Abstract 3374: Effect of bevacizumab and dexamethasone on plasma ultrafiltrate (UF) and cerebrospinal fluid (CSF) pharmacokinetics (PKs) of carboplatin in a non-human primate (NHP) model.

2013 ◽  
Author(s):  
Srivandana Akshintala ◽  
Cynthia M. Lester-McCully ◽  
Robert F. Murphy ◽  
Brigitte C. Widemann ◽  
Katherine E. Warren
Keyword(s):  
Cerebrospinal Fluid ◽  
Csf Pharmacokinetics ◽  
Human Primate ◽  
Plasma Ultrafiltrate

scholarly journals EXTH-57. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE PROCASPASE-ACTIVATING COMPOUND, PAC-1, FOLLOWING ORAL ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi97-vi97
Author(s):  
Cynthia Lester McCully ◽  
Rafael Cruz ◽  
Alexander V Lyubimov ◽  
Alexander D Zakharov ◽  
James H Fischer ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Oral Administration ◽  
Primate Model ◽  
Human Primate

scholarly journals Accumulation of uremic solutes in the cerebrospinal fluid in experimental acute renal failure

2019 ◽  
Vol 317 (2) ◽  
pp. F296-F302 ◽  
Author(s):  
Robert DeWolfe Mair ◽  
Huy Nguyen ◽  
Ting-Ting Huang ◽  
Natalie S. Plummer ◽  
Tammy L. Sirich ◽  
...  
Keyword(s):  
Renal Failure ◽  
Cerebrospinal Fluid ◽  
Acute Renal Failure ◽  
Great Majority ◽  
Sham Operation ◽  
Csf Levels ◽  
Operation Control ◽  
Uremic Solutes ◽  
The Brain ◽  
Plasma Ultrafiltrate

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy ( n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.

scholarly journals Cerebrospinal fluid dynamics with its surgical implications

2020 ◽  
pp. 459-462
Author(s):  
Harold E. Vasquez ◽  
Yeider A. Durango-Espinosa ◽  
Ezequiel Garcia-Ballestas ◽  
B.V. Murlimanju ◽  
Andrei Fernandes Joaquim ◽  
...  
Keyword(s):  
Fluid Dynamics ◽  
Cerebrospinal Fluid ◽  
Review Article ◽  
Cerebrospinal Fluid Dynamics ◽  
Outflow Resistance ◽  
Csf Pressure ◽  
Pathological Conditions ◽  
Pressure Dynamics ◽  
Csf Physiology ◽  
Plasma Ultrafiltrate

Cerebrospinal fluid (CSF) is largely (70-80%) produced by the choroids plexus of the ventricles and is considered as the plasma ultrafiltrate. While CSF formation, circulation, and composition appear to be physiological and physical, its absorption appears to be mainly physical. The formation, composition, circulation, absorption, and changes in pathological conditions of CSF are discussed briefly in this review article. The CSF pressure dynamics studies provide information about the tightness, elastance, or outflow resistance of the CSF in the CNS. We believe that the present study shall help to provide essential details of CSF physiology which are important to many disciplines including radiology, neurology, and neurosurgery.

scholarly journals Ultrasensitive detection of PrPSc in the cerebrospinal fluid and blood of macaques infected with bovine spongiform encephalopathy prion

2014 ◽  
Vol 95 (11) ◽  
pp. 2576-2588 ◽  
Author(s):  
Yuichi Murayama ◽  
Kentaro Masujin ◽  
Morikazu Imamura ◽  
Fumiko Ono ◽  
Hiroaki Shibata ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Bovine Spongiform Encephalopathy ◽  
White Blood Cells ◽  
Clinical Signs ◽  
Cynomolgus Macaque ◽  
Cellular Protein ◽  
Spongiform Encephalopathy ◽  
Peripheral Tissues ◽  
Human Primate

Prion diseases are characterized by the prominent accumulation of the misfolded form of a normal cellular protein (PrPSc) in the central nervous system. The pathological features and biochemical properties of PrPSc in macaque monkeys infected with the bovine spongiform encephalopathy (BSE) prion have been found to be similar to those of human subjects with variant Creutzfeldt–Jakob disease (vCJD). Non-human primate models are thus ideally suited for performing valid diagnostic tests and determining the efficacy of potential therapeutic agents. In the current study, we developed a highly efficient method for in vitro amplification of cynomolgus macaque BSE PrPSc. This method involves amplifying PrPSc by protein misfolding cyclic amplification (PMCA) using mouse brain homogenate as a PrPC substrate in the presence of sulfated dextran compounds. This method is capable of amplifying very small amounts of PrPSc contained in the cerebrospinal fluid (CSF) and white blood cells (WBCs), as well as in the peripheral tissues of macaques that have been intracerebrally inoculated with the BSE prion. After clinical signs of the disease appeared in three macaques, we detected PrPSc in the CSF by serial PMCA, and the CSF levels of PrPSc tended to increase with disease progression. In addition, PrPSc was detectable in WBCs at the clinical phases of the disease in two of the three macaques. Thus, our highly sensitive, novel method may be useful for furthering the understanding of the tissue distribution of PrPSc in non-human primate models of CJD.

scholarly journals Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model

2015 ◽  
Vol 75 (5) ◽  
pp. 923-928 ◽  
Author(s):  
Diane E. Cole ◽  
Cynthia M. Lester-McCully ◽  
Brigitte C. Widemann ◽  
Katherine E. Warren
Keyword(s):  
Cerebrospinal Fluid ◽  
Akt Inhibitor ◽  
Primate Model ◽  
Human Primate

scholarly journals Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model

2017 ◽  
Vol 132 (3) ◽  
pp. 401-407 ◽  
Author(s):  
James C. League-Pascual ◽  
Cynthia M. Lester-McCully ◽  
Shaefali Shandilya ◽  
Lukas Ronner ◽  
Louis Rodgers ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Chemotherapeutic Agents ◽  
Intranasal Delivery ◽  
Primate Model ◽  
Human Primate

scholarly journals EPCT-09. CNS LEVELS OF PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL: COMPARISON OF BLOOD AND CEREBROSPINAL FLUID PHARMACOKINETIC METHODS AND MALDI MSI

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i48-i48
Author(s):  
Katherine Warren ◽  
Cynthia Lester McCully ◽  
Rafael Cruz Garcia ◽  
Sylwia Stopka ◽  
Michael Regan ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Model Comparison ◽  
Ex Vivo ◽  
Clinical Activity ◽  
Ionization Mass ◽  
Primate Model ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Limit Of Quantitation ◽  
Human Primate

Abstract Adequate exposure (effective concentration over time) of a therapeutic agent at its site of action is essential for antitumor efficacy. Given constraints of repeat tissue sampling, non-human primate models predictive of pharmacokinetics in pediatric patients have been utilized to assess central nervous system (CNS) exposure. Assessment of cerebrospinal fluid (CSF) drug levels have been used to extrapolate CNS penetration but the relationship of CSF drug levels with tissue distribution is unclear. Utilizing microdialysis, we previously demonstrated geographic variability of drug permeability across the blood:brain barrier (BBB), but this technique is complex and has a high standard deviation. We, therefore, explored a novel technique, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to compare plasma, CSF, and tissue drug levels in a terminal non-human primate model. Panobinostat, an HDAC inhibitor in clinical trials for DIPG/DMG, was selected for study as it has previously demonstrated poor CNS tissue penetration but suggested modest clinical activity. Methods Panobinostat (p.o., dose 1.6 mg/kg) was administered to non-tumor bearing primates (n=2). One hour following administration (Tmax), blood and CSF were collected, the animal euthanized, brain and spinal cord extracted, and immediately frozen at -80. Panobinostat distribution was mapped on ex vivo sagittal tissue sections using MALDI MSI. To provide specificity and degree of permeability, anatomical structures were segmented for analysis to determine drug concentrations. Blood, CSF and tissue levels of panobinostat were measured via LC-MS/MS. Results Segmentation analysis revealed quantifiable panobinostat, particularly in the lateral ventricles and choroid plexus, and also in the subventricular zone and brainstem, although the overall panobinostat concentration was below the limit of quantitation in these areas. Conclusions Although not reflected in CSF PK, panobinostat is widely distributed in brain tissue. MALDI MSI allows regional assessment of panobinostat penetration and complements CSF pharmacokinetics.

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