scholarly journals Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

2005 ◽  
Vol 103 (5) ◽  
pp. 923-929 ◽  
Author(s):  
Michal T. Krauze ◽  
Ryuta Saito ◽  
Charles Noble ◽  
Matyas Tamas ◽  
John Bringas ◽  
...  
Keyword(s):  
Trypan Blue ◽  
High Speed ◽  
Volume Of Distribution ◽  
Blue Dye ◽  
Agarose Gel ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Content Type ◽  
Fine Print

Object. Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. Methods. The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 µl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macaca fascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-µl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. Conclusions. The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.

A realistic brain tissue phantom for intraparenchymal infusion studies

2004 ◽  
Vol 101 (2) ◽  
pp. 314-322 ◽  
Author(s):  
Zhi-Jian Chen ◽  
George T. Gillies ◽  
William C. Broaddus ◽  
Sujit S. Prabhu ◽  
Helen Fillmore ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Bromophenol Blue ◽  
Agarose Gel ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Force Profile ◽  
The Brain ◽  
Fine Print

Object. The goal of this study was to validate a simple, inexpensive, and robust model system to be used as an in vitro surrogate for in vivo brain tissues in preclinical and exploratory studies of infusion-based intraparenchymal drug and cell delivery. Methods. Agarose gels of varying concentrations and porcine brain were tested to determine the infusion characteristics of several different catheters at flow rates of 0.5 and 1 µl per minute by using bromophenol blue (BPB) dye (molecular weight [MW] ∼690) and gadodiamide (MW ∼573). Magnetic resonance (MR) imaging and videomicroscopy were used to measure the distribution of these infusates, with a simultaneous measurement of infusion pressures. In addition, the forces of catheter penetration and movement through gel and brain were measured. Agarose gel at a 0.6% concentration closely resembles in vivo brain with respect to several critical physical characteristics. The ratio of distribution volume to infusion volume of agarose was 10 compared with 7.1 for brain. The infusion pressure of the gel demonstrated profiles similar in configuration and magnitude to those of the brain (plateau pressures 10–20 mm Hg). Gadodiamide infusion in agarose closely resembled that in the brain, as documented using T1-weighted MR imaging. Gadodiamide distribution in agarose gel was virtually identical to that of BPB dye, as documented by MR imaging and videomicroscopy. The force profile for insertion of a silastic catheter into agarose gel was similar in magnitude and configuration to the force profile for insertion into the brain. Careful insertion of the cannula using a stereotactic guide is critical to minimize irregularity and backflow of infusate distribution. Conclusions. Agarose gel (0.6%) is a useful surrogate for in vivo brain in exploratory studies of convection-enhanced delivery.

Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion

2002 ◽  
Vol 97 (4) ◽  
pp. 905-913 ◽  
Author(s):  
Russell R. Lonser ◽  
Stuart Walbridge ◽  
Kayhan Garmestani ◽  
John A. Butman ◽  
Hugh A. Walters ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Magnetic Resonance ◽  
Mr Imaging ◽  
Histological Analysis ◽  
Volume Of Distribution ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Large Molecular Weight ◽  
Fine Print

Object. Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood—brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem. Methods. Three primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 µl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and midbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94), with a Vd/Vi ratio of 8.7 ± 1.2 (mean ± standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal gliosis that was limited to the region immediately surrounding the cannula track. Conclusions. First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes.

Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer

2005 ◽  
Vol 102 (1) ◽  
pp. 90-97 ◽  
Author(s):  
David Croteau ◽  
Stuart Walbridge ◽  
Paul F. Morrison ◽  
John A. Butman ◽  
Alexander O. Vortmeyer ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Real Time ◽  
Ct Scanning ◽  
Quantitative Autoradiography ◽  
Cerebral White Matter ◽  
Low Molecular Weight ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Fine Print

Object. Convection-enhanced delivery (CED) is increasingly used to distribute therapeutic agents to locations in the central nervous system. The optimal application of convective distribution of various agents requires the development of imaging tracers to monitor CED in vivo in real time. The authors examined the safety and utility of an iodine-based low-molecular-weight surrogate tracer for computerized tomography (CT) scanning during CED. Methods. Various volumes (total volume range 90–150 µ1) of iopamidol (MW 777 D) were delivered to the cerebral white matter of four primates (Macaca mulatta) by using CED. The distribution of this imaging tracer was determined by in vivo real-time and postinfusion CT scanning (≤ 5 days after infusion [one animal]) as well as by quantitative autoradiography (14C-sucrose [all animals] and 14C-dextran [one animal]), and compared with a mathematical model. Clinical observation (≤ 5 months) and histopathological analyses were used to evaluate the safety and toxicity of the tracer delivery. Real-time CT scanning of the tracer during infusion revealed a clearly definable region of perfusion. The volume of distribution (Vd) increased linearly (r2 = 0.97) with an increasing volume of infusion (Vi). The overall Vd/Vi ratio was 4.1 ± 0.7 (mean ± standard deviation) and the distribution of infusate was homogeneous. Quantitative autoradiography confirmed the accuracy of the imaged distribution for a small (sucrose, MW 359 D) and a large (dextran, MW 70 kD) molecule. The distribution of the infusate was identifiable up to 72 hours after infusion. There was no clinical or histopathological evidence of toxicity in any animal. Conclusions. Real-time in vivo CT scanning of CED of iopamidol appears to be safe, feasible, and suitable for monitoring convective delivery of drugs with certain features and low infusion volumes.

Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue—cannula sealing time

1999 ◽  
Vol 90 (2) ◽  
pp. 315-320 ◽  
Author(s):  
Michael Y. Chen ◽  
Russell R. Lonser ◽  
Paul F. Morrison ◽  
Lance S. Governale ◽  
Edward H. Oldfield
Keyword(s):  
Target Location ◽  
Regional Distribution ◽  
Small Animal ◽  
Volume Of Distribution ◽  
National Institutes Of Health ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
The Central Nervous System ◽  
Clinically Significant ◽  
Fine Print

Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time.Methods. The authors used convection to deliver 4 µl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 µl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis.Higher rates of infusion (1 and 5 µl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 ± 11.7% and 30.3 ± 7.8% [mean ± standard deviation], respectively) compared with lower rates (0.1 µl/minute [4 ± 3.6%] and 0.5 µl/minute [5.2 µ 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 µl/minute (95.1 ± 2.8%) compared with higher rates (85.2 ± 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7 ± 8.1% and 21.1 ± 7.5%, respectively) than the smaller cannula (32 gauge [5.2 ± 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery.Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

Convection-enhanced delivery into the rat brainstem

2002 ◽  
Vol 96 (5) ◽  
pp. 885-891 ◽  
Author(s):  
David I. Sandberg ◽  
Mark A. Edgar ◽  
Mark M. Souweidane
Keyword(s):  
Fluorescein Isothiocyanate ◽  
Volume Of Distribution ◽  
Convection Enhanced Delivery ◽  
Cross Sectional ◽  
Pontine Nucleus ◽  
Content Type ◽  
Distribution Parameters ◽  
Rat Brainstem ◽  
Cannula Placement ◽  
Fine Print

Object. Convection-enhanced delivery (CED) can be used safely to achieve high local infusate concentrations within the brain and spinal cord. The use of CED in the brainstem has not been previously reported and may offer an alternative method for treating diffuse pontine gliomas. In the present study the authors tested CED within the rat brainstem to assess its safety and establish distribution parameters. Methods. Eighteen rats underwent stereotactic cannula placement into the pontine nucleus oralis without subsequent infusions. Twenty rats underwent stereotactic cannula placement followed by infusion of fluorescein isothiocyanate (FITC)—dextran at a constant rate (0.1 µl/minute) until various total volumes of infusion (Vis) were reached: 0.5, 1, 2, and 4 µl. Additional rats underwent FITC—dextran infusion (Vi 4 µl) and were observed for 48 hours (five animals) or 14 days (five animals). Serial (20-µm thick) brain sections were imaged using confocal microscopy with ultraviolet illumination, and the volume of distribution (Vd) was calculated using computer image analysis. Histological analysis was performed on adjacent sections. No animal exhibited a postoperative neurological deficit, and there was no histological evidence of tissue disruption. The Vd increased linearly (range 15.4–55.8 mm3) along with increasing Vi, with statistically significant correlations for all groups that were compared (p < 0.022). The Vd/Vi ratio ranged from 14 to 30.9. The maximum cross-sectional area of fluorescence (range 9.8–20.9 mm2) and the craniocaudal extent of fluorescence (range 2.8–5.1 mm) increased with increasing Vi. Conclusions. Convection-enhanced delivery can be safely applied to the rat brainstem with substantial and predictable Vds. This study provides the basis for investigating delivery of various candidate agents for the treatment of diffuse pontine gliomas.

Early alterations in cerebral hemodynamics, brain metabolism, and blood-brain barrier permeability in experimental intracerebral hemorrhage

1999 ◽  
Vol 91 (6) ◽  
pp. 1013-1019 ◽  
Author(s):  
E-Jian Lee ◽  
Yu-Chang Hung ◽  
Ming-Yang Lee
Keyword(s):  
Intracerebral Hemorrhage ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Trypan Blue ◽  
Brain Barrier ◽  
Blue Dye ◽  
Content Type ◽  
Group A ◽  
Group B ◽  
Fine Print

Object. The authors sought to ascertain the nature of the hemodynamic and metabolic derangement underlying acute pathophysiological events that occur after intracerebral hemorrhage (ICH).Methods. Cerebral perfusion pressure (CPP), flow velocity (FV) of the middle cerebral artery, and the arteriovenous contents of oxygen and lactate were investigated in 24 dogs subjected to sham operations (Group A, four animals) or intracerebral injections of 3 ml (Group B, 11 animals) or 5 ml (Group C, nine animals) autologous arterial blood. Twelve additional dogs received intravenous injections of 2% Evans blue or trypan blue dye to evaluate blood-brain barrier (BBB) changes. Within 1 hour, animals with ICH exhibited a rise in FV associated with significant reductions (p < 0.05) in CPP and the arteriovenous content difference (AVDO2). In Group C animals significant increases in lactate concentration were found in arterial and superior sagittal sinus (SSS) samples compared with those in the other two groups (p < 0.05). Additionally, perihematomal dye extravasation was observed in animals subjected to ICH and trypan blue dye injections, with profound and mild leakages in Group C and Group B animals, respectively, but not in Group A and Evans blue dye—injected animals. During the subsequent 4 hours, the FV and AVDO2 returned to normal in Group B animals, indicating a balanced cerebral metabolic rate for oxygen (CMRO2) compared with a deranged CMRO2 in Group C animals due to their lowered FV and AVDO2. However, no coupling increase in brain lactate clearance in Group C animals accounted for either the early lactate elevation in SSS or the decrease in CMRO2.Conclusions. Profound reductions in CPP and brain oxygenation after ICH may rapidly exhaust hemodynamic compensation and, thus, impede cerebral homeostasis; however, these reductions only modestly enhance anaerobic glycolysis. Furthermore, the data suggest that a selective increase in permeability, rather than anatomical disruption, of the BBB is involved in the acute pathophysiological events that occur after ICH, which may provide a possible gateway for systemic arterial lactate entering the SSS.

Invasion of human glioma biopsy specimens in cultures of rodent brain slices: a quantitative analysis

2002 ◽  
Vol 97 (1) ◽  
pp. 169-176 ◽  
Author(s):  
Sophie de Boüard ◽  
Christo Christov ◽  
Jean-Sébastien Guillamo ◽  
Lina Kassar-Duchossoy ◽  
Stéphane Palfi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Brain Slices ◽  
Lower Grade ◽  
Human Glioma ◽  
Newborn Mice ◽  
Content Type ◽  
Biopsy Specimens ◽  
Rodent Brain ◽  
Fine Print

Object. The reliable assessment of the invasiveness of gliomas in vitro has proved elusive, because most invasion assays inadequately model in vivo invasion in its complexity. Recently, organotypical brain cultures were successfully used in short-term invasion studies on glioma cell lines. In this paper the authors report that the invasiveness of human glioma biopsy specimens directly implanted into rodent brain slices by using the intraslice implantation system (ISIS) can be quantified with precision. The model was first validated by the demonstration that, in long-term studies, established glioma cells survive in the ISIS and follow pathways of invasion similar to those in vivo. Methods. Brain slices (400 µm thick) from newborn mice were maintained on millicell membranes for 15 days. Cells from two human and one rodent glioblastoma multiforme (GBM) cell lines injected into the ISIS were detected by immunohistochemistry or after transfection with green fluorescent protein—containing vectors. Preferential migration along blood vessels was identified using confocal and fluorescent microscopy. Freshly isolated (≤ 24 hours after removal) 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate—prelabeled human glioma biopsy specimens were successfully implanted in 19 (83%) of 23 cases, including 12 GBMs and seven lower grade gliomas (LGGs). Morphometric quantification of distance and density of tumor cell invasion showed that the GBMs were two to four times more invasive than the LGGs. Heterogeneity of invasion was also observed among GBMs and LGGs. Directly implanted glioma fragments were more invasive than spheroids derived from the same biopsy specimen. Conclusions. The ISIS combines a high success rate, technical simplicity, and detailed quantitative measurements and may, therefore, be used to study the invasiveness of biopsy specimens of gliomas of different grades.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo

1994 ◽  
Vol 80 (3) ◽  
pp. 527-534 ◽  
Author(s):  
Yasuhiro Matsuda ◽  
Keiichi Kawamoto ◽  
Katsuzo Kiya ◽  
Kaoru Kurisu ◽  
Kazuhiko Sugiyama ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Tumor Volume ◽  
Collagen Gel ◽  
Antitumor Effects ◽  
Histological Changes ◽  
Content Type ◽  
The Relationship ◽  
Fine Print

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

Circumferential fracture of the skull base causing craniocervical dislocation

2002 ◽  
Vol 97 (1) ◽  
pp. 118-122 ◽  
Author(s):  
Ganesh Rao ◽  
Adam S. Arthur ◽  
Ronald I. Apfelbaum
Keyword(s):  
High Speed ◽  
Unusual Case ◽  
Motor Vehicle ◽  
Neurological Impairment ◽  
Craniocervical Junction ◽  
Motor Vehicle Accidents ◽  
Review Of The Literature ◽  
Content Type ◽  
Vehicle Accidents ◽  
Fine Print

✓ Fractures of the craniocervical junction are common in victims of high-speed motor vehicle accidents; indeed, injury to this area is often fatal. The authors present the unusual case of a young woman who sustained a circumferential fracture of the craniocervical junction. Despite significant trauma to this area, she suffered remarkably minor neurological impairment and made an excellent recovery. Her injuries, treatment, and outcome, as well as a review of the literature with regard to injuries at the craniocervical junction, are discussed.

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