68 research outputs found
Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life
<p>Abstract</p> <p>Background</p> <p>The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas.</p> <p>Methods</p> <p>Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1<sup>st </sup>bolus of Gd-DTPA over the first hour, and then re-imaged with a 2<sup>nd </sup>bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.</p> <p>Results</p> <p>The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine-lysine-bradykinin and labradimil increased the blood half-life of Gd-DTPA sufficiently enough to increase significantly the tumor tissue Gd-DTPA area under the time-concentration curve.</p> <p>Conclusion</p> <p>Metabolically stable bradykinin B2 receptor agonists, methionine-lysine-bradykinin and labradimil, enhance the transvascular delivery of small chemotherapy drugs across the BBTB of malignant gliomas by increasing the blood half-life of the co-infused drug. The selectivity of the increase in drug delivery into the malignant glioma tissue, but not into normal brain tissue or skeletal muscle tissue, is due to the inherent porous nature of the BBTB of malignant glioma microvasculature.</p
The case for studying other planetary magnetospheres and atmospheres in Heliophysics
Heliophysics is the field that "studies the nature of the Sun, and how it
influences the very nature of space - and, in turn, the atmospheres of
planetary bodies and the technology that exists there." However, NASA's
Heliophysics Division tends to limit study of planetary magnetospheres and
atmospheres to only those of Earth. This leaves exploration and understanding
of space plasma physics at other worlds to the purview of the Planetary Science
and Astrophysics Divisions. This is detrimental to the study of space plasma
physics in general since, although some cross-divisional funding opportunities
do exist, vital elements of space plasma physics can be best addressed by
extending the expertise of Heliophysics scientists to other stellar and
planetary magnetospheres. However, the diverse worlds within the solar system
provide crucial environmental conditions that are not replicated at Earth but
can provide deep insight into fundamental space plasma physics processes.
Studying planetary systems with Heliophysics objectives, comprehensive
instrumentation, and new grant opportunities for analysis and modeling would
enable a novel understanding of fundamental and universal processes of space
plasma physics. As such, the Heliophysics community should be prepared to
consider, prioritize, and fund dedicated Heliophysics efforts to planetary
targets to specifically study space physics and aeronomy objectives
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