tecadenoson, beta-blocker esmolol, and their combination.
Methods and results: Twenty-one patients (age 58 ± 7 years, 13 men) with AF were randomly assigned to either 75, 150, or 300 μg intravenous tecadenoson. Tecadenoson was administered alone (Dose Period 1) and in combination (Dose Period 2) with esmolol (100 μg/kg/min for 10 min then 50 μg/kg/min for 50 min). Heart rate (HR) and AFR were estimated for every 10 min long recording segment. Similarly, for every 10 min segment, the variability of RR intervals was assessed, as standard deviation, pNN20, pNN50, pNN80, and the root of the mean squared differences of successive RR intervals, and irregularity was assessed by non-linear measures such as regularity index (R) and approximate entropy. A marked decrease in HR was observed after both tecadenoson injections, whereas almost no changes could be seen in the AFR. The variability parameters were increased after the first tecadenoson bolus injection. In contrast, the irregularity parameters did not change after tecadenoson. When esmolol was infused, all the variability parameters further increased.
Conclusion: Modification of AV node conduction can increase RR variability but does not affect regularity of RR intervals or AFR.