Preference for a Novel Oral Alternative to Parenterally Administered Medications.

Background: Rani Therapeutics is developing a robotic pill (RP), an oral drug delivery platform called RaniPill that can deliver a number of biotherapeutics with high bioavailability; eliminating the need for injections. While patients in general prefer oral to injectable therapies, preference for a more frequent oral regimen compared to a less frequent injectable regimen is unknown. Two marketing surveys were conducted to gather data on preference for oral versus injectable therapies.

A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects.

Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli.

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation.

Background: There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity.

Objective: The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats.

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine-A pharmacokinetic and pharmacodynamic study.

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof-of-concept study was performed in 17 anesthetized, laparotomized swine.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late Ii), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

Late sodium current (late I) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF).

Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog).

Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine.

Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333nM) that has a good separation of late versus peak Nav1.5 current, but did not have a favorable CNS safety window due to high brain penetration (3-fold higher partitioning into brain vs plasma) coupled with potent inhibition of brain sodium channel isoforms (Nav1.1, 1.

Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats.

Late Na(+) current (INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs.

Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes.

Objective: Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone.

Ranolazine reduces remodeling of the right ventricle and provoked arrhythmias in rats with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that often results in right ventricular (RV) failure and death. During disease progression, structural and electrical remodeling of the right ventricle impairs pump function, creates proarrhythmic substrates, and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in patients with PAH that are not directly addressed by currently available therapies.

Blockade of Na+ channels in pancreatic α-cells has antidiabetic effects.

Pancreatic α-cells express voltage-gated Na(+) channels (NaChs), which support the generation of electrical activity leading to an increase in intracellular calcium, and cause exocytosis of glucagon. Ranolazine, a NaCh blocker, is approved for treatment of angina. In addition to its antianginal effects, ranolazine has been shown to reduce HbA1c levels in patients with type 2 diabetes mellitus and coronary artery disease; however, the mechanism behind its antidiabetic effect has been unclear.

The beneficial effects of ranolazine on cardiac function after myocardial infarction are greater in diabetic than in nondiabetic rats.

Ranolazine (RAN) is known to exert both anti-ischemic and antidiabetic actions. Thus, this study has explored the hypothesis that RAN would have greater effect on the recovery of cardiac function in diabetic mellitus (DM) rat hearts following myocardial infarction (MI). Myocardial infarction was induced in nondiabetic (MI, n = 14) and diabetic (streptozotocin induced; DM-MI, n = 13) Wistar rats by permanent ligation of the left coronary artery.

Selective inhibition of the late sodium current has no adverse effect on electrophysiological or contractile function of the normal heart.

Inhibition of cardiac late Na(+) current (I(Na,L)) decreases sodium-dependent calcium overload in diseased hearts. Because INa,L is small in the absence of disease, its inhibition is not expected to significantly alter function of the normal heart. To test this hypothesis, we determined the effects of GS-458967 (GS967), a novel selective inhibitor of I(Na,L) (IC(50) = 0.

Reduction of free fatty acids, safety, and pharmacokinetics of oral GS-9667, an A(1) adenosine receptor partial agonist.

GS-9667, a new selective, partial agonist of the A(1) adenosine receptor (AR), may represent an effective therapy for Type 2 diabetes (T2DM) and dyslipidemia via lowering of free fatty acids (FFA). The objectives of the studies were to evaluate the effects of single and multiple doses of GS-9667 on plasma FFA concentrations, its pharmacokinetics (PK) and safety/tolerability. Two studies were conducted.

A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias.

Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias.

Adenosine A₁ receptors do not play a major role in the regulation of lipogenic gene expression in hepatocytes.

Activation of adenosine A₁ receptors was reported to promote fatty acid synthesis in AML-12 cells, by increasing the expression of SREBP-(1c) (sterol regulatory binding protein 1c) and FAS (fatty acid synthase). Since these findings have important therapeutic implications for the discovery of adenosine A₁ receptor agonists, further studies were undertaken to determine the expression and functional relevance of adenosine A₁ receptor in the liver. To that end, we used two classes of distinct adenosine A₁ receptor agonists: CPA (N⁶-cyclopentyl-adenosine), a full agonist and GS-9667 (2-{6-[((1R,2R)-2-hydroxycyclopentyl)-amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol), a partial agonist.

Ranolazine increases β-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice.

In addition to its anti-ischemic and antianginal effects, ranolazine has been shown to lower hemoglobin A(1c) (HbA(1c)) in patients with coronary artery disease and diabetes. The present study was undertaken to test the hypothesis that ranolazine lowers HbA(1c) because of improved glucose homeostasis in an animal model. Diabetes in mice was induced by giving multiple low doses of streptozotocin.

Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome.

Objective: We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris.

Research Design And Methods: Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.

Ranolazine as a cardioplegia additive improves recovery of diastolic function in isolated rat hearts.

Background: Ranolazine (Ran), an antianginal agent, inhibits late Na(+) current. The purpose of this study was to determine whether there was an added benefit of adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion.

Methods And Results: Isolated rat hearts were Langendorff-perfused and exposed to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of reperfusion.

Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion.

We tested the effect of the antianginal agent ranolazine on ventricular arrhythmias in an ischemic model using two protocols. In protocol 1, anesthetized rats received either vehicle or ranolazine (10 mg/kg, iv bolus) and were subjected to 5 min of left coronary artery (LCA) occlusion and 5 min of reperfusion with electrocardiogram and blood pressure monitoring. In protocol 2, rats received either vehicle or three doses of ranolazine (iv bolus followed by infusion) and 20 min of LCA occlusion.

A1 adenosine receptor: role in diabetes and obesity.

Adenosine mediates its diverse effects via four subtypes (A(1), A(2A), A(2B) and A(3)) of G-protein-coupled receptors. The A(1) adenosine receptor (A(1)AR) subtype is the most extensively studied and is well characterized in various organ systems. The A(1)ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A(1)ARs.

Ranolazine as an adjunct to cardioplegia: a potential new therapeutic application.

The purpose of this study was to examine the therapeutic potential of ranolazine, a novel antianginal drug, as an adjunctive therapy to hyperkalemic cardioplegia. Rat hearts were Langendorff-perfused and exposed to 40 minutes of ischemia and 30 minutes of reperfusion without (control) or with cardioplegia or cardioplegia with 50 micromol/L ranolazine. During ischemia, cardioplegia prolonged time to contracture, defined as the time to reach an intraventricular pressure of 20 mm Hg, from 12 +/- 1 minute (control) to 25 +/- 2 minutes (P < .

Partial A1 adenosine receptor agonist regulates cardiac substrate utilization in insulin-resistant rats in vivo.

Reducing the availability and uptake of fatty acids is a plausible pharmaceutical target to ameliorate glucose intolerance and insulin resistance. CVT-3619 [2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino]purin-9-yl(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol] is a partial A(1) adenosine receptor agonist with antilipolytic properties. Aims of the present study were to examine the acute effects of CVT-3619 on whole-body and cardiac glucose and fatty acid kinetics in vivo in normal and diet-induced insulin-resistant rats.

Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits.

Ranolazine [Ranexa; (+/-)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] is novel anti-ischemic agent that has been shown to inhibit late I(Na) and I(Kr) and to have antiarrhythmic effects in various preclinical in vitro models. This study was undertaken to investigate the effects of ranolazine on drug-induced Torsade de Pointes (TdP) in vivo. TdP was induced by an I(Kr) blocker, clofilium, in anesthetized, alpha(1)-agonist-sensitized rabbits.