β-Adrenoreceptor-Blocking Agents and the Blood-Brain Barrier

1980 ◽  
Vol 59 (s6) ◽  
pp. 453s-455s ◽  
Author(s):  
J. M. Cruickshank ◽  
G. Neil-Dwyer ◽  
M. M. Cameron ◽  
J. McAinsh
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Plasma Ratio ◽  
Blocking Agents ◽  
Drug Plasma ◽  
Neurosurgical Patients ◽  
Receptor Blockers ◽  
High Concentrations ◽  
Β Receptor ◽  
The Brain

1. Sixteen neurosurgical patients received (oral) β-adrenoreceptor-blocking agents (β-receptor blockers) for 3–22 days. 2. Lipophilic β-receptor blockers (propranolol) and metoprolol appeared in cerebrospinal fluid at concentrations similar to the free drug plasma concentration. 3. Cerebrospinal fluid concentrations of β-receptor blockers were poor predictors of brain concentrations 4. Both lipophilic β-receptor blockers appeared in high concentrations in the brain: the brain/plasma ratio was approximately 15:1. 5. Hydrophilic atenolol appeared at low concentrations in brain tissue (about 20 times lower than the lipophilic β-receptor blockers): the brain/plasma ratio was approximately 0.1:1. 6. Central nervous system-related side effects associated mainly with lipophilic β-receptor blockers possibly result from high brain tissue concentrations.

scholarly journals Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico, In Vitro, and In Vivo Investigation

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Paul Curley ◽  
Rajith K. R. Rajoli ◽  
Darren M. Moss ◽  
Neill J. Liptrott ◽  
Scott Letendre ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Drug Distribution ◽  
Pbpk Modeling ◽  
Once Daily ◽  
Plasma Ratio ◽  
Human Data ◽  
High Concentrations ◽  
The Brain

ABSTRACT Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight−1) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (C max) were predicted to be 3,184 ng ml−1 (interquartile range [IQR], 2,219 to 4,851 ng ml−1), 49.9 ng ml−1 (IQR, 36.6 to 69.7 ng ml−1), and 50,343 ng ml−1 (IQR, 38,351 to 65,799 ng ml−1) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg−1), the median plasma and brain tissue concentrations in rats were 69.7 ng ml−1 (IQR, 44.9 to 130.6 ng ml−1) and 702.9 ng ml−1 (IQR, 475.5 to 1,018.0 ng ml−1), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.

Brain volume changes in spontaneous intracranial hypotension: Revisiting the Monro-Kellie doctrine

Cephalalgia ◽  
2020 ◽  
pp. 033310242095038
Author(s):  
Jr-Wei Wu ◽  
Yen-Feng Wang ◽  
Shu-Shya Hseu ◽  
Shu-Ting Chen ◽  
Yung-Lin Chen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Intracranial Hypotension ◽  
Spontaneous Intracranial Hypotension ◽  
Fluid Volume ◽  
Tissue Volume ◽  
Fixed Constant ◽  
The Brain ◽  
Cerebrospinal Fluid Volume

Objectives In the application of the Monro-Kellie doctrine in spontaneous intracranial hypotension, the brain tissue volume is generally considered as a fixed constant. Traditionally, cerebral venous dilation is thought to compensate for decreased cerebrospinal fluid. However, whether brain tissue volume is invariable has not yet been explored. The objective of this study is to evaluate whether brain tissue volume is fixed or variable in spontaneous intracranial hypotension patients using automatic quantitative methods. Methods This retrospective and longitudinal study analyzed spontaneous intracranial hypotension patients between 1 January 2007 and 31 July 2015. Voxel-based morphometry was used to examine brain volume changes during and after the resolution of spontaneous intracranial hypotension. Brain structure volume was analyzed using Statistical Parametric Mapping version 12 and FMRIB Software Library v6.0. Post-treatment neuroimages were used as surrogate baseline measures. Results Forty-four patients with spontaneous intracranial hypotension were analyzed (mean [standard deviation] age, 37.8 [8.5] years; 32 female and 12 male). The whole brain tissue volume was decreased during spontaneous intracranial hypotension compared to follow-up (1180.3 [103.5] mL vs. 1190.4 [93.1] mL, difference: −10.1 mL [95% confidence interval: −18.4 to −1.8 mL], p = 0.019). In addition, ventricular cerebrospinal fluid volume was decreased during spontaneous intracranial hypotension compared to follow-up (15.8 [6.1] mL vs. 18.9 [6.9] mL, difference: −3.2 mL [95% confidence interval: −4.5 to −1.8 mL], p < 0.001). Longer anterior epidural cerebrospinal fluid collections, as measured by number of vertebral segments, were associated with greater reduction of ventricular cerebrospinal fluid volume (Pearson’s r = −0.32, p = 0.036). Conclusion The current study found the brain tissue volume and ventricular cerebrospinal fluid are decreased in spontaneous intracranial hypotension patients. The change in ventricular cerebrospinal fluid volume, but not brain tissue volume change, was associated with the severity of spinal cerebrospinal fluid leakage. These results challenge the assumption that brain tissue volume is a fixed constant.

Detection of adiponectin in cerebrospinal fluid in humans

2007 ◽  
Vol 293 (4) ◽  
pp. E965-E969 ◽  
Author(s):  
Markus Neumeier ◽  
Johanna Weigert ◽  
Roland Buettner ◽  
Josef Wanninger ◽  
Andreas Schäffler ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Serum Concentration ◽  
Physiological Function ◽  
The Body ◽  
Serum Adiponectin ◽  
Albumin Ratio ◽  
Adiponectin Mrna ◽  
Low Levels ◽  
High Concentrations ◽  
The Brain

Adiponectin circulates in the body in high concentrations, and 100-fold lower amounts were described in the cerebrospinal fluid (CSF) of mice, whereas in humans, contradictory results have been published. To clarify whether adiponectin is present in human CSF and is derived from the circulation, it was determined in human CSF and plasma of 52 nonselected patients. Adiponectin was detected by immunoblot in CSF and was quantified in CSF and serum by ELISA. CSF adiponectin was positively correlated to systemic levels, and the CSF/serum adiponectin ratio was correlated to the CSF/serum albumin ratio. Furthermore, disturbed function of the blood-brain barrier (BBB) was associated with an elevated CSF/serum adiponectin ratio. Adiponectin mRNA was not found in the brain, indicating that adiponectin crosses the BBB and/or the blood-cerebrospinal fluid barrier (BCB). Rat adiponectin with a COOH-terminal tag was injected into the tail vein of rats and was detected 3 h later in CSF. However, CSF adiponectin in humans and rats was ∼0.1% of the serum concentration and therefore was below the 0.5% expected in the CSF because of the residual leakage of an undisturbed BBB/BCB. Taken together, data from the present study show that adiponectin in human CSF is far below the level expected by the baseline BBB/BCB permeability, indicating that adiponectin enters the brain much less efficiently than albumin, thus supporting recent data that exclude adiponectin transport to the CSF. Additional studies are needed to reveal whether these low levels of adiponectin in CSF have a physiological function.

Cerebrospinal Fluid pH and Monoamine and Glucolytic Metabolites in Alzheimer's Disease

1974 ◽  
Vol 124 (580) ◽  
pp. 280-287 ◽  
Author(s):  
C. G. Gottfries ◽  
Åke Kjällquist ◽  
Urban Pontén ◽  
B. E. Roos ◽  
G. Sundbärg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Homovanillic Acid ◽  
Monoamine Metabolites ◽  
Hydroxyindoleacetic Acid ◽  
The Brain ◽  
Valid Information

Determinations of acid monoamine metabolites, such as homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), in cerebrospinal fluid (CSF) give valid information on the metabolism of the corresponding amines in the brain tissue (Moir et al., 1970; Roos, 1970). The monoamine metabolites in the CSF are related to age. The concentrations of HVA and 5-HIAA increase with age (Gottfries et al., 1971). Probenecid blocks the elimination of HVA and 5-HIAA from brain tissue to blood (Neff et al., 1964, 1967; Werdinius, 1966) and from CSF to blood (Guldberg et al., 1966; Olsson and Roos, 1968). Probenecid thus normally induces an increase in the concentrations of the acid monoamine metabolites in the CSF, which is related to the turnover of monoamines in the brain tissue.

Polyol content of cerebrospinal fluid in brain-tumor patients

1989 ◽  
Vol 70 (2) ◽  
pp. 183-189 ◽  
Author(s):  
Satoru Watanabe ◽  
Junko Kamiyama ◽  
Hiroo Chigasaki ◽  
Shigetake Yoshioka
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Malignant Tumors ◽  
Glioblastoma Cells ◽  
Tumor Patients ◽  
Glucose Content ◽  
Content Type ◽  
Before And After ◽  
The Mean ◽  
The Brain

✓ In order to investigate whether cerebrospinal fluid (CSF) polyols are consumed by brain tissue, the concentration of seven polyols in the CSF and the serum of 30 patients with intracranial tumor and 17 control individuals was measured by gas chromatography. The mean polyol content in the control samples showed that the fructose, inositol, and glucitol levels were significantly greater in CSF than in serum. A comparison of the lumbar CSF from control subjects and 11 patients with malignant tumors exposed to the CSF snowed the fructose and inositol levels to be significantly lower (54% and 45%, respectively) and the glucose content to be slightly higher (110%) in the tumor cases. These differences were markedly greater in the ventricular than in the lumbar CSF and greater in patients with tumors exposed to the CSF space than in those with tumors buried in the brain tissue. In ventricular CSF obtained from seven patients with malignant brain tumors before and after radio— and/or chemotherapy, significant increases in fructose (34%) and glucitol (48%) levels were found, but the other polyols did not change significantly. In culture, the human glioblastoma cell growth rate was higher in the medium containing fructose and glucose than in that containing glucose alone. A notable amount of fructose and glucose was consumed by cultured glioblastoma cells. The roles of polyols contained in CSF and the effects of fructose on the growth of cultured glioblastoma cells are discussed in light of these findings and of previous reports.

scholarly journals Isavuconazole Diffusion in Infected Human Brain

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Claire Rouzaud ◽  
Vincent Jullien ◽  
Anne Herbrecht ◽  
Bruno Palmier ◽  
Simona Lapusan ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Plasma Concentration ◽  
Brain Tissue ◽  
Radical Surgery ◽  
Neurological Complication ◽  
Lymphocytic Leukemia ◽  
Normal Brain ◽  
Granulomatous Disease ◽  
Normal Brain Tissue ◽  
The Brain

ABSTRACT We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained in the infected brain tissue clearly differ from those obtained in the normal brain tissue and the cerebrospinal fluid.

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.

Establishment of Method for the Determination of Aggregated α-Synuclein in DLB Patient Using RT-QuIC Assay

2020 ◽  
Vol 27 ◽  
Author(s):  
Seok-Joo Park ◽  
Yun-Jung Lee ◽  
Jeong-Ho Park ◽  
Hyoung-Tae Jin ◽  
Myoung-Ju Choi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Brain Homogenate ◽  
Related Disease ◽  
Highly Sensitive ◽  
Potential Methods ◽  
The Brain

Background: The accumulation of aggregated α-synuclein (αSyn) is known as one of the critical reasons to exhibit their variable molecular pathologies and phenotypes in synucleinopathies. Recent studies suggested that the real-time quaking-induced conversion (RT-QuIC) assay is one of the potential methods to detect these αSyn aggregates and could detect the aggregated αSyn in the brain tissue and cerebrospinal fluid (CSF) using the propensity of the prion-like oligomerization. Objective: We tried to optimize the αSyn RT-QuIC assay based on the aggregation of αSyn in brain samples of synucleinopathies by comparing the conditions of the recently reported αSyn RT-QuIC assays. Methods: This study applied a highly sensitive RT-QuIC assay using recombinant αSyn (rαSyn) to detect aggregated αSyn in the brain tissue from dementia with Lewy bodies (DLB). Results: This study compared αSyn RT-QuIC assays under conditions such as beads, rαSyn as substrate, reaction buffers, and fluorescence detectors. We observed that the addition of beads and the use of 6x His-tagged rαSyn as substrate help to obtain higher positive responses from αSyn RTQuIC assay seeding with brain homogenate (BH) of DLB and phosphate buffer-based reaction showed higher positive responses than HEPES buffer-based reaction on both fluorescent microplate readers. We also observed that the DLB BHs gave positive responses within ~15–25 h, which is faster high positive responses than recently reported assays. Conclusion: This established αSyn RT-QuIC assay will be able to apply to the early clinical diagnosis of αSyn aggregates related disease in various biofluids such as CSF.

scholarly journals Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

2016 ◽  
Vol 27 (7) ◽  
pp. 2877-2885 ◽  
Author(s):  
Gregor Jost ◽  
Thomas Frenzel ◽  
Jessica Lohrke ◽  
Diana Constanze Lenhard ◽  
Shinji Naganawa ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Contrast Agents ◽  
Brain Tissue ◽  
The Brain

Incorporation of adenosine and its metabolites into brain nucleotides

1980 ◽  
Vol 239 (2) ◽  
pp. H212-H219 ◽  
Author(s):  
H. R. Winn ◽  
T. S. Park ◽  
R. R. Curnish ◽  
R. Rubio ◽  
R. M. Berne
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Venous Blood ◽  
Perfusion Fluid ◽  
Specific Activities ◽  
Adenine Nucleotide Pool ◽  
The Brain

Dogs were subjected to cerebrospinal fluid (CSF) convesity-cisternal perfusion with [U-14C]adenosine, [U-14C]inosine, or [U-14C]hypoxanthine to determine the mechanism of incorporation of these purines into brain adenine nucleotides. After craniotomy, brain tissue was frozen in situ, and the adenine nucleotides were separated by chromatography. A portion of the nucleotide fraction from the brain and [U-14C]purine from CSF were hydrolyzed enzymatically to nucleosides and bases and the specific activities (SA) measured. The pathway of incorporation of adenosine and inosine was determined by comparing the ratio of SA nucleoside to SA base obtained from degraded brain to that obtained from degraded CSF. Adenosine was directly phosphorylated to AMP, but inosine was degraded before incorporation into brain nucleotides. By comparing the SA of the brain nucleotides to that of the purine precursor in the cerebral spinal perfusion fluid, the incorporation of adenosine was found to be sevenfold greater than that of inosine or hypoxanthine. Measurement of the radioactivity in sagittal venous blood during convexity-cisternal perfusion yielded a larger percentage of counts after perfusion with [U-14C]inosine than with adenosine or hypoxanthine. In comparison to other tissues, a unique salvage system thus exists in the brain for adenosine that serves to conserve the adenine nucleotide pool.

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