scholarly journals Convection-Enhanced Arborizing Catheter System Improves Local/Regional Delivery of Infusates Versus a Single-Port Catheter in Ex Vivo Porcine Brain Tissue

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Egleide Y. Elenes ◽  
Jason N. Mehta ◽  
Fang-Chi Hsu ◽  
Christopher T. Whitlow ◽  
Waldermar Debinski ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Single Port ◽  
Ex Vivo ◽  
Volume Of Distribution ◽  
Port Catheter ◽  
Convection Enhanced Delivery ◽  
Alternative Approach ◽  
The Brain ◽  
Regional Delivery ◽  
Porcine Brain Tissue

Abstract Standard treatment for glioblastoma is noncurative and only partially effective. Convection-enhanced delivery (CED) was developed as an alternative approach for effective loco-regional delivery of drugs via a small catheter inserted into the diseased brain. However, previous CED clinical trials revealed the need for improved catheters for controlled and satisfactory distribution of therapeutics. In this study, the arborizing catheter, consisting of six infusion ports, was compared to a reflux-preventing single-port catheter. Infusions of iohexol at a flow rate of 1 μL/min/microneedle were performed, using the arborizing catheter on one hemisphere and a single-port catheter on the contralateral hemisphere of excised pig brains. The volume dispersed (Vd) of the contrast agent was quantified for each catheter. Vd for the arborizing catheter was significantly higher than for the single-port catheter, 2235.8 ± 569.7 mm3 and 382.2 ± 243.0 mm3, respectively (n = 7). Minimal reflux was observed; however, high Vd values were achieved with the arborizing catheter. With simultaneous infusion using multiple ports of the arborizing catheter, high Vd was achieved at a low infusion rate. Thus, the arborizing catheter promises a highly desirable large volume of distribution of drugs delivered to the brain for the purpose of treating brain tumors.

scholarly journals PDTM-30. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi193-vi194
Author(s):  
Erica Power ◽  
Julian Rechberger ◽  
Liang Zhang ◽  
David Daniels
Keyword(s):  
Molecular Weight ◽  
Single Injection ◽  
Fluorescent Microscopy ◽  
Molecular Size ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Microscopy Imaging ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED. METHODS Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain. RESULTS The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017). CONCLUSIONS As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.

A phase I study of convection-enhanced delivery of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Zhiping Zhou ◽  
Pat Zanzonico ◽  
...  
Keyword(s):  
Dose Level ◽  
Therapeutic Strategy ◽  
Absorbed Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Overall Survival Rate ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
The Mean ◽  
The Brain

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.

scholarly journals SCIDOT-17. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi275-vi275
Author(s):  
Julian S Rechberger ◽  
Erica A Power ◽  
Liang Zhang ◽  
Ian Olson ◽  
Victor M Lu ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Drug Distribution ◽  
Molecular Size ◽  
Pediatric Brain Tumors ◽  
Volume Of Distribution ◽  
Hydraulic Pressure ◽  
Convection Enhanced Delivery ◽  
Cross Sectional ◽  
Orthotopic Xenograft Model ◽  
The Brain

Abstract Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors without cure. One of the major challenge sin DIPG treatment is the effective delivery of therapeutic agents across the blood-brain barrier (BBB) to the tumor and surrounding infiltrating cells. Therefore, strategies that enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a technique that bypasses the BBB and increases drug distribution by applying hydraulic pressure to deliver compounds directly and evenly into a target region. However, knowledge in CED pharmacology and convective kinetics is still lacking. In an effort to characterize the feasibility, safety, and distribution in the brain based on molecular size of the delivered agent, we performed infusions of FITC-dextran (range 3,000 Da–150,000 Da) comparing CED and osmotic pump-based delivery into the brainstem of rodents. We calculated the area and volume of distribution (Vd) of the FITC-dextran throughout the brain. Our data showed that the Vd decreased exponentially with increased molecular weight of the FITC-dextran. Interestingly, the Vdcan maintain linearity at lower molecular weights. Maximal cross-sectional area and craniocaudal extension of fluorescence also decreased when lowering the infusate size. In addition, we developed a patient-derived DIPG orthotopic xenograft model and performed an image-guided CED cannula installation in the tumor bed. Using 3D bioluminescence imaging and computed tomography, we determined the tumor volume and the positioning of the cannula in the bulk tumor. The summation of these results supports CED as a promising technique for treating DIPG tumors. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens and, ultimately, offers hope to patients and families with this devastating disease.

scholarly journals Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

2015 ◽  
Vol 123 (6) ◽  
pp. 1569-1577 ◽  
Author(s):  
Xiaotong Fan ◽  
Brian D. Nelson ◽  
Yi Ai ◽  
David K. Stiles ◽  
Don M. Gash ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Rhesus Macaques ◽  
Insertion Site ◽  
Volume Of Distribution ◽  
Mri Contrast Agent ◽  
Convection Enhanced Delivery ◽  
Mri Contrast ◽  
Chronic Infusion ◽  
System 1 ◽  
The Brain

OBJECT Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. METHODS The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. RESULTS All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. CONCLUSIONS These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

Monitoring of r-Hirudin Anticoagulation during Cardiopulmonary Bypass – Assessment of the Whole Blood Ecarin Clotting Time

1997 ◽  
Vol 77 (05) ◽  
pp. 0920-0925 ◽  
Author(s):  
Bernd Pötzsch ◽  
Katharina Madlener ◽  
Christoph Seelig ◽  
Christian F Riess ◽  
Andreas Greinacher ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Whole Blood ◽  
Heart Surgery ◽  
Ex Vivo ◽  
Open Heart Surgery ◽  
Clotting Time ◽  
Blood Samples ◽  
Alternative Approach ◽  
Ecarin Clotting Time

SummaryThe use of recombinant ® hirudin as an anticoagulant in performing extracorporeal circulation systems including cardiopulmonary bypass (CPB) devices requires a specific and easy to handle monitoring system. The usefulness of the celite-induced activated clotting time (ACT) and the activated partial thromboplastin time (APTT) for r-hirudin monitoring has been tested on ex vivo blood samples obtained from eight patients treated with r-hirudin during open heart surgery. The very poor relationship between the prolongation of the ACT and APTT values and the concentration of r-hirudin as measured using a chromogenic factor Ila assay indicates that both assays are not suitable to monitor r-hirudin anticoagulation. As an alternative approach a whole blood clotting assay based on the prothrombin-activating snake venom ecarin has been tested. In vitro experiments using r-hirudin- spiked whole blood samples showed a linear relationship between the concentration of hirudin added and the prolongation of the clotting times up to a concentration of r-hirudin of 4.0 µg/ml. Interassay coefficients (CV) of variation between 2.1% and 5.4% demonstrate the accuracy of the ecarin clotting time (ECT) assay. Differences in the interindividual responsiveness to r-hirudin were analyzed on r-hirudin- spiked blood samples obtained from 50 healthy blood donors. CV- values between 1.8% and 6% measured at r-hirudin concentrations between 0.5 and 4 µg/ml indicate remarkably slight differences in r-hirudin responsiveness. ECT assay results of the ex vivo blood samples linearily correlate (r = 0.79) to the concentration of r-hirudin. Moreover, assay results were not influenced by treatment with aprotinin or heparin. These findings together with the short measuring time with less than 120 seconds warrant the whole blood ECT to be a suitable assay for monitoring of r-hirudin anticoagulation in cardiac surgery.

scholarly journals Synthesis and pharmacokinetic characterisation of a fluorine-18 labelled brain shuttle peptide fusion dimeric affibody

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahiro Morito ◽  
Ryuichi Harada ◽  
Ren Iwata ◽  
Yiqing Du ◽  
Nobuyuki Okamura ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Post Injection ◽  
Affibody Molecule ◽  
Positron Emission ◽  
A Cell ◽  
Protein Binders ◽  
Rapid Clearance ◽  
Labelling Method ◽  
The Brain ◽  
Ex Vivo Study

AbstractBrain positron emission tomography (PET) imaging with radiolabelled proteins is an emerging concept that potentially enables visualization of unique molecular targets in the brain. However, the pharmacokinetics and protein radiolabelling methods remain challenging. Here, we report the performance of an engineered, blood–brain barrier (BBB)-permeable affibody molecule that exhibits rapid clearance from the brain, which was radiolabelled using a unique fluorine-18 labelling method, a cell-free protein radiosynthesis (CFPRS) system. AS69, a small (14 kDa) dimeric affibody molecule that binds to the monomeric and oligomeric states of α-synuclein, was newly designed for brain delivery with an apolipoprotein E (ApoE)-derived brain shuttle peptide as AS69-ApoE (22 kDa). The radiolabelled products 18F-AS69 and 18F-AS69-ApoE were successfully synthesised using the CFPRS system. Notably, 18F-AS69-ApoE showed higher BBB permeability than 18F-AS69 in an ex vivo study at 10 and 30 min post injection and was partially cleared from the brain at 120 min post injection. These results suggest that small, a brain shuttle peptide-fused fluorine-18 labelled protein binders can potentially be utilised for brain molecular imaging.

Natural product-based nanomedicine: Recent advances and issues for the treatment of Alzheimer's disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Choy Ker Woon ◽  
Wong Kah Hui ◽  
Razif Abas ◽  
Muhammad Huzaimi Haron ◽  
Srijit Das ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Medicinal Plants ◽  
Drug Transport ◽  
The Elderly ◽  
Current Evidence ◽  
Alternative Approach ◽  
Progressive Neurodegeneration ◽  
The Brain

: Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and its severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano- sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material’s bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicine-based approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

2007 ◽  
Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Diffusion Tensor ◽  
Therapeutic Potential ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Large Molecules ◽  
Macromolecular Drugs ◽  
Interstitial Transport ◽  
Blood Spinal Cord Barrier ◽  
The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

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