Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema

1991 â—½  
Vol 74 (6) â—½  
pp. 956-961 â—½  
Author(s):  
Rafael J. Tamargo â—½  
Allen K. Sills â—½  
Carla S. Reinhard â—½  
Michael L. Pinn â—½  
Donlin M. Long â—½  
...  
Keyword(s):  
Controlled Release â—½  
Plasma Concentrations â—½  
Ethylene Vinyl Acetate â—½  
Peritumoral Edema â—½  
Content Type â—½  
9L Gliosarcoma â—½  
Dexamethasone Group â—½  
The Brain â—½  
Fine Print

✓ Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 µg of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.

Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes

1992 â—½  
Vol 76 (3) â—½  
pp. 513-519 â—½  
Author(s):  
Stephen C. Saris â—½  
Paul Spiess â—½  
Daniel M. Lieberman â—½  
Shan Lin â—½  
Stuart Walbridge â—½  
...  
Keyword(s):  
Brain Tumors â—½  
Interleukin 2 â—½  
Tumor Infiltrating Lymphocytes â—½  
Similar Response â—½  
Content Type â—½  
Primary Brain Tumors â—½  
Infiltrating Lymphocytes â—½  
The Brain â—½  
Fine Print

✓ Methods have recently been described for the isolation and expansion of lymphocytes that have trafficked into animal and human tumors. These CD8-positive tumor-infiltrating lymphocytes (TIL's) have exceptional trafficking ability to, and efficacy against, tumor targets in extracranial sites. Prior to Phase I clinical trials for patients with gliomas, adoptive immunotherapy with TIL's was studied in a mouse model of primary brain tumors to determine if intracerebral tumors have a similar response. Glioma 261 (GL261) tumors were grown in the subcutaneous space of C57BL/6 mice. After enzymatic digestion, the cells were incubated in vitro with interleukin-2 (IL-2) until a confluent population of T lymphocytes was present. The in vitro efficacy of these TIL's was tested against fresh GL261 targets with a chromium release assay; the in vivo efficacy was tested against GL261 tumors in the liver and against irradiated and nonirradiated GL261 tumors in the brain. Mice received one of the following: intraperitoneal saline; intraperitoneal IL-2 (7500 to 50,000 U three times daily for 5 days); IL-2 plus intravenous TIL's (1 to 3 × 107 cells); 10 Gy cranial irradiation; irradiation plus IL-2; or irradiation plus IL-2 plus TIL's. The TIL preparation killed 77% of tumor targets in 4 hours at an effector:target ratio of 100:1. In animals with GL261 tumors in the liver, at 2 weeks there were 93 ± 37, 128 ± 45, and 21 ± 14 liver metastases in the control, IL-2, and IL-2 plus TIL groups, respectively. However, in animals with GL261 tumors in the brain, no treatment group had an increased survival rate compared to the control group. It is concluded that, although TIL and IL-2 immunotherapy can be used effectively to treat brain tumors in vitro and at sites outside the central nervous system, it is ineffective against the same type of tumor in the brain. Different methods of delivery or different combinations of these immunomodulators may be more effective; however, based on these findings, treatment of patients with IL-2 and TIL cannot be recommended until efficacy has been demonstrated in an animal model.

In vitro photoradiation therapy of the rat 9L gliosarcoma

1986 â—½  
Vol 64 (5) â—½  
pp. 775-779 â—½  
Author(s):  
Douglas Hamilton â—½  
John D. S. McKean â—½  
John Tulip â—½  
Donald Boisvert â—½  
Judy Cummins
Keyword(s):  
Trypan Blue â—½  
Glioma Cells â—½  
Laser Source â—½  
Trypan Blue Exclusion â—½  
Content Type â—½  
9L Gliosarcoma â—½  
Trypan Blue Exclusion Test â—½  
9L Glioma â—½  
Fine Print

✓ The authors have investigated various factors involved in the photoradiation treatment of 9L glioma cells. The cells were grown in tissue culture and exposed to light from a laser source that allowed accurate quantitation of the light energy. Cell death was determined following treatment using the trypan blue exclusion test. It was shown that the treatment is very wavelength-dependent following the absorption spectrum of hematoporphyrin derivative (HPD). The absorption peaks in the lower part of the spectrum are more efficient than those of higher wavelengths. Photoradiation therapy is more effective the higher the concentration of HPD. Intensity of light is a very important factor in calculating the total dose of light necessary for this treatment.

A realistic brain tissue phantom for intraparenchymal infusion studies

2004 â—½  
Vol 101 (2) â—½  
pp. 314-322 â—½  
Author(s):  
Zhi-Jian Chen â—½  
George T. Gillies â—½  
William C. Broaddus â—½  
Sujit S. Prabhu â—½  
Helen Fillmore â—½  
...  
Keyword(s):  
Mr Imaging â—½  
Bromophenol Blue â—½  
Agarose Gel â—½  
Convection Enhanced Delivery â—½  
Content Type â—½  
Force Profile â—½  
The Brain â—½  
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.

Pharmacokinetics of controlled-release polymers in the subarachnoid space after subarachnoid hemorrhage in rabbits

2004 â—½  
Vol 101 (1) â—½  
pp. 99-103 â—½  
Author(s):  
Gustavo Pradilla â—½  
Paul P. Wang â—½  
Federico G. Legnani â—½  
James L. Frazier â—½  
Rafael J. Tamargo
Keyword(s):  
Subarachnoid Hemorrhage â—½  
Controlled Release â—½  
Evans Blue â—½  
Subarachnoid Space â—½  
Blue Dye â—½  
Content Type â—½  
Cisterna Magna â—½  
Pharmacokinetic Properties â—½  
Fine Print

Object. Implantation of controlled-release polymers into the subarachnoid space to deliver drugs for treatment of vasospasm after subarachnoid hemorrhage (SAH) is currently of interest. Among the issues regarding local delivery of drugs in the subarachnoid space, however, are the extent of diffusion and the rate of release of the loaded agents. In this study Evans blue dye (EBD) was loaded into controlled-release polymers and its pharmacokinetic properties were determined in vitro and in vivo by using a rabbit model of SAH. Methods. Ethylene—vinyl acetate copolymer (EVAc) was loaded 40% (w:w) with EBD and its pharmacokinetics were spectrophotometrically determined in vitro by examining three EBD—EVAc polymers. Additional polymers were implanted either into the frontal lobe or into the cisterna magna of 16 New Zealand White rabbits. Subarachnoid hemorrhage was induced in eight of the animals by an injection of 1.5 ml of arterial blood into the cisterna magna. The animals were killed 3 or 14 days postoperatively, their brains and spinal cords were harvested, and samples of each were placed in formamide for dye extraction and quantification. Specimens were examined macroscopically and the concentrations of EBD were determined with the aid of a spectrophotometer. The EBD—EVAc polymers continuously released EBD over a 133-day period. The controlled release of the dye into the subarachnoid space in either location resulted in staining of the entire central nervous system (CNS) in rabbits when the polymers were placed either on the frontal lobe or in the cisterna magna. The EBD diffusion covered a distance of at least 40 cm. The presence of blood in the subarachnoid space did not interfere with the diffusion. Conclusions. In this study the authors define the rate and extent of diffusion of EBD from controlled-release polymers placed in the subarachnoid space under conditions of SAH. Evans blue dye diffused through the entire rabbit CNS, covering a distance greater than that of the longest dimension of the hemicircumference of the subarachnoid space around the human brain. The pharmacokinetic properties of EBD—EVAc polymers are comparable to those of antivasospasm agents that are successfully used in animal models of SAH.

The role of minocycline in the treatment of intracranial 9L glioma

1995 â—½  
Vol 82 (4) â—½  
pp. 635-640 â—½  
Author(s):  
Jon D. Weingart â—½  
Eric P. Sipos â—½  
Henry Brem
Keyword(s):  
Controlled Release â—½  
Survival Time â—½  
Median Survival â—½  
Median Survival Time â—½  
Tumor Resection â—½  
Tumor Implantation â—½  
Content Type â—½  
9L Gliosarcoma â—½  
Controlled Release Polymer â—½  
Fine Print

✓ This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

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

1984 â—½  
Vol 61 (6) â—½  
pp. 1113-1119 â—½  
Author(s):  
James E. Boggan â—½  
Robert Walter â—½  
Michael S. B. Edwards â—½  
Janis K. Borcich â—½  
Richard L. Davis â—½  
...  
Keyword(s):  
Brain Tumor â—½  
Tumor Model â—½  
Normal Brain â—½  
Hematoporphyrin Derivative â—½  
Content Type â—½  
9L Gliosarcoma â—½  
Video Fluorescence Microscopy â—½  
Brain Tumor Model â—½  
The Brain â—½  
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.

In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors

1994 â—½  
Vol 80 (3) â—½  
pp. 535-540 â—½  
Author(s):  
Zvi Ram â—½  
Stuart Walbridge â—½  
John D. Heiss â—½  
Kenneth W. Culver â—½  
R. Michael Blaese â—½  
...  
Keyword(s):  
Brain Tumors â—½  
Interleukin 2 â—½  
Lymphocytic Infiltration â—½  
Content Type â—½  
The Brain â—½  
Tumor Eradication â—½  
Fine Print

✓ The authors have recently shown the feasibility of eradicating brain tumors using in vivo retroviral-mediated transduction of tumors with the herpes simplex thymidine kinase (HStk) gene and ganciclovir therapy. However, thymidine kinase-transduced subcutaneous tumors in immunocompromised (athymic) mice were less responsive to this therapy than in immunocompetent animals, suggesting a role of the immune system in the process of tumor eradication. Broad suppression of humoral and cell-mediated immunity is found in patients with malignant gliomas. Interleukin-2 (IL-2) production and IL-2 receptor expression are decreased in glioma patients. These findings and the proposed association between lymphocytic infiltration of brain tumors and survival suggest that immune response modifiers may be useful in treating glioma patients. To evaluate the role of local cytokine expression by tumor cells, alone or combined with HStk gene transfer and ganciclovir therapy, the authors investigated the efficacy of tumor (9L gliosarcoma) eradication in Fischer rats by in vitro and in vivo tumor transduction with the IL-2 gene alone or with a combined vector carrying both the HStk and IL-2 genes. Tumors injected with HStk vector-producer cells alone, with or without ganciclovir, and rats inoculated in the brain and subcutaneously with 9L cells that had previously been transduced in vitro served as controls. Murine vector-producer cells (3 × 106/50 µl) were injected into the brain tumors 7 days after tumor inoculation. Ganciclovir (15 mg/kg) was administered intraperitoneally twice daily for 10 days to animals that received HStk with or without IL-2 vector-producer cells, starting 5 days after producer-cell injection. The experiment was repeated with continuous daily treatment of all rats with oral dexamethasone (0.5 mg/kg). Rats were sacrificed 21 days after tumor inoculation, and the brains were removed for histological and immunohistochemical analysis for IL-2. Within each experimental group, tumors were found in a similar proportion in the dexamethasone-treated and untreated rats. Large brain tumors developed in all 10 rats that had been inoculated with 9L cells which had been pretransduced in vitro with the IL-2 gene, whereas only three of eight rats receiving subcutaneous inoculation of similar cells developed palpable tumors. No enhancement of tumor eradication was observed by adding the IL-2 gene in the HStk vector construct compared to the use of the vector with HStk alone. Lymphocytic infiltration was absent in all dexamethasone-treated rats but was observed in all treatment groups not receiving steroids. The degree of lymphocytic infiltration was not enhanced by intratumoral injection of IL-2 or IL-2/HStk vector-producer cells. The findings suggest a limited role, if any, for immune enhancement by transduction with IL-2 to eradicate brain tumors, either used alone or in combination with HStk.

Efficacy of controlled-release papaverine pellets in preventing symptomatic cerebral vasospasm

2001 â—½  
Vol 95 (1) â—½  
pp. 44-50 â—½  
Author(s):  
Tayfun Dalbasti â—½  
Murat Karabiyikoglu â—½  
Nurcan Ozdamar â—½  
Nezih Oktar â—½  
Sedat Cagli
Keyword(s):  
Controlled Release â—½  
Sustained Release â—½  
Treated Group â—½  
Local Application â—½  
Control Group â—½  
In Vitro Tests â—½  
Aneurysm Surgery â—½  
Content Type â—½  
Fine Print

Object. Vasospasm as a complication of subarachnoid hemorrhage is a major concern in clinical practice. The systemic drugs in current use are of limited value. Topical, intrathecal, or intraarterial papaverine administered during surgical or angiographic procedures is a potent vasodilating drug; however, hypotension limits its systemic application. Local application of papaverine in a biodegradable controlled- or sustained-release matrix is proposed for vasospasm prophylaxis to be used in patients scheduled for aneurysm surgery. Methods. Controlled-release papaverine (PapaCR) drug pellets were prepared using the biodegradable aliphatic polyester poly(DL-lactide-co-glycolide) as the carrier matrix. In vitro tests were performed to determine drug kinetics. One hundred seventeen patients, 73 assigned to the control group and 44 assigned to the PapaCR-treated group, participated in this study. Patients who were deemed to be at high risk for the development of vasospasm were selected to participate in the study. During aneurysm surgery, drug pellets were placed in cisterns over arterial segments. In two patients, cerebrospinal fluid was sampled every 6 hours for the first 5 days through a lumbar catheter that had been inserted at the beginning of aneurysm surgery. The incidence of clinical vasospasm and Glasgow Outcome Scale scores in the patients were evaluated statistically. The results of in vitro studies showed that effective local concentrations of papaverine could be maintained for more than 10 days. The first-degree drug-release profile was demonstrated using this design. In clinical studies no adverse effects due to the drug were seen. The PapaCR effectively prevented development of clinical vasospasm, and outcome scores were significantly better in patients in the treated group. Conclusions. Local application of controlled- or sustained-release papaverine can be safely used in preventing vasospasm.

A cannula for use in ultrasonically guided biopsies of the brain

1983 â—½  
Vol 59 (5) â—½  
pp. 905-907 â—½  
Author(s):  
Jonathan M. Rubin â—½  
George J. Dohrmann
Keyword(s):  
Precise Location â—½  
Content Type â—½  
Biopsy Procedure â—½  
The Brain â—½  
Fine Print â—½  
Guidance Device

✓ The authors describe a cannula that has been modified to improve its visibility during ultrasonically guided biopsies of the brain. To enhance the echogenicity of the tip of the cannula, six parallel rings, 0.25 to 0.30 mm deep and 0.40 to 0.50 mm apart, were etched into the tip of the cannula. The cannula was also lengthened to approximately 19 cm to permit its unencumbered passage through any biopsy guidance device that may be employed. Detailing the precise location of the tip of the biopsy cannula is most important. The tip of this modified probe is much more echogenic and hence more easily seen ultrasonically than it would be otherwise, both in vivo and in vitro. This modified cannula is useful in any ultrasonically guided intracranial biopsy procedure.

Ischemic tolerance in the rat neocortex following hypothermic preconditioning

2000 â—½  
Vol 93 (5) â—½  
pp. 845-851 â—½  
Author(s):  
Shinsaku Nishio â—½  
Masatoshi Yunoki â—½  
Zong-Fu Chen â—½  
Matthew J. Anzivino â—½  
Kevin S. Lee
Keyword(s):  
Protein Synthesis â—½  
Cerebral Infarction â—½  
Ischemic Tolerance â—½  
Protein Synthesis Inhibitor â—½  
Synthesis Inhibitor â—½  
Content Type â—½  
Series Of Experiments â—½  
The Brain â—½  
Fine Print

Object. Ischemic neuronal damage associated with neurological and other types of surgery can have severe consequences for functional recovery after surgery. Hypothermia administered during and/or after ischemia has proved to be clinically beneficial and its effects often rival or exceed those of other therapeutic strategies. In the present study the authors examined whether transient hypothermia is an effective preconditioning stimulus for inducing ischemic tolerance in the brain.Methods. Adult rats were subjected to a 20-minute period of hypothermic preconditioning followed by an interval ranging from 6 hours to 7 days. At the end of this interval, the animals were subjected to transient focal ischemia induced by clamping one middle cerebral artery and both carotid arteries for 1 hour. The volume of cerebral infarction was assessed 1 or 7 days postischemia. In the first series of experiments, hypothermic preconditioning (28.5°C) with a postconditioning interval of 1 day reduced the extent of cerebral infarction measured 1 and 7 days postischemia. In the second series, hypothermic preconditioning (31.5°C) with postconditioning intervals of 6 hours, 1 day, or 2 days (but not 7 days) reduced the extent of cerebral infarction measured 1 day postischemia. Treatment with the protein synthesis inhibitor anisomycin blocked the protective effect of hypothermic preconditioning. In a final series of experiments, in vitro brain slices prepared from hypothermia-preconditioned (nonischemic) animals were shown to tolerate a hypoxic challenge better than slices prepared from unconditioned animals.Conclusions. These findings indicate that hypothermic preconditioning induces a form of delayed tolerance to focal ischemic damage. The time course over which tolerance occurs and the ability of a protein synthesis inhibitor to block tolerance suggest that increased expression of one or more gene products is necessary to establish tissue tolerance following hypothermia. The attenuation of hypoxic injury in vitro following in vivo preconditioning indicates that tolerance is due, at least in part, to direct effects on the brain neuropil. Hypothermic preconditioning could provide a relatively low-risk approach for improving surgical outcome after invasive surgery, including high-risk neurological and cardiovascular procedures.

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