High-dose dipyridamole is safe and easily reversed with intravenous aminophylline. The sensitivity and specificity of dipyridamole and dobutamine stress testing were statistically more accurate than results obtained with treadmill protocols when SPECT is used to image the heart. High-dose dipyridamole resulted in greater changes in heart rate and blood pressure response than seen with standard-dose dipyridamole. Associated side effects can be easily reversed with the administration of intravenous aminophylline without significant complications. The sensitivity, specificity, and accuracy of single photon emission computed tomography using high-dose dipyridamole are 100%, 88.9%, and 97.9%, respectively, for the overall presence or absence of disease when compared with coronary arteriography. This is significantly (P < 0.005) greater than that obtained by treadmill nuclear imaging protocols, independent imaging agent.
Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK may modulate ABCG2-mediated resistance to clofarabine by regulating the formation of clofarabine monophosphate. We demonstrate that ABCG2 influence on clofarabine cytotoxicity was markedly influenced by dCK activity. When dCK expression was reduced by siRNA, clofarabine cytotoxicity was strongly reduced by enhanced ABCG2-mediated efflux. Conversely, dCK overexpression blunted ABCG2-mediated efflux of clofarabine by increasing the formation of clofarabine nucleotides. The use of an ABCG2 inhibitor confirmed that ABCG2 export of clofarabine is maximal when dCK levels are minimal. Analysis of intracellular clofarabine metabolites suggested that ABCG2 exported clofarabine more readily than clofarabine monophosphate. That ABCG2 primarily effluxes clofarabine, but not chlorfarabine-monophosphate was confirmed by HPLC analysis of drug exported from ABCG2 over expressing cells. Because the level and function of dCK and ABCG2 vary substantially among other types of cancer, these findings have important implications not only for clofarabine therapy but for purine nucleoside therapy in general. Therefore we propose that addition of ABCG2 inhibitors would effectively increase the anti-tumor efficacy of purine nucleosides by blocking drug efflux which may be a significant mode of resistance when dCK levels are low.
Objectives Abacavir (ABC) oral clearance, adjusted for body size, is approximately 2 times higher for children than adults with a corresponding difference in dose regimens. However, there are limited data available in the adolescent population. The pharmacokinetics (PKs) of ABC and primary metabolites were determined in HIV-1–infected children and adolescents to evaluate age and patient characteristics as a basis for adjusting ABC dose regimens and to assess the influence of metabolite formation on PK parameters. Methods Pediatric subjects 9–18 years of age receiving antiretroviral therapy for HIV-1 infection were stratified by Tanner stage and given a single 8 mg/kg dose of ABC oral solution. Blood samples (n = 10) were obtained over 8 hours and measured for ABC, glucuronide, and carboxylate metabolites using high-performance liquid chromatography. PK parameters for children (Tanner stages 1–2; TS1) and adolescents (Tanner stages 3–5; TS2) were compared. Results Twenty-five subjects were enrolled. ABC mean (range) maximum concentration (Cmax; μg/mL), area under the curve (μg·hr/mL), half-life (hours), and apparent clearance (CL/F; mL/min per kg) for TS1 and TS2 were 3.5 (1.2–5.6) vs 3.4 (1.8–5.9), 8.0 (2.1– 18.6) vs 8.9 (3.1–17.2), 1.3 (0.7–2.5) vs 1.4 (0.9–1.9), and 22.1 (7.0– 59.2) vs 18.4 (7.7–42.9) and not significantly different. Age, Tanner stage, and sex were not correlated with ABC clearance by univariate analysis. The ratios of metabolites to ABC area under the curve were correlated with ABC clearance as were the ratios of metabolites to ABC concentrations at the 6-hour time point. Conclusions ABC oral clearance in HIV-1-infected pediatric patients does not change during puberty, is similar to younger children, and is higher than previously published in adults. Therefore, dosing adolescents as adults should be reexamined. Intersubject PK variability is substantial and is not correlated with body size or age but more likely due to differences in metabolite formation that may be genetic in origin.
Voriconazole and posaconazole are triazole antifungal compounds used in the treatment of fungal infections. Therapeutic drug monitoring of both compounds is recommended in order to guide drug dosing to achieve optimal blood concentrations. In this chapter we describe an HPLC-ESI-MS/MS method for the quantification of both compounds in human plasma or serum following a simple specimen preparation procedure. Specimen preparation consists of protein precipitation using methanol and acetonitrile followed by a cleanup step that involves filtration through a cellulose acetate membrane. The specimen is then injected into an HPLC-ESI-MS/MS equipped with a C18 column and separated over an acetonitrile gradient. Quantification of the drugs in the specimen is achieved by comparing the response of the unknown specimen to that of the calibrators in the standard curve using multiple reaction monitoring.
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