scholarly journals Translational CNS Steady-State Drug Disposition Model in Rats, Monkeys, and Humans for Quantitative Prediction of Brain-to-Plasma and Cerebrospinal Fluid-to-Plasma Unbound Concentration Ratios

2021 ◽  
Vol 23 (4) ◽  
Author(s):  
Sho Sato ◽  
Kota Matsumiya ◽  
Kimio Tohyama ◽  
Yohei Kosugi
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Concentration Ratio ◽  
Prediction Models ◽  
Drug Disposition ◽  
Quantitative Prediction ◽  
Unbound Concentration ◽  
Disposition Model ◽  
The Brain

AbstractCapturing unbound drug exposure in the brain is crucial to evaluate pharmacological effects for drugs acting on the central nervous system. However, to date, there are no reports of validated prediction models to determine the brain-to-plasma unbound concentration ratio (Kp,uu,brain) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (Kp,uu,CSF) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict Kp,uu,brain and Kp,uu,CSF across rats, monkeys, and humans by estimating the relative activity factors (RAF) for MDR1 and BCRP in addition to scaling factors (γ and σ) using the molecular weight, logD, CSF bulk flow, and in vitro transport activities of these transporters. In this study, 68, 26, and 28 compounds were tested in the rat, monkey, and human models, respectively. Both the predicted Kp,uu,brain and Kp,uu,CSF values were within the 3-fold range of the observed values (71, 73, and 79%; 79, 88, and 78% of the compounds, respectively), indicating successful prediction of Kp,uu,brain and Kp,uu,CSF in the three species. The overall predictivity of the RAF approach is consistent with that of the relative expression factor (REF) approach. As the established model can predict Kp,uu,brain and Kp,uu,CSF using only in vitro and physicochemical data, this model would help avoid ethical issues related to animal use and improve CNS drug discovery workflow.

scholarly journals Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Human CNS barrier-forming organoids with cerebrospinal fluid production

Science ◽  
2020 ◽  
Vol 369 (6500) ◽  
pp. eaaz5626 ◽  
Author(s):  
Laura Pellegrini ◽  
Claudia Bonfio ◽  
Jessica Chadwick ◽  
Farida Begum ◽  
Mark Skehel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Secretion ◽  
Fluid Production ◽  
New Compounds ◽  
High Degree ◽  
The Brain ◽  
Degree Of Similarity ◽  
By Products

Cerebrospinal fluid (CSF) is a vital liquid, providing nutrients and signaling molecules and clearing out toxic by-products from the brain. The CSF is produced by the choroid plexus (ChP), a protective epithelial barrier that also prevents free entry of toxic molecules or drugs from the blood. Here, we establish human ChP organoids with a selective barrier and CSF-like fluid secretion in self-contained compartments. We show that this in vitro barrier exhibits the same selectivity to small molecules as the ChP in vivo and that ChP-CSF organoids can predict central nervous system (CNS) permeability of new compounds. The transcriptomic and proteomic signatures of ChP-CSF organoids reveal a high degree of similarity to the ChP in vivo. Finally, the intersection of single-cell transcriptomics and proteomic analysis uncovers key human CSF components produced by previously unidentified specialized epithelial subtypes.

Exchange of calcium between blood, brain, and cerebrospinal fluid

1965 ◽  
Vol 208 (6) ◽  
pp. 1058-1064 ◽  
Author(s):  
Leonard Graziani ◽  
Anthony Escriva ◽  
Robert Katzman
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Brain Tissue ◽  
Specific Activity ◽  
Ventricular System ◽  
Passive Diffusion ◽  
Bulk Fluid ◽  
Fluid Formation ◽  
The Brain ◽  
Rate Of Movement

Ca exchange was measured in anesthetized cats during steady-state ventriculocisternal perfusions. When Ca45 was added to the perfusate the efflux coefficient from CSF averaged 0.025 ml/min of CSF cleared of Ca45. This coefficient was independent of CSF Ca concentration, indicating passive diffusion. About onethird of this isotope was recovered in brain tissue, two-thirds presumably diffused into blood. The brain radioactivity was localized to areas immediately adjacent to the CSF pathway. When the isotope was given systemically, the efflux coefficient into the ventricular system averaged 0.015 ml/min of serum effectively cleared of Ca45. In these experiments the specific activity of the CSF approached that of the serum. At the same time the specific activity of the brain Ca was low. Hence, the chief source of the Ca entering CSF must be blood. The rate of movement of Ca45 from blood to CSF was not altered when CSF formation was suppressed by adding acetazolamide or lowering the pH of the perfusate. This suggests that Ca transport is independent of the bulk fluid formation.

scholarly journals Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

2019 ◽  
Author(s):  
Jihye Kim ◽  
Michal Hetman ◽  
Eyas M. Hattab ◽  
Joshua Joiner ◽  
Brian Alejandro ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Zika Virus ◽  
Neurological Complications ◽  
Brain Infection ◽  
The Central Nervous System ◽  
The Brain ◽  
Host Brain

ABSTRACTZika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear.Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. We show that ZIKV infects pericytes in the choroid plexus, and that ZIKV infection of pericytes is dependent on AXL receptor tyrosine kinase. Using an in vitro Transwell system, we highlight the possibility of ZIKV to move from the blood side to CSF side, across the choroid plexus epithelial layers, via a nondestructive pathway (e.g., transcytosis). Finally, we demonstrate that brain infection is significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. Taken together, our results suggest that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.AUTHOR SUMMARYZika virus invades the human brains and causes Zika-associated neurological complications; however, the mechanism(s) by which Zika virus accesses the central nerves system remain unclear. Understanding of the cellular and molecular mechanisms will shed light on development of novel therapeutic and prophylactic targets for Zika virus and other neurotropic viruses. Here we use in vivo and in vitro models to understand how Zika virus enters the brain. In mouse models, we found that Zika virus infects pericytes in the choroid plexus at very early stages of infection and neutralization of Zika virus in the cerebrospinal fluid significantly attenuate the brain infection. Further we show evidence that Zika virus can cross the epithelial cell layers in the choroid plexus from the blood side. Our research highlights that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.

CONGENITAL TOXOPLASMOSIS

PEDIATRICS ◽  
1949 ◽  
Vol 4 (4) ◽  
pp. 432-442
Author(s):  
SVEN GARD ◽  
J. HENNING MAGNUSSON ◽  
F. WAHLGREN ◽  
GUNNAR GILLE
Keyword(s):  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Body Temperature ◽  
Liver Biopsy ◽  
Neutralization Test ◽  
High Titer ◽  
Congenital Toxoplasmosis ◽  
The Body ◽  
The Brain

An account is given of congenital toxoplasmosis in a child who died at the age of 43 days. The patient, who was somnolent from birth, showed the following symptoms: bilateral microphthalmia and chronic bilateral uveitis; considerable hydrocephalus internus, mainly symmetric, cerebral calcifications and pronounced typical changes in the cerebrospinal fluid, hypoprothrombinemia and eosinophilia; enlargement of the liver and spleen; marked lability of the body temperature with wide variations. The postmortem findings, both macroscopic and microscopic, were typical in every respect, with pronounced necrotic encephalitis in the cerebrum and characteristic foci of granulomata in the brainstem and the spinal cord. Toxoplasma in the form of pseudocysts were demonstrated in the affected parts of the brain. Typical Toxoplasma were isolated from the spinal fluid on three occasions, from material obtained by liver biopsy and from pieces of brain and spleen removed at autopsy. Serum from the patient as well as from the mother gave a positive neutralization test in rabbits. The in vitro dye test according to Sabin and Feldman yielded a positive result with a high titer value. The strain of Toxoplasma isolated ("G. L.") seems to be serologically identical with the American strains "RH" and "LM."

scholarly journals Leukocyte Recruitment in the Cerebrospinal Fluid of Mice with Experimental Meningitis Is Inhibited by an Antibody to Junctional Adhesion Molecule (Jam)

1999 ◽  
Vol 190 (9) ◽  
pp. 1351-1356 ◽  
Author(s):  
Aldo Del Maschio ◽  
Ada De Luigi ◽  
Ines Martin-Padura ◽  
Manfred Brockhaus ◽  
Tamas Bartfai ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Adhesion Molecule ◽  
Brain Parenchyma ◽  
Immunoglobulin Superfamily ◽  
Leukocyte Transmigration ◽  
Leukocyte Accumulation ◽  
Brain Barrier Permeability ◽  
The Brain

The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood–brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

Thyroxine transport from blood to brain via transthyretin synthesis in choroid plexus

1990 ◽  
Vol 258 (2) ◽  
pp. R338-R345 ◽  
Author(s):  
G. Schreiber ◽  
A. R. Aldred ◽  
A. Jaworowski ◽  
C. Nilsson ◽  
M. G. Achen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Thyroid Hormones ◽  
Choroid Plexus ◽  
Intravenous Injection ◽  
Rat Liver ◽  
Specific Radioactivity ◽  
Perfusion Medium ◽  
The Brain

The transport of thyroxine from the bloodstream to the brain and the synthesis and secretion of transthyretin (formerly called prealbumin) were studied in rats and in sheep choroid plexus perfused in vitro. Rat choroid plexus contained 4.4 micrograms and rat liver 0.39 micrograms transthyretin mRNA per gram wet tissue. The specific radioactivity of transthyretin isolated from cerebrospinal fluid of rats 60 min after intravenous injection of [14C]leucine was greater than 50 times that of transthyretin from serum. After adding [14C]leucine to the perfusion medium of an in vitro perfused sheep choroid plexus, highly radioactive transthyretin was isolated from freshly secreted cerebrospinal fluid collected from the exposed choroid plexus surface. Secretion of newly synthesized transthyretin into the perfusion medium could not be demonstrated. After intravenous injection of [125I]-thyroxine into rats, a maximum in the curve of radioactivity in tissue plotted against time after injection was observed first for choroid plexus, thereafter for cerebrospinal fluid, and still later for cortex and striatum. Based on the obtained data, a hypothesis is derived for the mechanism of the transport of thyroid hormones from the bloodstream to the brain involving transthyretin synthesized in choroid plexus and secreted into the cerebrospinal fluid.

Distribution of bisphenol A in the neuroendocrine organs of female rats

2004 ◽  
Vol 20 (1-5) ◽  
pp. 41-50 ◽  
Author(s):  
CS Kim ◽  
PP Sapienza ◽  
IA Ross ◽  
W Johnson ◽  
HMD Luu ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Bisphenol A ◽  
Pituitary Gland ◽  
Partition Coefficients ◽  
Female Rats ◽  
Fischer 344 ◽  
Neuroendocrine Organs ◽  
Oral Doses ◽  
The Brain

The distribution of 14C-bisphenol A (BPA) in plasma and neuroendocrine organs was determined in Fischer 344 female rats following three oral doses (0.1, 10 or 100 mg/kg). Plasma and tissue maximum concentrations (Cmax) were reached within 15-30 min of dosing. Plasma areas-under-the-curve (AUC) ranged from 0.06 to 53.9 mg-h/mL. The AUCs of the pituitary gland and uterus/gonads were 16-21% higher than that of plasma. The AUCs of hypothalamus and the rest of the brain were 43.7% and 77% of the plasma AUCs, respectively. In the brain tissue, the exposure increased linearly with the oral dose, as the dose was increased from 0.1 to 10 and 100 mg/kg; the exposure in the brain relative to the plasma increased by factors of 1, 1.19 and 1.24. This indicates that the brain barrier systems do not limit the access of the lipophilic BPA to the brain. The increases of the uterus/gonads relative to the plasma were 1, 1.07 and 1.04. Tissue partitioning was also examined in vitro by the uptake of 14C-BPA. The BPA tissue/blood partition coefficients were as follows: heart, 7.5; liver, 6.1; kidney, 6.4; fat, 3.6; muscle, 2.6; breast, 3.6; ovaries, 9.1; uterus, 5.9; stomach, 5.1; and small intestine, 6.7. The tissue/cerebrospinal fluid partition coefficients were as follows: pituitary gland, 12.8; brain stem, 6.1; cerebellum, 6.4; hippocampus, 7.1; hypothalamus, 6.1; frontal cortex, 4.9; and caudate nucleus, 6.8.

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