Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.

Purpose: Lifirafenib is an investigational, reversible inhibitor of B-RAF, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with - or -mutated solid tumors.

Methods: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib.

The Selective Late Sodium Current Inhibitor Eleclazine, Unlike Amiodarone, Does Not Alter Defibrillation Threshold or Dominant Frequency of Ventricular Fibrillation.

Introduction: We examined the effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter defibrillators (ICDs).

Methods And Results: In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex through jugular vein. ICDs were implanted subcutaneously.

The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism.

Background: Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs.

Combined actions of ivabradine and ranolazine reduce ventricular rate during atrial fibrillation.

Introduction: Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF.

Methods And Results: Ivabradine (maximum clinical dose, 0.

If inhibition in the atrioventricular node by ivabradine causes rate-dependent slowing of conduction and reduces ventricular rate during atrial fibrillation.

Background: If channels are functionally expressed in atrioventricular (AV) nodal tissue.

Objective: The purpose of this study was to address whether the prototypical If inhibitor, ivabradine, at clinically safe concentrations can slow AV node conduction to reduce ventricular rate (VR) during atrial fibrillation (AF).

Methods: Effects of ivabradine (0.

Ranolazine terminates atrial flutter and fibrillation in a canine model.

Background: Ranolazine has been shown to have antiarrhythmic properties.

Objective: We tested the hypothesis that intravenous ranolazine would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model.

Methods: In 6 dogs with sterile pericarditis, we performed electrophysiological measurements of the atrial effective refractory period (AERP) and conduction time (CT) while pacing from the right atrial appendage, Bachmann bundle, and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms before and after the administration of ranolazine.

Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model.

Background: Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis.

Objective: To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI.

Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation.

Background: In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node.

Objective: The purpose of this study was to examine whether dronedarone inhibits If at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node.

Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown.

Dronedarone's inhibition of If current is the primary mechanism responsible for its bradycardic effect.

Introduction: The mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of If are plausible.

Methods And Results: In anesthetized pigs, we compared the effects of dronedarone to the prototypical If inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated.

The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: effect of ranolazine.

Aims: Clinical utility of QTc prolongation as a predictor for sudden cardiac death (SCD) has not been definitely established. Ranolazine causes modest QTc prolongation, yet it shows antiarrhythmic properties. We aimed to determine the association between prolonged QTc and risk of SCD, and the effect of ranolazine on this relationship.

Low doses of ranolazine and dronedarone in combination exert potent protection against atrial fibrillation and vulnerability to ventricular arrhythmias during acute myocardial ischemia.

Background: Coronary artery disease carries dual risk for atrial tachyarrhythmias and sudden cardiac death.

Objective: To examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias.

Methods: In chloralose-anesthetized, open-chest Yorkshire pigs (n = 15), the proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%.

GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse.

Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A(2B) Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A(2B) AdoR with 3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling.

The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.

Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis.

Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.

Rationale: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux.

Objective: Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine.

Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs.

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.

Effect of body mass index on the efficacy, side effect profile, and plasma concentration of fixed-dose regadenoson for myocardial perfusion imaging.

Background: There are limited data on the effect of body mass index (BMI) on the actions of fixed-dose regadenoson. The purpose of this study was to determine the effect of BMI on the efficacy, side effects, and plasma concentration of regadenoson for Myocardial Perfusion Imaging (MPI).

Methods And Results: The study included 2,015 subjects from the ADVANCE MPI trials.

Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Background: Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered.

Discovery of a novel A2B adenosine receptor antagonist as a clinical candidate for chronic inflammatory airway diseases.

Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability.

Selective, high affinity A(2B) adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines.

A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A(2B) AdoR (K(i)=6 nM and 7 nM, respectively) and greater selectivity for the human A(1), A(2A), and A(3) AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A(2B) AdoR.

Effect of a specific and selective A(2B) adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma.

It has been previously proposed that adenosine plays an important role in the pathogenesis of asthma. The proposed mechanism of action for nucleoside adenosine is to activate A(2B) adenosine receptors (AR) and to indirectly modulate levels of mediators in the lung. In vivo data supporting the role of A(2B) AR in airway reactivity and inflammation in allergic animal models are lacking.

N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists.

A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K(iL) value of 1 nM for the A(1)-AdoR and >5000-fold selectivity over the A(3) and A(2A)-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring displayed subnanomolar affinity for the A(1)-AdoR (K(iL)=0.

Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury.

Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels.

A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase.

Adenosine is a signaling nucleoside that has been proposed to contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. Previous studies suggest that adenosine might play an important role in modulating levels of inflammatory mediators in the lung. Because airway epithelium is an important cellular source of inflammatory mediators, the objective of the present study was to determine whether adenosine affects the expression and release of inflammatory cytokines from human bronchial epithelial cells (HBECs).

Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: high affinity and selective A2B adenosine receptor antagonists.

Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines.