The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

1992 ◽  
Vol 76 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Stuart A. Grossman ◽  
Carla Reinhard ◽  
O. Michael Colvin ◽  
Mark Chasin ◽  
Robert Brundrett ◽  
...  
Keyword(s):  
New Zealand ◽  
Brain Tissue ◽  
Direct Injection ◽  
Normal Brain ◽  
Local Concentration ◽  
Content Type ◽  
Drug Concentrations ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

The effects of mechanical immobilization on sutural development in the growing rabbit

1980 ◽  
Vol 53 (6) ◽  
pp. 794-801 ◽  
Author(s):  
William J. Foley ◽  
Vincent G. Kokich
Keyword(s):  
New Zealand ◽  
Biological Response ◽  
Bone Union ◽  
Coronal Suture ◽  
Content Type ◽  
Bone Bridge ◽  
Age Related ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ Methyl-2-cyanoacrylate was used to mechanically immobilize the coronal suture unilaterally in a series of New Zealand white rabbits at varying ages. The animals were separated into groups; some were sacrificed at 30 days and some at 60 days postoperatively. Amalgam markers were placed in the parietal and frontal bones across the coronal suture, and were measured immediately after surgery and at the time of sacrifice to confirm mechanical immobility. The animals were studied radiographically and histologically in order to document the presence or absence of sutural bone union. Based on the results of this study, it appears that immobilization of the coronal suture results in the formation of an ectocranial periosteal bone bridge in rabbits less than 8 weeks of age. Bone union was not found in animals older than 8 weeks of age. This age-related difference in response is believed to be due to decreased periosteal depository activity on the ectocranial surface of the calvaria once the brain ceases to expand actively. Furthermore, bone union or synostosis was never seen within or across the internal portion of the sutural ligament. It is suggested, therefore, that sutural immobilization at young ages in the rabbit does not result in sutural synostosis and that the term “periosteal bone bridge” should be used when referring to this biological response.

Uptake of tritiated methotrexate by mouse brain tumors after intravenous or intrathecal administration

1974 ◽  
Vol 40 (6) ◽  
pp. 706-716 ◽  
Author(s):  
Yukitaka Ushio ◽  
Toru Hayakawa ◽  
Heitaro Mogami
Keyword(s):  
Brain Tumors ◽  
Brain Tissue ◽  
Intravenous Injection ◽  
Malignant Gliomas ◽  
Intrathecal Administration ◽  
Drug Dosage ◽  
Content Type ◽  
Radioactive Assay ◽  
The Brain ◽  
Fine Print

✓ Malignant gliomas were induced in strain ddN mice by intracerebral implantation of a 20-methylcholanthrene pellet. The uptake and distribution of tritiated methotrexate (MTX-3H) in the tumor were investigated by radioactive assay and radioautography after single intravenous or intrathecal injections. By either route, a large amount of MTX-3H was taken up by gliomas, and a significantly higher concentration was observed in tumor than in the brain tissue. At 24 hours after intrathecal administration, the uptake of MTX-3H by gliomas exceeded that achieved after intravenous injection, although the drug dosage in the latter was 10 times that in the former.

Influence of oxygen therapy on glucose—lactate metabolism after diffuse brain injury

2004 ◽  
Vol 101 (2) ◽  
pp. 323-329 ◽  
Author(s):  
Michael Reinert ◽  
Benoit Schaller ◽  
Hans Rudolf Widmer ◽  
Rolf Seiler ◽  
Ross Bullock
Keyword(s):  
Brain Injury ◽  
Brain Tissue ◽  
Brain Metabolism ◽  
Arterial Line ◽  
Content Type ◽  
Diffuse Brain Injury ◽  
Lactate Levels ◽  
The Brain ◽  
Fine Print ◽  
Diffuse Brain

Object. Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. Methods. A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. Conclusions. Increasing the FiO2 influences dialysate glucose and lactate levels in injured brain tissue. Using an FiO2 of 1 influences brain metabolism in such a way that lactate is significantly reduced and glucose significantly increased. No changes in dialysate glucose and lactate values were found in the noninjured brain.

Dynamic determination of human glioma invasion in vitro

1998 ◽  
Vol 89 (3) ◽  
pp. 441-447 ◽  
Author(s):  
Svein J. T. Nygaard ◽  
Hans K. R. Haugland ◽  
Ole Didrik Laerum ◽  
Morten Lund-Johansen ◽  
Rolf Bjerkvig ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Brain Tissue ◽  
Normal Brain ◽  
Tumor Spheroids ◽  
Normal Brain Tissue ◽  
Content Type ◽  
Biopsy Specimens ◽  
Fine Print

Object. The goal of this study was to evaluate whether there is any relationship between survival of patients with brain tumor and tumor proliferation or tumor invasion in vitro. Methods. Samples of freshly resected brain tumors from 14 patients with glioblastoma multiforme (GBM) were directly grown as three-dimensional multicellular spheroids. The tumor spheroids were cocultured with fetal rat brain cell aggregates (BCAs), used to represent an organotypical normal brain tissue model. Before the coculture, the tumor spheroids and the BCAs were stained with two different carbocyanine dyes, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) and 3,3′-dioctadecycloxacarbocyanine perchlorate (DiO), respectively. During the coculture, confocal laser scanning microscopy allowed a sequential analysis of tumor cell invasion by visualizing dynamic aspects of the invasive process. Single cocultures were examined at three different time points (24, 48, and 96 hours). During the observation period there was a change in the structural morphology of the cocultures, with a progressive decrease in BCA volume. Furthermore, the scanning confocal micrographs revealed a bidirectional movement of tumor cells and normal cells into brain and tumor tissue, respectively. It is also shown that there is a considerable variation in the rate of BCA destruction in cocultures of glioma spheroids generated directly from biopsy specimens. This variation is seen both between spheroids generated from the same biopsy as well as between spheroids that are grown from different biopsy specimens. Cell proliferation measured by Ki-67 immunohistochemical analysis of biopsy samples obtained in the same patients revealed a correlation between tumor cell proliferation and tissue destruction of the BCAs, as determined by a reduction in BCA volume (p = 0.0338). No correlation was found when survival was related to the same parameters (p > 0.05). Conclusions. The present work provides a model for quick and efficient assessment of dynamic interactions between tumor and normal brain tissue shortly after surgery.

Progressive ventricular enlargement in cats in the absence of transmantle pressure gradients

1987 ◽  
Vol 67 (1) ◽  
pp. 88-92 ◽  
Author(s):  
Kenneth Shapiro ◽  
Ira J. Kohn ◽  
Futoshi Takei ◽  
Corinna Zee
Keyword(s):  
Brain Tissue ◽  
Subarachnoid Space ◽  
Pressure Gradients ◽  
Content Type ◽  
Cisterna Magna ◽  
Sagittal Sinus ◽  
Intracisternal Injection ◽  
The Mean ◽  
The Brain ◽  
Fine Print

✓ Intracranial pressure (ICP) was measured simultaneously at multiple sites in cats to determine if transmantle pressure gradients were present in progressive hydrocephalus. The cats underwent craniectomy and intracisternal injection of kaolin; 4 to 9 weeks later ICP was measured at the ventricle, cisterna magna, and convexity subarachnoid space, and in the brain tissue and the sagittal sinus. In 13 cats in which ventricular size conformed to previously established norms for duration of hydrocephalus, there were no demonstrable gradients of pressure at any of the sites of measurement according to one-way analysis of variance (p > 0.05). The mean (± standard error of the mean) peak and trough pressures (in mm Hg) at each site were: ventricle, 12.7 ± 0.7 and 12.0 ± 0.6; cisterna magna, 12.9 ± 0.8 and 12.3 ± 0.7; subarachnoid space, 12.7 ± 0.8 and 12.1 ± 0.7; brain tissue, 12.9 ± 0.9 and 12.4 ± 0.9; and sagittal sinus, 13.1 ± 0.8 and 11.9 ± 0.8. These results indicate that ventricular expansion can progress without measurable transmantle pressure gradients.

Functional and phenotypic differences between glioblastoma multiforme—derived and normal human brain endothelial cells

2005 ◽  
Vol 102 (4) ◽  
pp. 699-705 ◽  
Author(s):  
Christiana Charalambous ◽  
Florence M. Hofman ◽  
Thomas C. Chen
Keyword(s):  
Brain Tumor ◽  
Growth Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Boyden Chamber ◽  
Normal Brain ◽  
Vascular Endothelial ◽  
Phenotypic Properties ◽  
Content Type ◽  
The Brain ◽  
Fine Print

Object. Glioblastomas multiforme (GBMs) are hypervascular tumors characterized by endothelial cell (EC) proliferation. There is increasing evidence that ECs that infiltrate systemic tumors are different from normal blood vessel cells; whether this difference is seen in the central nervous system between GBM and normal brain tissue is not known. The goal of this investigation was to characterize and compare the functional and phenotypic properties of GBM-associated ECs and normal brain ECs. Methods. Human ECs were isolated from fresh tissue specimens, purified using flow cytometry, and characterized by immunostaining. Proliferation was measured by determining bromodeoxyuridine incorporation and Ki-67 staining, and by performing the monotetrazolium assay. The migration rate of the cells was determined using the modified Boyden chamber technique. Apoptosis was evaluated by performing the TUNEL assay, cell death enzyme-linked immunosorbent assay (ELISA), and annexin V staining. Growth factor production was analyzed using the ELISA technique. The brain tumor ECs differed from normal brain ECs morphologically and by their expression and distribution of specific markers (that is, vascular endothelial cadherin [VE-cadherin] and CD31). Functional differences between the two cell populations were also evident. The brain tumor ECs proliferated more slowly and underwent less apoptosis than normal brain ECs; however, the tumor ECs migrated faster than the normal ECs. The normal ECs were sensitive to growth factors such as vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), whereas the tumor ECs were not. In addition, the brain tumor ECs constitutively produced higher levels of ET-1 and VEGF, compared with the normal ECs. Conclusions. The data demonstrated that ECs derived from normal brain and from GBMs have significant phenotypic and functional distinctions. Further characterization of brain tumor ECs is essential for efficient antiangiogenic treatment of gliomas.

The effect of craniectomy on the biomechanics of normal brain

1987 ◽  
Vol 67 (4) ◽  
pp. 573-578 ◽  
Author(s):  
Shizuo Hatashita ◽  
Julian T. Hoff
Keyword(s):  
White Matter ◽  
Brain Tissue ◽  
Volume Index ◽  
Normal Brain ◽  
Tissue Pressure ◽  
Content Type ◽  
Cerebrovascular Resistance ◽  
Tissue Resistance ◽  
Tissue Compliance ◽  
Fine Print

✓ Does an open skull alter the fundamental biomechanical properties of normal brain tissue? This question was studied in 32 anesthetized cats, 16 of which underwent a standard craniectomy (2.5 × 2.0 cm) in the left frontoparietal region. Brain tissue pressure, regional cerebral blood flow (rCBF), and brain water content were measured from the same area of cortical gray and white matter, and intracranial pressure (ICP) was recorded from the cisterna magna. Brain tissue resistance, tissue compliance, and the pressure-volume index were analyzed in response to a bolus injection of saline into brain tissue or the cisterna magna. Cerebrovascular resistance was also calculated. In craniectomized animals 2 hours after surgery, ICP had fallen to 3.75 ± 0.39 mm Hg, and cortical gray and white matter tissue pressure had fallen to 3.19 ± 0.47 and 4.69 ± 0.54 mm Hg, respectively (mean ± standard error of the mean); these variables did not fall further over 4 hours. The pressure-volume index in the same animals increased significantly from 0.67 ± 0.01 to 0.86 ± 0.04 ml. Tissue compliance rose in the cortical gray matter but tissue resistance fell, approximating that found in subjacent white matter. There was no significant difference between animals with and without craniectomy in rCBF, cerebrovascular resistance, or brain water content in either gray or white matter. These findings indicate that in the cat craniectomy causes an increase in the compensatory capacity of the intracranial cavity to increased volume. The data also indicate that cortical tissue has high hydraulic conductivity and compliance when the skull is opened.

Role of dural fenestrations in acute subdural hematoma

2001 ◽  
Vol 95 (2) ◽  
pp. 263-267 ◽  
Author(s):  
Joseph N. Guilburd ◽  
Gil E. Sviri
Keyword(s):  
Brain Tissue ◽  
Surgical Decompression ◽  
Acute Subdural Hematoma ◽  
Intensive Care Treatment ◽  
Content Type ◽  
Poor Outcomes ◽  
Dural Opening ◽  
The Impact ◽  
The Brain ◽  
Fine Print

Object. Patients with acute subdural hematomas (ASDHs) have higher mortality and lower functional recovery rates compared with those of other head-injured patients. Early surgical decompression and active intensive care treatment represent, so far, the best way to assist these patients. Paradoxically, one of the factors contributing to poor outcomes in cases of ASDHs could be rapid surgical decompression, owing to the severe extrusion of the brain through the craniotomy defect in response to acute brain swelling. To avoid the deleterious consequences of abrupt decompression of the subdural space with disruption of brain tissue, the authors have adopted a new surgical technique for evacuation of ASDHs. This procedure consists of creating multiple fenestrations of the dura (MFD) in a meshlike fashion and removing clots through the small dural openings that are left open, avoiding the creation of a wide dural opening and the disruption of and additional damage to brain tissue. Methods. Thirty-one patients (26 male and five female patients with a mean age of 32.5 years) harboring ASDHs were treated using this method. On admission there were 16 patients (51.5%) with Glasgow Coma Scale (GCS) scores of 3 to 5, 11 patients (35.5%) with GCS scores of 6 to 8, and four patients (12.9%) with GCS scores of 9 to 12. Postoperative computerized tomography scans of the brain revealed evacuation of more than 80% of the hematoma in 29 of 31 patients. The overall mortality rate in this group was 51.6%. Conclusions. This preliminary report of a new surgical approach for patients who have sustained ASDHs should be considered to avoid abrupt disruption of the brain and to allow the gradual and gentle release of subdural clots. This is especially important in cases in which there are severe midline shifts and a tight brain. Further clinical studies should be conducted in a more selected series to estimate the impact of this new procedure on morbidity and mortality rates.

Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging

2003 ◽  
Vol 98 (3) ◽  
pp. 584-590 ◽  
Author(s):  
Tung T. Nguyen ◽  
Yashdip S. Pannu ◽  
Cynthia Sung ◽  
Robert L. Dedrick ◽  
Stuart Walbridge ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Computerized Tomography ◽  
Ct Scanning ◽  
Therapeutic Agents ◽  
Content Type ◽  
Drug Concentrations ◽  
The Brain ◽  
Fine Print

Object. Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, including brain tumors, neurodegenerative diseases, and seizure disorders. An analysis of the treatment efficacy and toxicity of this approach requires confirmation that the infusion is distributed to the targeted region and that the drug concentrations are in the therapeutic range. Methods. To confirm accurate delivery of therapeutic agents during CED and to monitor the extent of infusion in real time, albumin-linked surrogate tracers that are visible on images obtained using noninvasive techniques (iopanoic acid [IPA] for computerized tomography [CT] and Gd—diethylenetriamine pentaacetic acid for magnetic resonance [MR] imaging) were developed and investigated for their usefulness as surrogate tracers during convective distribution of a macromolecule. The authors infused albumin-linked tracers into the cerebral hemispheres of monkeys and measured the volumes of distribution by using CT and MR imaging. The distribution volumes measured by imaging were compared with tissue volumes measured using quantitative autoradiography with [14C]bovine serum albumin coinfused with the surrogate tracer. For in vivo determination of tracer concentration, the authors examined the correlation between the concentration of the tracer in brain homogenate standards and CT Hounsfield units. They also investigated the long-term effects of the surrogate tracer for CT scanning, IPA-albumin, on animal behavior, the histological characteristics of the tissue, and parenchymal toxicity after cerebral infusion. Conclusions. Distribution of a macromolecule to clinically significant volumes in the brain is possible using convection. The spatial dimensions of the tissue distribution can be accurately defined in vivo during infusion by using surrogate tracers and conventional imaging techniques, and it is expected that it will be possible to determine local concentrations of surrogate tracers in voxels of tissue in vivo by using CT scanning. Use of imaging surrogate tracers is a practical, safe, and essential tool for establishing treatment volumes during high-flow interstitial microinfusion of the central nervous system.

Distribution of hematoporphyrin derivative in the rat 9L gliosarcoma brain tumor analyzed by digital video fluorescence microscopy

1984 ◽  
Vol 61 (6) ◽  
pp. 1113-1119 ◽  
Author(s):  
James E. Boggan ◽  
Robert Walter ◽  
Michael S. B. Edwards ◽  
Janis K. Borcich ◽  
Richard L. Davis ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Model ◽  
Normal Brain ◽  
Hematoporphyrin Derivative ◽  
Content Type ◽  
9L Gliosarcoma ◽  
Video Fluorescence Microscopy ◽  
Brain Tumor Model ◽  
The Brain ◽  
Fine Print

✓ A digital video fluorescence microscopy technique was used to evaluate the distribution of hematoporphyrin derivative (HPD) in the rat intracerebral 9L gliosarcoma brain-tumor model at 4, 24, 48, and 72 hours after intravenous administration of 10 mg/kg of the drug. Compared to surrounding normal brain, there was significant preferential uptake of HPD into the tumor. In sections surveyed, fluorescence reached a maximum value by 24 hours; however, only 33% to 44% of the tumor was fluorescent. In contrast, fluorescence within the surrounding normal brain was maximum at 4 hours, but was present in less than 1% of the brain tissue evaluated. The effect of HPD sensitization to a laser light dose (633 nm) of 30 joules/sq cm delivered through the intact skull was evaluated histologically in 10 rats. A patchy coagulation necrosis, possibly corresponding to the distribution of HPD fluorescence seen within the tumor, was observed. There was evidence that photoradiation therapy (PRT) affects defective tumor vasculature and that a direct tumor cell toxicity spared normal brain tissue. Despite these findings, limited uptake of HPD in tumor and the brain adjacent to tumor may decrease the effectiveness of PRT in the 9L gliosarcoma brain-tumor model. Because of the similarity between the capillary system of the 9L tumor and human brain tumors, PRT may have a limited therapeutic effect in patients with malignant brain tumors.

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