Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes.

BACKGROUND: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine. METHODS: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy. RESULTS: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%). CONCLUSIONS: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society.

Importance of Both Early Reperfusion and Therapeutic Hypothermia in Limiting Myocardial Infarct Size Post-Cardiac Arrest in a Porcine Model.

OBJECTIVES: The aim of this study was to test the hypothesis that hypothermia and early reperfusion are synergistic for limiting infarct size when an acutely occluded coronary is associated with cardiac arrest. BACKGROUND: Cohort studies have shown that 1 in 4 post-cardiac arrest patients without ST-segment elevation has an acutely occluded coronary artery. However, many interventional cardiologists remain unconvinced that immediate coronary angiography is needed in these patients. METHODS: Thirty-two swine (mean weight 35 ± 5 kg) were randomly assigned to 1 of the following 4 treatment groups: group A, hypothermia and reperfusion; group B, hypothermia and no reperfusion; group C, no hypothermia and reperfusion; and group D, no hypothermia and no reperfusion. The left anterior descending coronary artery was occluded with an intracoronary balloon, and ventricular fibrillation was electrically induced. Cardiopulmonary resuscitation was begun after 4 min of cardiac arrest. Defibrillation was attempted after 2 min of cardiopulmonary resuscitation. Resuscitated animals randomized to hypothermia were rapidly cooled to 34°C, whereas those randomized to reperfusion had such after 45 min of left anterior descending coronary artery occlusion. RESULTS: At 4 h, myocardial infarct size was calculated. Group A had the smallest infarct size at 16.1 ± 19.6% (p < 0.05). Group C had an intermediate infarct size at 29.5 ± 20.2%, whereas groups B and D had the largest infarct sizes at 41.5 ± 15.5% and 41.1 ± 15.0%, respectively. CONCLUSIONS: Acute coronary occlusion is often associated with cardiac arrest, so treatment of resuscitated patients should include early coronary angiography for potential emergent reperfusion, while providing hypothermia for both brain and myocardial protection. Providing only early hypothermia, while delaying coronary angiography, is not optimal.

Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects.

Glucagon-like peptide-1 (GLP-1) has protective effects in the heart. We hypothesized that GLP-1 would mitigate coronary microvascular and left ventricular (LV) dysfunction if administered after cardiac arrest and resuscitation (CAR). Eighteen swine were subjected to ventricular fibrillation followed by resuscitation. Swine surviving to return of spontaneous circulation (ROSC) were randomized to receive an intravenous infusion of either human rGLP-1 (10 pmol·kg(-1)·min(-1); n = 8) or 0.9% saline (n = 8) for 4 h, beginning 1 min after ROSC. CAR caused a decline in coronary flow reserve (CFR) in control animals (pre-arrest, 1.86 ± 0.20; 1 h post-ROSC, 1.3 ± 0.05; 4 h post-ROSC, 1.25 ± 0.06; P < 0.05). GLP-1 preserved CFR for up to 4 h after ROSC (pre-arrest, 1.31 ± 0.17; 1 h post-ROSC, 1.5 ± 0.01; 4 h post-ROSC, 1.55 ± 0.22). Although there was a trend toward improvement in LV relaxation in the GLP-1-treated animals, overall LV function was not consistently different between groups. 8-iso-PGF(2α), a measure of reactive oxygen species load, was decreased in post-ROSC GLP-1-treated animals [placebo, control (NS): 38.1 ± 1.54 pg/ml; GLP-1: 26.59 ± 1.56 pg/ml; P < 0.05]. Infusion of GLP-1 after CAR preserved coronary microvascular and LV diastolic function. These effects may be mediated through a reduction in oxidative stress.