Occasional reports have suggested that infants with congenital heart disease may have an increased risk of severe illness from respiratory syncytial virus (RSV) infection. We prospectively studied 699 infants hospitalized during the winters of 1976 through 1980, when RSV was prevalent in the community; 229 of these infants had proved RSV infections acquired either before admission or during hospitalization; 27 had both congenital heart disease and RSV infection, and 46 had congenital heart disease without RSV infection. Infected infants with congenital heart disease had significantly more severe illness than those without congenital heart disease, as judged by the requirement for intensive care and assisted ventilation and by the mortality rate (37 per cent vs. 1.5 per cent, P less than 0.01). The infection was acquired nosocomially by 21 per cent of infected infants; the mortality rate from nosocomial infection was also higher in infants with congenital heart disease (44 per cent vs. 5 per cent, P less than 0.01). Pulmonary hypertension was the one condition particularly associated with severe RSV illness. Eight of the 11 infants (73 per cent) with congenital heart disease and pulmonary hypertension died during their RSV illness. The courses in infants with congenital heart disease with and without RSV infection were also compared. Their ages, types of cardiac lesions, and incidence of pulmonary hypertension were similar, but the infants with RSV infection had a higher mortality rate (37 per cent vs. 6.5 per cent, P less than 0.1).
SPRYCEL (dasatinib; Bristol-Myers Squibb, Princeton, NJ) is a multiple kinase inhibitor that potently inhibits Bcr-Abl, Src family (Src, Lck, Yes, Fyn), c-Kit, EPHA2, and platelet-derived growth factor receptor  kinases (Lombardo et al., 2004;Shah et al., 2004;Das et al., 2006). It is currently approved in the United States and European Union to treat chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec, Novartis, Basel, Switzerland). Unlike imatinib mesylate, which binds to the closed confirmation of Bcr-Abl kinase, dasatinib was designed to bind to both the open and closed form of the enzyme (Shah et al., 2004;Tokarski et al., 2006). Because of this binding property and the ability to inhibit multiple kinases, including Src, dasatinib is effective in tumors that are resistant to imatinib mesylate (O'Hare et al., 2005;Schittenhelm et al., 2006). Clinical studies have shown that dasatinib shows clinical response in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate treatment Hochhaus et al., 2006;Talpaz et al., 2006;Quintas-Cardama et al., 2007).Numerous in vitro and in vivo studies have been conducted with dasatinib in nonclinical species to understand its absorption, distribution, metabolism, and excretion (ADME) properties and gauge the suitability of these species as toxicological models Kamath et al., 2008). The metabolic profiles from in vitro studies in liver microsomes, and hepatocytes showed good correlation with the in vivo profiles generated after a single p.o. dose of [14 C]dasatinib to rats and monkeys. The primary metabolites of dasatinib Article, publication date, and citation information can be found at
NEDD4-2 (also known as NEDD4L, neural precursor cell expressed developmentally down-regulated 4-like) is a ubiquitin protein ligase of the Nedd4 family which is known to bind and regulate a number of membrane proteins to aid in their internalization and turnover. Several of the NEDD4-2 substrates include ion channels, such as the epithelial and voltage-gated sodium channels. Given the critical function of NEDD4-2 in regulating membrane proteins, this ligase is essential for the maintenance of cellular homeostasis. In this article we review the biology and function of this important ubiquitin-protein ligase and discuss its pathophysiological significance.
Dasatinib is a tyrosine kinase inhibitor (including BCR-ABL and the SRC family) that is effective in patients with chronic myeloid leukemia. Dasatinib has pH-dependent solubility and is bioavailable as an oral formulation. The effect of gastric pH modifiers on dasatinib pharmacokinetics is evaluated in an open-label, randomized, 3-period, 3-treatment crossover study. Twenty-four healthy subjects receive treatment A (2 doses of dasatinib 50 mg separated by 12 hours), treatment B (famotidine 40 mg given 2 hours after dasatinib 50 mg and 10 hours before another dose of dasatinib 50 mg), and treatment C (30 mL of an antacid containing aluminum/magnesium hydroxides given 2 hours before dasatinib 50 mg and concomitantly with dasatinib 50 mg 12 hours after the previous dasatinib dose); a 7-day washout separates each treatment period. When famotidine is administered 2 hours after dasatinib, dasatinib exposure is similar to dasatinib administered alone. However, dasatinib exposure is reduced by approximately 60% when famotidine is administered 10 hours before dasatinib dosing. In contrast, dasatinib exposure is unchanged when antacid (Maalox) is administered 2 hours before dasatinib; but when the antacid is coadministered with dasatinib, dasatinib exposure is reduced by approximately 55% to 58%. This indicates that H(2)-receptor antagonists should not be coadministered with dasatinib. Dasatinib may be administered with acid-neutralizing antacids if the doses are temporally separated by at least 2 hours.
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