Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

PURPOSE: This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. METHODS: Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. RESULTS: Twenty-two patients (14 men and 8 women; mean age of 52.6± 12.1 years) were recruited. The vancomycin Cmin was 3.63 ± 1.64 mg/L in CSF and 13.38 ± 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 ± 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). CONCLUSIONS: There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats

Epilepsy Research ◽

10.1016/j.eplepsyres.2003.12.007 ◽

2004 ◽

Vol 58 (2-3) ◽

pp. 85-91 ◽

Cited By ~ 70

Author(s):

Heidrun Potschka ◽

Steffen Baltes ◽

Wolfgang Löscher

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Multidrug Transporters ◽

Blood Brain ◽

Barrier Penetration

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Holey barrier

The Journal of Cell Biology ◽

10.1083/jcb.200304039 ◽

2003 ◽

Vol 161 (3) ◽

pp. 459-460 ◽

Cited By ~ 68

Author(s):

Karl Matter ◽

Maria S. Balda

Keyword(s):

Small Molecules ◽

Blood Brain Barrier ◽

Transmembrane Protein ◽

Brain Barrier ◽

Brain Endothelial Cell ◽

Critical Determinant ◽

Blood Brain ◽

Functional Part ◽

Selective Diffusion ◽

Selective Increase

Endothelial tight junctions (TJs)**Abbreviations used in this paper: BBB, blood-brain barrier; BEC, brain endothelial cell; TJ, tight junction. are an important functional part of the blood-brain barrier (BBB). In this issue, Nitta et al. (2003) demonstrate that claudin-5, a transmembrane protein of TJs, is a critical determinant of BBB permeability in mice. Unexpectedly, knockout of claudin-5 did not result in a general breakdown of TJs but in a selective increase in paracellular permeability of small molecules. This suggests that the BBB can be manipulated to allow selective diffusion of small molecules and makes claudin-5 a possible target for the development of drugs for this purpose.

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