Publications

BACKGROUND

Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.

OBJECTIVE

The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.

METHODS

The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.

RESULTS

Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.

CONCLUSIONS

Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

Atrophy of the rotator cuff muscles is a factor that complicates the treatment of a massive rotator cuff tear (RCT). However, the molecular mechanisms that govern the development of muscle atrophy after RCTs have not been well defined. The Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in maintaining muscle mass in response to mechanical loading. The role of this pathway in the development of muscle atrophy after a massive RCT remains unknown. The purpose of this study was to investigate the regulation of the Akt/mTOR pathway in the development of muscle atrophy after a RCT and suprascapular nerve (SSN) injury. We evaluated the activity of the Akt/mTOR signaling pathway and how this pathway interacts with two atrophy-related genes, MuRF-1 and MAFbx, in supraspinatus muscles of rats that underwent unilateral complete rotator cuff tendon transection or SSN transection. Akt/mTOR activity was significantly reduced after tendon rupture, but increased after nerve injury. MuRF-1 and MAFbx were only up-regulated following denervation. These results suggest that tendon transection leads to a decrease in protein synthesis with down-regulation of the Akt/mTOR signaling pathway, whereas denervation leads to an increase in protein degradation via up-regulation of expression of MuRF-1 and MAFbx.