Quantitative Intracerebral Microdialysis Studies to Determine Unbound Extracellular Fluid Drug Concentrations in Discrete Areas of the Brain

2018 ◽  
Vol 80 (1) ◽  
pp. 7.18.1-7.18.19 ◽  
Author(s):  
Matthew R. Durk
Keyword(s):  
Extracellular Fluid ◽  
Intracerebral Microdialysis ◽  
Drug Concentrations ◽  
The Brain

scholarly journals Striking Differences in Glucose and Lactate Levels between Brain Extracellular Fluid and Plasma in Conscious Human Subjects: Effects of Hyperglycemia and Hypoglycemia

2002 ◽  
Vol 22 (3) ◽  
pp. 271-279 ◽  
Author(s):  
Walid M. Abi-Saab ◽  
David G. Maggs ◽  
Tim Jones ◽  
Ralph Jacob ◽  
Vinod Srihari ◽  
...  
Keyword(s):  
Human Subjects ◽  
Intractable Epilepsy ◽  
Extracellular Fluid ◽  
Intracerebral Microdialysis ◽  
Brain Extracellular Fluid ◽  
Lactate Levels ◽  
A Site ◽  
Clamp Study ◽  
The Relationship ◽  
The Brain

Brain levels of glucose and lactate in the extracellular fluid (ECF), which reflects the environment to which neurons are exposed, have never been studied in humans under conditions of varying glycemia. The authors used intracerebral microdialysis in conscious human subjects undergoing electro-physiologic evaluation for medically intractable epilepsy and measured ECF levels of glucose and lactate under basal conditions and during a hyperglycemia–hypoglycemia clamp study. Only measurements from nonepileptogenic areas were included. Under basal conditions, the authors found the metabolic milieu in the brain to be strikingly different from that in the circulation. In contrast to plasma, lactate levels in brain ECF were threefold higher than glucose. Results from complementary studies in rats were consistent with the human data. During the hyperglycemia–hypoglycemia clamp study the relationship between plasma and brain ECF levels of glucose remained similar, but changes in brain ECF glucose lagged approximately 30 minutes behind changes in plasma. The data demonstrate that the brain is exposed to substantially lower levels of glucose and higher levels of lactate than those in plasma; moreover, the brain appears to be a site of significant anaerobic glycolysis, raising the possibility that glucose-derived lactate is an important fuel for the brain.

A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
Jana Portnow ◽  
Behnam Badie ◽  
Timothy W. Synold ◽  
Alexander Annala ◽  
Bihong Chen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Human Study ◽  
Tumor Resection ◽  
Cytosine Deaminase ◽  
High Grade Glioma ◽  
Intracerebral Microdialysis ◽  
High Grade ◽  
Drug Concentrations ◽  
Average Maximum ◽  
The Brain

2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.

scholarly journals A 3D brain unit model to further improve prediction of local drug distribution within the brain

2019 ◽  
Author(s):  
Esmée Vendel ◽  
Vivi Rottschäfer ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Extracellular Fluid ◽  
Drug Distribution ◽  
Drug Binding ◽  
Brain Capillaries ◽  
Drug Concentrations ◽  
Unit Model ◽  
Quantitative Understanding ◽  
The Impact ◽  
The Brain ◽  
Excellent Tool

AbstractThe development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and trancellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed.In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.Author summaryInsights on how a drug distributes within the brain over both time and space are still limited. Here, we develop a ‘3D brain unit model’ in order to understand the factors that control drug concentrations within a small piece of brain tissue, the 3D brain unit. In one 3D brain unit, the brain capillaries, which are the smallest blood vessels of the brain, surround the brain extracellular fluid (ECF). The blood-brain barrier (BBB) is located between the brain capillaries and the brain ECF. The model describes the impact of brain capillary blood flow, transport across the BBB, diffusion, flow and drug binding on the distribution of a drug within the brain ECF. We distinguish between free (unbound) drug and drug that is bound to binding sites within the brain. We show that all of the above mentioned factors affect drug concentrations within brain ECF in an interdependent manner. The 3D brain unit model that we have developed is an excellent tool to increase our understanding of how local drug concentrations within the brain ECF are affected by brain transport and binding processes.

EXTH-52. SYSTEMIC AND BRAIN PHARMACOKINETICS OF THE AMP-ACTIVATED PROTEIN KINASE SELECTIVE INHIBITOR SBI-0206965 AS A POTENTIAL THERAPEUTIC AGENT FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi175
Author(s):  
Janki Desai ◽  
Mruniya Gawali ◽  
Aniruddha Karve ◽  
Gary Gudelsky ◽  
Larry Sallans ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Protein Kinase ◽  
Venous Blood ◽  
Intraperitoneal Administration ◽  
Extracellular Fluid ◽  
Intracerebral Microdialysis ◽  
Unbound Fraction ◽  
Compound C ◽  
Amp Activated Protein Kinase ◽  
The Brain

Abstract PURPOSE AMP-activated protein kinase (AMPK) is a molecular hub for cellular metabolic control. Recent evidence suggests that AMPK is a “druggable” novel target for the treatment of Glioblastoma Multiforme (GBM). However, AMPK-inhibitory compounds are largely limited to compound C, which has a poor selectivity profile. SBI-0206965 is a diaminopyrimidine derivative that directly inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C. The current studies provide insights into systemic pharmacokinetics and plasma to brain partitioning of SBI-0206965. METHODS We conducted an intracerebral microdialysis study employing jugular vein-cannulated Sprague Dawley rats (males, 6- 8 weeks). Serial brain extracellular fluid (ECF) and venous blood samples were collected up to 10 hrs following intraperitoneal administration of SBI-0206965 (25 mg/kg). These samples were then quantitated for SBI-0206965 levels using a LC/MS method (Thermo Scientific LTQ-FT™, Ionization: Electrospray Ionization; positive ion). PK analysis was performed using the Non–Compartmental Analysis (Phoenix® WinNonlin 8.2 Certara USA, Inc.). RESULTS Plasma and ECF peak concentrations (Cmax) were 7.15 µM and 0.68 µM, whereas the time to peak (Tmax) were 0.5 and 1 hr, respectively. The plasma and brain ECF elimination half-lives were 1.5 and 3 hours, respectively. Plasma protein binding of SBI-0206965 was 82%. A comparison of the brain ECF Cmax and area under the curve (AUC) to corresponding plasma values suggested that the brain partitioning of the compound was 10-18%. When corrected for unbound fraction in plasma the AUC ratio was 0.86. Thus, these studies show that SBI-0206965 has adequate brain penetration. Further studies are now in progress to assess selectivity of SBI-0206965 for AMPK expressing cell lines, efficacy against patient-derived GBM and PK in tumor-bearing mice. CONCLUSION Results from this study will help to design optimal dosing regimen of SBI-0206965 in our efforts to explore AMPK as a GBM-specific drug target.

scholarly journals The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions

2020 ◽  
Vol 37 (7) ◽  
Author(s):  
Esmée Vendel ◽  
Vivi Rottschäfer ◽  
Elizabeth C.M. de Lange
Keyword(s):  
Brain Tissue ◽  
Network Model ◽  
Drug Exposure ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Drug Concentrations ◽  
Induced Changes ◽  
The Impact ◽  
The Brain ◽  
Unit Network

Abstract Purpose We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF). Methods The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF. The model includes the distribution of unbound drug within blood plasma, coupled with the distribution of drug within brain ECF and incorporates brain capillaryblood flow, passive paracellular and transcellular BBB transport, active BBB transport, brain ECF diffusion, brain ECF bulk flow, and specific and nonspecific brain tissue binding. All of these processes may change under disease conditions. Results We show that the simulated disease-induced changes in brain tissue characteristics significantly affect drug concentrations within the brain ECF. Conclusions We demonstrate that the 3D brain unit network model is an excellent tool to gain understanding in the interdependencies of the factors governing spatial-temporal drug concentrations within the brain ECF. Additionally, the model helps in predicting the spatial-temporal brain ECF concentrations of existing drugs, under both normal and disease conditions.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

scholarly journals Kinetics of a nucleoside release from lactide-caprolactone and lactide-glycolide polymers in vitro.

2000 ◽  
Vol 47 (1) ◽  
pp. 59-64
Author(s):  
T Kryczka ◽  
P Grieb ◽  
M Bero ◽  
J Kasperczyk ◽  
P Dobrzynski
Keyword(s):  
Formation Rate ◽  
Local Treatment ◽  
Extracellular Fluid ◽  
Brain Extracellular Fluid ◽  
Artificial Cerebrospinal Fluid ◽  
Fluid Formation ◽  
Further Development ◽  
Kinetics Of ◽  
The Brain

We assessed the rate of release of a model nucleoside (adenosine, 5%, w/w) from nine different lactide-glycolide or lactide-caprolactone polymers. The polymer discs were eluted every second day with an artificial cerebrospinal fluid at the elution rate roughly approximating the brain extracellular fluid formation rate. Adenosine in eluate samples was assayed by HPLC. Three polymers exhibited a relatively constant release of adenosine for over four weeks, resulting in micromolar concentrations of nucleoside in the eluate. This points to the necessity of further development of polymers of this types as intracerebral nucleoside delivery systems for local treatment of brain tumors.

scholarly journals Universal Glia to Neurone Lactate Transfer in the Nervous System: Physiological Functions and Pathological Consequences

Biosensors ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 183 ◽  
Author(s):  
Carolyn L. Powell ◽  
Anna R. Davidson ◽  
Angus M. Brown
Keyword(s):  
Glial Cells ◽  
Lactate Production ◽  
Extracellular Fluid ◽  
Pathological Conditions ◽  
Motor End Plate ◽  
Lactate Uptake ◽  
The Brain ◽  
Intense Debate ◽  
Lateral Sclerosis ◽  
Glucose Availability

Whilst it is universally accepted that the energy support of the brain is glucose, the form in which the glucose is taken up by neurones is the topic of intense debate. In the last few decades, the concept of lactate shuttling between glial elements and neural elements has emerged in which the glial cells glycolytically metabolise glucose/glycogen to lactate, which is shuttled to the neural elements via the extracellular fluid. The process occurs during periods of compromised glucose availability where glycogen stored in astrocytes provides lactate to the neurones, and is an integral part of the formation of learning and memory where the energy intensive process of learning requires neuronal lactate uptake provided by astrocytes. More recently sleep, myelination and motor end plate integrity have been shown to involve lactate shuttling. The sequential aspect of lactate production in the astrocyte followed by transport to the neurones is vulnerable to interruption and it is reported that such disparate pathological conditions as Alzheimer’s disease, amyotrophic lateral sclerosis, depression and schizophrenia show disrupted lactate signalling between glial cells and neurones.

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