Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier

1988 ◽  
Vol 69 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Stephen C. Saris ◽  
Steven A. Rosenberg ◽  
Robert B. Friedman ◽  
Joshua T. Rubin ◽  
David Barba ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Albumin Level ◽  
Brain Barrier ◽  
Lymphokine Activated Killer Cells ◽  
Content Type ◽  
Blood Brain ◽  
Recombinant Interleukin 2 ◽  
Fine Print

✓ Recombinant interleukin-2 (rIL-2) is an immunotherapeutic agent with efficacy against certain advanced cancers. The penetration of rIL-2 across the blood-cerebrospinal fluid (CSF) barrier was studied in 12 cancer patients who had no evidence of tumor involvement of the central nervous system. At different times during treatment with intravenous rIL-2, CSF was withdrawn either continuously for 8 to 26 hours via a lumbar subarachnoid catheter (in eight patients) or by a single lumbar puncture (in four). Bioassay showed the appearance of rIL-2 in lumbar CSF 4 to 6 hours after the first intravenous dose, a rise over 2 to 4 hours to a plateau of 3 to 9 U/ml, and clearance to less than 0.1 U/ml by 10 hours after the last dose. An abnormally elevated CSF albumin level in two of the twelve patients indicated alteration of the blood-brain barrier. There were no abnormalities in the CSF glucose level or white blood cell count. The CSF pharmacokinetics contrast with the rapid elimination of rIL-2 from plasma and demonstrate significant blood-CSF barrier penetration. These data support the possibility of achieving CSF levels of rIL-2 that are adequate to maintain activity of lymphokine-activated killer cells after parenteral administration, and argue for rIL-2-associated disruption of the human blood-brain barrier in some patients.

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

1989 ◽  
Vol 70 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Joseph T. Alexander ◽  
Stephen C. Saris ◽  
Edward H. Oldfield
Keyword(s):  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Tumor Bearing ◽  
Blood Brain ◽  
Significant Difference ◽  
Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

Selective blood-tumor barrier disruption by leukotrienes

1992 ◽  
Vol 77 (3) ◽  
pp. 407-410 ◽  
Author(s):  
Chung-Ching Chio ◽  
Takehiko Baba ◽  
Keith L. Black
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Barrier Permeability ◽  
Content Type ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Mean ◽  
Fine Print

✓ The authors have previously reported that intracarotid infusion of 5 µg leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5 µg to 50.0 µg (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using 14C aminoisobutyric acid. The transfer constant for permeability (Ki) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0 µg compared to vehicle alone (90.00 ±21.14, 92.68 ± 15.04, and 80.17 ± 16.15 vs. 39.37 ± 6.45 µl/gm/min, respectively; mean ± standard deviation; p < 0.01). No significant change in Ki within the tumors was observed at the 0.5-µg LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, Ki was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean Ki value was still high at 15 minutes (92.68 ± 15.04 µl/gm/min), but declined at 30 minutes (56.58 ± 12.50 µl/gm/min) and 60 minutes (55.40 ± 8.10 µl/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotrienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 was the most potent, increasing the permeability value 37½ fold compared with vehicle alone (139.86 ± 23.95 vs. 39.37 ± 6.45 µl/gm/min).

In vivo assessment of the window of barrier opening after osmotic blood—brain barrier disruption in humans

2000 ◽  
Vol 92 (4) ◽  
pp. 599-605 ◽  
Author(s):  
Tali Siegal ◽  
Rina Rubinstein ◽  
Felix Bokstein ◽  
Allan Schwartz ◽  
Alexander Lossos ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
Photon Emission ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Content Type ◽  
Blood Brain ◽  
The Mean ◽  
Fine Print

Object. Osmotic blood—brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans.Methods. Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies.The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02 ± 0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19 ± 0.18. After 40 minutes no significant change was noted (mean index 2.13 ± 0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36 ± 0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33 ± 0.08) but at 480 minutes the mean indices had returned to the baseline level.Conclusions. Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.

Temporary cortical blindness following angiography

1974 ◽  
Vol 40 (5) ◽  
pp. 583-586 ◽  
Author(s):  
Norman H. Horwitz ◽  
Louis Wener
Keyword(s):  
Blood Brain Barrier ◽  
Striate Cortex ◽  
Cortical Blindness ◽  
Brain Barrier ◽  
Content Type ◽  
Blood Brain ◽  
Theoretical Considerations ◽  
Fine Print

✓ Temporary cortical blindness as a complication of posterior angiography is reported in 11 patients and compared with 30 similar cases previously reported. Theoretical considerations of etiology implicate transitory alterations of the blood-brain barrier in the striate cortex.

The blood-brain barrier following experimental subarachnoid hemorrhage

1983 ◽  
Vol 58 (3) ◽  
pp. 338-344 ◽  
Author(s):  
Eric W. Peterson ◽  
Erico R. Cardoso
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Arterial Hypertension ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Hemodynamic Variable ◽  
Content Type ◽  
Blood Brain ◽  
Intracisternal Injection ◽  
Experimental Subarachnoid Hemorrhage ◽  
Fine Print

✓ In three groups of cats, the authors studied the effect of subarachnoid hemorrhage (SAH) on the permeability of the blood-brain barrier (BBB) to the penetration of Evans blue-protein complex. One group received arterial hypertension alone, one group SAH alone, and one group SAH followed by arterial hypertension. Animals subjected to arterial hypertension alone showed areas of BBB breakdown. However, when cats were rendered hypertensive after SAH, there were no demonstrable BBB lesions. The SAH was produced by intracisternal injection of whole blood and hypertension by the intravenous injection of metaraminol. The preservation of the BBB after SAH is discussed. Vasospasm is considered as a possible hemodynamic variable responsible for the protection of the BBB from hypertensive damage. The need for a new model is proposed to further investigate the state of the BBB after SAH.

Blood—brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain

2004 ◽  
Vol 101 (2) ◽  
pp. 303-309 ◽  
Author(s):  
David Yarnitsky ◽  
Yossi Gross ◽  
Adi Lorian ◽  
Alon Shalev ◽  
Itschak Lamensdorf ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Sphenopalatine Ganglion ◽  
Parasympathetic Innervation ◽  
Content Type ◽  
Blood Brain ◽  
The Brain ◽  
Fine Print ◽  
Stimulation Of

Object. Drug delivery across the blood—brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. Methods. Using a craniotomy—cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate—dextran (4–250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. Conclusions. Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

The kallikrein-kinin system as mediator in vasogenic brain edema

1984 ◽  
Vol 61 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Klaus Maier-Hauff ◽  
Alexander J. Baethmann ◽  
Manfred Lange ◽  
Ludwig Schürer ◽  
Andreas Unterberg
Keyword(s):  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Vasogenic Edema ◽  
Brain Barrier ◽  
Kinin System ◽  
Content Type ◽  
Blood Brain ◽  
Kallikrein Kinin System ◽  
Fine Print ◽  
Edematous Brain

✓ Vasogenic edema was induced in mongrel cats by cold injury to study uptake and activation of the plasma-kallikrein-kinin system in central nervous system (CNS) tissue. A method was developed for quantitative assessment of kinin formation in affected brain tissue areas. Gross disruption of the blood-brain barrier by focal trauma causes marked penetration of plasma kininogens into necrotic and edematous brain tissue. Moreover, the kallikrein-kinin (KK) system was activated in both necrotic and perifocal edematous areas, and was markedly enhanced by additional cerebral ischemia. Formation of kinins in necrotic brain tissue led to consumption of approximately 60% to 80% of the amount of kininogens being taken up. In perifocal edematous tissue, formation of kinins was less pronounced, or even absent. However, if cerebral ischemia evolved after severe intracranial hypertension, kinins were also formed in the perifocal edematous brain. The intravascular origin of kininogens found in pathological tissue areas secondary to injury was deduced from the observation that cerebral tissue of the contralateral hemisphere with an intact blood-brain barrier had no measurable quantities of kininogens. Consumption of plasma kininogens or formation of kinins were assessed as the difference of the total amount of plasma kininogens taken up into the tissue minus the amount of kininogens found in the brain at postmortem examination. The data indicate that uptake and activation of the plasma-KK system might occur under all pathological conditions in which blood-brain barrier damage permits cerebral penetration of plasma proteins, such as with cerebral contusion, focal ischemia, and tumors. The potent pathophysiological mechanisms induced by kinins in CNS tissue, such as formation of brain edema, microcirculatory dysfunction, and enhancement of blood-brain barrier permeability, together with their formation in focal and perifocal pathological brain tissue, provide further support for a mediator function of the KK system. Methods that specifically interfere with the formation of kinins in damaged brain should therefore be expected to attenuate vasogenic edema.

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