QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization.

The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.

The clinical impact of increased sensitivity PT and APTT coagulation assays.

To determine how more-sensitive prothrombin time (PT) and activated partial thromboplastin time (aPTT) reagents affected the number and distribution of abnormal test results and whether the increased sensitivity for deficiencies resulted in improved diagnosis of clinically significant coagulopathies, we retrospectively compared preoperative coagulation screening data for 140 children undergoing open heart surgery after the reagent change with a similar group of 135 before the change. The more sensitive reagents resulted in a higher rate of abnormal values, but no increase in the identification of clinically significant hemostatic abnormalities. Of 67 patients with abnormal aPTTs in the group screened with more sensitive reagents, 63 had no further workup. No patients in either group were diagnosed subsequently with a coagulopathy because of unexpected bleeding. An abnormal test result did not predict the need for perioperative blood products. We hypothesize that the high frequency of abnormal aPTTs led to physician "desensitization" about the merit of coagulation screening. Therefore, we question the usefulness of preoperative coagulation screening of the pediatric cardiac surgery patient, particularly since lasting changes in physician perception regarding the clinical significance of abnormal values may lead to missed diagnoses in other settings.

Nitric oxide-mediated heme oxidation and selective beta-globin nitrosation of hemoglobin from normal and sickle erythrocytes.

Nitric oxide (NO) has been reported to modulate the oxygen affinity of blood from sickle cell patients (SS), but not that of normal adult blood (AA), with little or no heme oxidation. However, we had found that the NO donor compounds 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO) and S-nitrosocysteine (CysNO) caused increased oxygen affinity of red cells from both AA and SS individuals and also caused significant methemoglobin (metHb) formation. Rapid kinetic experiments in which HbA(0), AA, or SS erythrocytes were mixed with CysNO or DEANO showed biphasic time courses indicative of initial heme oxidation followed by reductive heme nitrosylation, respectively. Hemolysates treated with CysNO showed by electrospray mass spectrometry a peak corresponding to a 29 mass unit increase (consistent with NO binding) of both the beta(A) and beta(S) chains but not of the alpha chains. Therapeutic use of NO in sickle cell disease may ultimately require further optimization of these competing reactions, i.e., heme reactivity (nitrosylation or oxidation) versus direct S-nitrosation of hemoglobin on the beta-globin.