BG9719 (CVT-124), an A ₁ Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy

Abstract

Background-Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown. Methods and Results-This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (PϽ0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-g/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses. Conclusions-In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A 1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.

Adenosine receptors as therapeutic targets

“…An A 1 AR antagonist, BG9719 (CVT-124), was in Phase II clinical trials (now discontinued) for the treatment of acute renal disorders in patients with congestive heart failure 159,160 . However, BG9719 contains an epoxide group, which is potentially chemically reactive.…”

Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology

“…Adenosine A1 receptor antagonists may increase diuresis and improve renal function in patients with ACHF [70].…”

Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure – Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers –

“…6 Several studies, which were mainly designed for HFrEF patients, reported that loop diuretic use was associated with increased morbidity and mortality. [7][8][9][10][11] It is also true, however, that there is no alternative medication to loop diuretics to effectively relieve congestive symptoms and that it is difficult to perform a randomized clinical trial from an ethical point of view.…”