Publications by authors named "Michael D Naimark"

4 Publications

  • Page 1 of 1

Effect of radiation on the penetration of irinotecan in rat cerebrospinal fluid.

Cancer Chemother Pharmacol 2011 Sep 16;68(3):721-31. Epub 2010 Dec 16.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Purpose: Anticancer agents are useful for treating brain tumors, but sub therapeutic concentrations due to decreased blood-brain barrier (BBB) penetration limit their effectiveness. This study evaluated the effect of cranial radiation on the pharmacokinetics of irinotecan in plasma and cerebrospinal fluid (CSF).

Methods: Rats (n = 48) were treated with irinotecan (10 mg/kg), and then administered 10 or 20 Gy or sham irradiation as control after drug. The pharmacokinetics for irinotecan, SN-38, and APC were measured in plasma and CSF over 6 h. Up to 7 plasma samples per animal were collected, and one CSF sample was collected per animal (serial sacrifice design). Population pharmacokinetic analysis was performed with NONMEM, and radiation tested as a covariate for the fraction of irinotecan (f(CSF)) entering the CSF.

Results: The estimate of f(CSF) (% and RSE) was 0.165 (73.5) for the control group and 0.265 (66.5) for radiation-treated groups, respectively (P < 0.05). Predictive check plots showed that the model adequately described the overall trend and variability in the observed data. The median values of bootstrap parameters were similar to the NONMEM estimates based on the original data set.

Conclusions: These results indicate that cranially administered radiation can increase the penetration of anticancer agents such as irinotecan into the CSF. Studies that evaluate radiation-fractionation, radiation-time course effect relationships, blood-brain barrier and blood-tumor barrier effects for irinotecan and other anticancer agents are warranted.
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http://dx.doi.org/10.1007/s00280-010-1542-3DOI Listing
September 2011

An intravital microscopy study of radiation-induced changes in permeability and leukocyte-endothelial cell interactions in the microvessels of the rat pia mater and cremaster muscle.

Brain Res Brain Res Protoc 2004 Apr;13(1):1-10

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Using intravital microscopy and a closed window method, we measured irradiation-induced changes in the vascular permeability and cell interactions in microcirculation networks of the rat pia mater; the same effects were monitored in the cremaster muscle as a control. The closed cranial window has many advantages, including long-term direct visualization of microcirculation. The method allows for repeated testing of the same vessel or network, thereby reducing variability. The method also allows for measurement of permeability changes and the accompanying leukocyte-endothelial cell interactions in the same network or vessel, which permits correlative studies of these phenomena. However, this method is not without challenges. The optical conditions are difficult, because the brain is three-dimensional and its parenchyma is more complex than the thinner, flatter peripheral tissues. To overcome this limitation, we performed a dynamic background subtraction. The background is dynamically related to vessel intensity, and changes in intensity were determined by eliminating the effects of neighboring and underlying vessels. We applied this method to studying the effects of ionizing radiation on the blood-brain barrier (BBB) permeability and cell interactions and the modulation of these effects by anti-ICAM-1 antibodies. Our results demonstrate that this method is sensitive to changes in these properties of the BBB.
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http://dx.doi.org/10.1016/j.brainresprot.2003.11.005DOI Listing
April 2004

Radiation-induced permeability and leukocyte adhesion in the rat blood-brain barrier: modulation with anti-ICAM-1 antibodies.

Brain Res 2003 Apr;969(1-2):59-69

Department of Radiation Oncology, Mail Stop 220, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.

We assessed the acute effects of radiation on the rat blood-brain barrier. A cranial window model and intravital microscopy were used to measure changes in permeability and leukocyte adhesion in pial vessels after a localized, single dose of 20 Gy. Permeability was assessed using five sizes of fluorescein isothiocyanate (FITC)-dextran molecules (4.4-, 10-, 38.2-, 70-, and 150-kDa) with measurements performed before and 2, 24, 48, 72 and 96 h after irradiation for the 4.4 and 38.2-kDa molecules and before and 24 h after irradiation for the other three molecules. To demonstrate the nature of blood-brain barrier permeability, we concurrently studied the permeability of microvessels in the cremaster muscle. In both tissues, permeability to FITC-dextran was significantly greater 24 h after irradiation than before (P<0.05). The exception was that radiation did not affect the permeability of pial vessels to the 150-kDa molecule. The particle-size dependence of the permeability changes in the brain were indicative of altered integrity of endothelial tight junctions and occurred concomitantly with an increase in cell adhesion which was determined by fluorescent labeling of leukocytes with rhodamine 6G. An early inflammatory response to irradiation was apparent in the brain 2 h after irradiation. The numbers of rolling and adherent leukocytes increased significantly and peaked at 24 h. Injection with the anti-ICAM-1 mAb significantly reduced leukocyte adhesion and permeability thereby linking the two processes. These findings provide a target to reduce radiation-related permeability and cell adhesion and potentially the side effects of radiation in the CNS.
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http://dx.doi.org/10.1016/s0006-8993(03)02278-9DOI Listing
April 2003

Dysfunctional microvascular conducted response in irradiated normal tissue.

Adv Exp Med Biol 2003 ;510:391-5

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

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http://dx.doi.org/10.1007/978-1-4615-0205-0_65DOI Listing
August 2003