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Author Notes:

Sadhana Jackson, Email: sadhana.jackson@nih.gov

JW and EN performed neurosurgical tumor resection and catheter placement in all patients.

TH, RTG and DM provided Cardiology support for all patients, assisted with protocol design and manuscript writing.

XY performed statistical design of the trial.

NMA, CP, WDF, MAR, performed pharmacologic analysis of patient samples.

SJ, SAG, MG, MAR, XY, DM, RTG and EN were all involved in the design of the protocol and intellectual content.

SJ, MAR, NMA and SAG were involved in the data analysis and interpretation for graphical display.

SJ, MG, and SAG consented patients, provided neuro-oncology support, coordinated supportive staff engagement and were major contributors in writing the manuscript.

All authors read and approved the final manuscript.

We are appreciative of the patients and families who agreed to participate on the study requiring ICU admission, catheter placement and frequent neurologic monitoring.

We are also thankful for the supportive ICU, nursing surgical and research staff who assisted with clinical care, trial execution and enrollment assessment of study patients.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by fellowship support T32GM066691 in Johns Hopkins Clinical pharmacology training program (Sadhana Jackson) and by the National Institutes of Health Clinical Center.

The project described was supported in part by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30CA006973 and UL1 TR 001079).

Grant Number UL1 TR 001079 is from the National Center for Advancing Translational Sciences (NCATS) a component of the NIH, and NIH Roadmap for Medical Research.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Temozolomide
  • Adenosine A(2A) agonist
  • Regadenoson
  • Microdialysis
  • Glioblastoma
  • High grade glioma
  • Blood-brain barrier
  • BLOOD-BRAIN-BARRIER
  • HIGH-GRADE GLIOMAS
  • DRUG DEVELOPMENT
  • P-GLYCOPROTEIN
  • RAT-BRAIN
  • MICRODIALYSIS
  • PERMEABILITY
  • PHARMACOKINETICS
  • DISRUPTION
  • DELIVERY

The effect of an adenosine - A(2A) agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

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Journal Title:

Fluids and Barriers of the CNS

Volume:

Volume 15, Number 1

Publisher:

, Pages 2-2

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: The blood-brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A$$subscript$$2A$atsubscriptat$ receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A$$subscript$$2A$atsubscriptat$ receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. Methods: Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m$$superscript$$2$atsuperscriptat$). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. Results: Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h μg/ml for temozolomide alone and 16.6 ± 2.87 h μg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h μg/ml with temozolomide alone and 3.0 ± 1.7 h μg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and T$$subscript$$max$atsubscriptat$ in brain were not significantly different. Conclusions: Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.

Copyright information:

2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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