title: Transient cerebral hypoperfusion enhances intraarterial carmustine deposition into brain tissue.
abstract: We hypothesized that bolus injections of lipid soluble chemotherapeutic drugs during transient cerebral hypoperfusion could significantly boost regional drug delivery. In the first two groups of New Zealand White rabbits we measured brain tissue carmustine concentrations after intravenous infusion, intraarterial infusion with normal perfusion, and after intraarterial injections during transient cerebral hypoperfusion. In the third group of animals we assessed the safety of the technique by assessing electroencephalographic changes for 6 h after flow arrest carmustine administration and subsequent histological examination. The brain tissue carmustine concentrations were fivefold to sevenfold higher when the drug was injected during cerebral hypoperfusion compared to a conventional intracarotid infusion (68.4 +/- 24.5 vs. 14.2 +/- 8.3 microg/g, n = 5 each, respectively, P < 0.0001). The brain tissue carmustine concentrations (y) were a linear function of the bolus dose (x) injected during cerebral hypoperfusion, y = 10.4 x x - 21 (R = 0.84, P < 0.001). Stable EEGs were recorded several hours after flow arrest carmustine exposure and histological examinations did not reveal any gross evidence of cerebral injury. Transient cerebral hypoperfusion during intraarterial bolus injection of carmustine significantly increases drug delivery. Clinical techniques that decrease CBF, such as, transient arterial occlusion by balloon tipped catheters, hyperventilation, hypothermia, induced hypotension, or transient circulatory arrest, could enhance intraarterial drug delivery to the brain. We believe that the mechanisms for improved drug delivery is the decrease in drug dilution by reduced or absent blood flow, decreased protein binding and a longer time for high concentrations of free drugs to transit through the blood brain barrier.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. sj121@columbia.edu
authors.forename: Shailendra
authors.initials: S
authors.lastname: Joshi
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Etu
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Suckow
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Cooper
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Feinmark
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
mesh_terms: D000241:Adenosine; D000319:Adrenergic beta-Antagonists; D000704:Analysis of Variance; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002339:Carotid Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D007261:Infusions, Intra-Arterial / Q000379:methods; D007262:Infusions, Intravenous / Q000379:methods; D019585:Intracranial Hypotension / Q000139:chemically induced; D002546:Ischemic Attack, Transient / Q000139:chemically induced; D008297:Male; D011412:Propanolamines; D011817:Rabbits; D018709:Statistics, Nonparametric; D014665:Vasodilator Agents
chemical_list: D000319:Adrenergic beta-Antagonists; D018906:Antineoplastic Agents, Alkylating; D011412:Propanolamines; D014665:Vasodilator Agents; D000241:Adenosine; C036604:esmolol; D002330:Carmustine