Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

PURPOSE: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders. METHODS: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders. RESULTS: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. CONCLUSION: Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.

The RegEx trial: a randomized, double-blind, placebo- and active-controlled pilot study combining regadenoson, a selective A(2A) adenosine agonist, with low-level exercise, in patients undergoing myocardial perfusion imaging.

BACKGROUND: Although vasodilator stress myocardial perfusion imaging (MPI) is increasingly performed with exercise, adenosine A(2A) receptor agonists have not been studied with exercise. OBJECTIVES: To determine the safety of administering regadenoson during exercise and, secondarily, to evaluate image quality, patient acceptance, and detection of perfusion defects. METHODS: Patients requiring pharmacologic MPI received a standard adenosine-supine protocol (AdenoSup, n = 60) and were then randomized (2:1) in a double-blind manner to low-level exercise with bolus intravenous injection of regadenoson (RegEx, n = 39) or placebo (PlcEx, n = 21). RESULTS: Adverse events occurred in 95%, 77%, and 33% of patients receiving AdenoSup, RegEx, and PlcEx, respectively. Peak heart rate was 13 beats per minute (bpm) and 21 bpm greater following RegEx compared to that following PlcEx and AdenoSup, respectively (P = .006 and <.001). Change from baseline in mean systolic blood pressure (SBP), change from baseline to nadir SBP, and percentage of patients with a decline in SBP by > or = 20 mm Hg showed no important differences between RegEx and PlcEx. No occurrences of 2nd degree or higher AV block were observed following RegEx or PlcEx; one patient developed 2nd degree AV block following AdenoSup. The mean heart-to-liver and heart-to-gut ratios were improved on RegEx vs AdenoSup: 0.85 (0.34) vs 0.65 (0.26), P < .001 and 1.1 (0.36) vs 0.97 (0.34), P < .001, respectively. Compared to AdenoSup, 70% of patients felt RegEx was much or somewhat better. CONCLUSIONS: Combining regadenoson with low-level exercise is feasible, well tolerated, and associated with fewer side effects compared to AdenoSup.

Safety of regadenoson, a selective adenosine A2A agonist, in patients with chronic obstructive pulmonary disease: A randomized, double-blind, placebo-controlled trial (RegCOPD trial).

BACKGROUND: Patients with reactive airways are at risk for adenosine-induced bronchoconstriction, mediated via A(2B) and/or A(3) adenosine receptors. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled crossover trial, we examined the safety of regadenoson, a selective adenosine A(2A) receptor agonist, in patients with moderate chronic obstructive pulmonary disease (COPD) (n = 38) and patients with severe COPD (n = 11) with a baseline mean forced expiratory volume in 1 second (FEV(1)) of 1.74 +/- 0.50 L and 1.0 +/- 0.35 L, respectively, 37% of whom had dyspnea during activities of daily living. Patients receiving glucocorticoids or oxygen and those with pretreatment wheezing were included. Short-acting bronchodilators were withheld for at least 8 hours before treatment. No differences emerged between regadenoson and placebo on multiple lung function parameters, including repeated FEV(1) and forced vital capacity, respiratory rate, pulmonary examinations, and oxygen saturation. The mean maximum decline in FEV(1) was 0.11 +/- 0.02 L and 0.12 +/- 0.02 L (P = .55) in patients after regadenoson and placebo, respectively, and new-onset wheezing was observed in 6% and 12%, respectively (P = .33). No patient required acute treatment with bronchodilators or oxygen. CONCLUSIONS: This pilot study showed the overall safety of regadenoson in 49 compromised outpatients with clinically stable moderate and severe chronic obstructive pulmonary disease.