Dasatinib Cerebrospinal Fluid Concentration and Plasma Pharmacokinetics: Potential for Central Nervous System Prophylaxis In Philadelphia Chromosome-Positive Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1807-1807
Author(s):  
Naoto Takahashi ◽  
Masatomo Miura ◽  
Stuart Scott ◽  
Hirobumi Saitoh ◽  
Mutsuhito Motegi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
T Test ◽  
Lymphoid Leukemia ◽  
Csf Levels ◽  
Philadelphia Chromosome Positive

Abstract Abstract 1807 Dasatinib (DA) is approved for use in imatinib-resistant or intolerant chronic myeloid leukemia (CML)/Philadelphia-positive acute lymphoid leukemia (Ph+ALL) and may also be useful for central nervous system (CNS) leukemia accompanied with CML/Ph+ALL; however, little is known about the relationship between DA pharmacokinetics and its ability to penetrate the blood-brain barrier. Consequently, we measured DA plasma and cerebrospinal fluid (CSF) levels by high-performance liquid chromatography in 20 samples obtained from 11 DA-treated patients (seven Ph+ALL and four lymphoid crisis CML). DA was detected in 10 CSF samples from five patients who were treated with 100 mg QD of DA (CSF C4h of detectable group; 3.526±2.604 ng/mL, 1.11–7.95 ng/mL), which was above the IC50 level for wild type BCR-ABL positive leukemia cells in vitro (0.8 nM = 0.39 ng/mL). However, DA was not detected in 10 CSF samples from 7 patients (CSF C4h of non-detectable group; <1.0 ng/mL). The concentration ratio of CSF to plasma was 3.90% (0.42-12.23%), which approached previously reported ratios for imatinib. There were significant differences in the AUC0-4 and the plasma C4h between the CSF detectable (D) and non-detectable (ND) patients (AUC0-4: 268.29±92.452 vs. 90.83±76.45, P=0.00019 by Student t-test, Figure 1; plasma C4h: 126.15±62.58 vs. 47.41±50.935, P=0.00637 by Student t-test). Moreover, there were significant correlations between CSF C4h and AUC0-4 (P<0.01, Figure 2) and between CSF C4h and plasma C2h (P<0.001), together suggesting that penetration of DA into the CSF may depend on DA plasma concentration. To investigate any influence of pharmacogenetic variation on CSF penetration, single nucleotide polymorphisms in genes involved in DA pharmacokinetics and transport (ABCB1, ABCG2, SLC22A1, SLC22A3, and CYP3A4/5) were interrogated; however, no significant correlation between CSF levels and genotype were observed. DA has a 325 fold greater potency than imatinib for inhibiting BCR-ABL tyrosine kinase, which undoubtedly influences the efficacy of DA for Philadelphia-chromosome positive CNS leukemia; however, our data suggest that clinical DA blood level monitoring may help estimate the penetration of DA to the CSF. Disclosures: No relevant conflicts of interest to declare.

Penetration of VP 16-213 into cerebrospinal fluid after high-dose intravenous administration.

1984 ◽  
Vol 2 (3) ◽  
pp. 215-220 ◽  
Author(s):  
P E Postmus ◽  
J J Holthuis ◽  
H Haaxma-Reiche ◽  
N H Mulder ◽  
L M Vencken ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Small Cell ◽  
High Dose ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Csf Levels ◽  
Dose Levels

VP 16-213 in standard doses is active against a number of solid tumors. Its penetration into the cerebrospinal fluid (CSF) is very limited at these dose levels. In 10 patients treated with high-dose VP 16-213 (0.9-2.5 g/m2), CSF levels of up to 0.54 microgram/mL were detected. In two patients with central nervous system (CNS) metastases of small cell lung cancer (SCLC) a response was seen after 1.0 and 1.5 g/m2 intravenously. High-dose VP 16-213 can possibly play a role in the treatment of CNS metastases of SCLC. Its application in late intensification regimens as a form of prophylaxis of CNS metastases should be investigated.

Myo-inositol transport in the central nervous system

1975 ◽  
Vol 228 (5) ◽  
pp. 1510-1518 ◽  
Author(s):  
R Spector ◽  
AV Lorenzo
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
Intraventricular Injection ◽  
Affinity Constant ◽  
Rapid Injection ◽  
The Central Nervous System

Free myo-inositol (inositol) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the cerebrospinal fluid was measured in rabbits. In vivo, inositol transport from blood into choroid plexus, CSF, and brain was saturable with an apparent affinity constant (K-t) of approximately 0.1 mM. The relative turnover of free inositol in choroid plexus (16 percent/h) was higher than in CSF 4percent/h) and brain (0.3percent/h) when meausred by tissue penetration of tracer [3-H]-labeled inositol injected into blood. However, the passage of tracer inositol was not greater than the passage of mannitol into brain when measured 15 s after a rapid injection of inositol and mannitol into the left common carotid artery. From the CSF, the clearance of inositol relative to inulin was saturable after the intraventricular injection of various concentrations of inositol and inulin. Moreover, a portion of the inositol cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [3-H-labeled myo-inositol against a concentration gradient by a specific, active, saturable process with a K-t of 0.2 mM inositol. These results were interpreted as showing that the entry of inositol into the central nervous system from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

scholarly journals Cerebrospinal fluid anandamide levels, cannabis use and psychotic-like symptoms

2013 ◽  
Vol 202 (5) ◽  
pp. 381-382 ◽  
Author(s):  
Celia J. A. Morgan ◽  
Emma Page ◽  
Carola Schaefer ◽  
Katharine Chatten ◽  
Amod Manocha ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Lower Risk ◽  
Endocannabinoid System ◽  
Cannabis Use ◽  
Psychotic Symptoms ◽  
Csf Levels ◽  
Drug Free

SummaryAnandamide is a ligand of the endocannabinoid system. Animals show a depletion following repeated Δ9-tetrahydrocannabinol (THC) administration but the effect of cannabis use on central nervous system levels of endocannabinoids has not been previously examined in humans. Cerebrospinal fluid (CSF) levels of the endocannabinoids anandamide, 2-arachidonoylglycerol (2-AG) and related lipids were tested in 33 volunteers (20 cannabis users). Lower levels of CSF anandamide and higher levels of 2-AG in serum were observed in frequent compared with infrequent cannabis users. Levels of CSF anandamide were negatively correlated with persisting psychotic symptoms when drug-free. Higher levels of anandamide are associated with a lower risk of psychotic symptoms following cannabis use.

scholarly journals Polar Infection of Echovirus-30 Causes Differential Barrier Affection and Gene Regulation at the Blood–Cerebrospinal Fluid Barrier

2020 ◽  
Vol 21 (17) ◽  
pp. 6268 ◽  
Author(s):  
Marie Wiatr ◽  
Ricardo Figueiredo ◽  
Carolin Stump-Guthier ◽  
Peter Winter ◽  
Hiroshi Ishikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Expression Profiles ◽  
Choroid Plexus Papilloma ◽  
Gene Expression Profiles ◽  
Barrier Properties ◽  
Echovirus 30 ◽  
Apical Side

Echovirus-30 (E-30) is responsible for the extensive global outbreaks of meningitis in children. To gain access to the central nervous system, E-30 first has to cross the epithelial blood–cerebrospinal fluid barrier. Several meningitis causing bacteria preferentially infect human choroid plexus papilloma (HIBCPP) cells in a polar fashion from the basolateral cell side. Here, we investigated the polar infection of HIBCPP cells with E-30. Both apical and basolateral infections caused a significant decrease in the transepithelial electrical resistance of HIBCPP cells. However, to reach the same impact on the barrier properties, the multiplicity of infection of the apical side had to be higher than that of the basolateral infection. Furthermore, the number of infected cells at respective time-points after basolateral infection was significantly higher compared to apical infection. Cytotoxic effects of E-30 on HIBCPP cells during basolateral infection were observed following prolonged infection and appeared more drastically compared to the apical infection. Gene expression profiles determined by massive analysis of cDNA ends revealed distinct regulation of specific genes depending on the side of HIBCPP cells’ infection. Altogether, our data highlights the polar effects of E-30 infection in a human in vitro model of the blood–cerebrospinal fluid barrier leading to central nervous system inflammation.

scholarly journals Detection of SARS-CoV-2 nucleic acid in CSF by ultrahigh depth sequencing in a patient with COVID-19 and neurological dysfunction: a case report

2020 ◽  
Author(s):  
Pan Xiang ◽  
Xinmin Xu ◽  
Xin Lu ◽  
Lili Gao ◽  
Huizhu Wang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Nucleic Acid ◽  
Neural Progenitor Cells ◽  
Central Nervous System Infection ◽  
Neurological Dysfunction ◽  
Human Neural Progenitor Cells ◽  
The Central Nervous System

Abstract Background: SARS-Coronavirus-2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), not only infects the respiratory tract, but also other organs. About a third of the inpatients of COVID-19 have neurological symptoms and in vitro experiments revealed that SARS-CoV-2 could infect human neural progenitor cells and brain organoids. However, the traditional test often reports negative owing to the low number of virus in the cerebrospinal fluid. To date, timely diagnosis of central nervous system infection of SARS-CoV-2 remains a challenge.Case presentation: On day 14 of COVID-19, seizures, maxillofacial convulsions, intractable hiccups and significant increase in intracranial pressure developed in a 56-year-old man. The RT-PCR of SARS-CoV-2 was negative. SARS-CoV-2 nucleic acid were detected in cerebrospinal fluid (CSF) by ultrahigh depth sequencing. The patient was successfully treated after 14 days of mechanical ventilation and treatment of pneumonia and neurological dysfunction.Conclusions: This case suggests SARS-CoV-2 can invade the central nervous system and relevant examinations with CSF including ultrahigh depth sequencing of SARS-CoV-2 are needed among COVID-19 patients with neurological dysfunction.

scholarly journals Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1005-1012 ◽  
Author(s):  
Kimmo Porkka ◽  
Perttu Koskenvesa ◽  
Tuija Lundán ◽  
Johanna Rimpiläinen ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Brain Barrier ◽  
Clinical Activity ◽  
Cns Relapse ◽  
Blood Brain ◽  
Philadelphia Chromosome Positive

Abstract Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome–positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL–mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

scholarly journals Pharmacokinetic-Pharmacodynamic Contributions to the Convulsant Activity of Fluoroquinolones in Rats

1999 ◽  
Vol 43 (6) ◽  
pp. 1511-1515 ◽  
Author(s):  
Annie Delon ◽  
Serge Bouquet ◽  
Francois Huguet ◽  
Valerie Brunet ◽  
Philippe Courtois ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Experimental Approach ◽  
In Vitro Experiments ◽  
Methyl Group ◽  
The Central Nervous System

ABSTRACT The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs’ ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ’s epileptogenic risk.

Sign in / Sign up

Export Citation Format

Share Document