Faculty Opinions recommendation of Impact of manganese on and transfer across blood-brain and blood-cerebrospinal fluid barrier in vitro.

ABSTRACT Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeation and low cerebrospinal fluid (CSF) concentrations but is effective in the treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro blood-brain barrier (BBB) model was serially infected with Candida albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml was then provided, and the vascular and CNS compartments were sampled 4 h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB at 1 mg/kg of body weight or LAMB at 5 mg/kg and were euthanized after 1, 3, 6, and 24 h. Evans blue dye solution (2%, 2 ml/kg) administered intravenously (i.v.) at 1 h prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using ultraperformance liquid chromatography. For selected rabbits, magnetic resonance imaging (MRI) scans performed on days 1 to 7 postinoculation were acquired before and after i.v. bolus administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) at 15-min intervals through 2 h postinjection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24 h of exposure (P = 0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35 ± 0.59 and 3.14 ± 0.89 times higher, respectively, than those in normal tissue (P ≤ 0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with a disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low cerebrospinal fluid concentrations.

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Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship withCYP2B6c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00280-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4511-4518 ◽

Cited By ~ 10

Author(s):

Sam Nightingale ◽

Tran Thi Hong Chau ◽

Martin Fisher ◽

Mark Nelson ◽

Alan Winston ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Neuronal Damage ◽

Brain Barrier ◽

Barrier Integrity ◽

Blood Brain ◽

Toxic Concentration ◽

Metabolite Concentrations ◽

Blood Brain Barrier Integrity

ABSTRACTEfavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxinin vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available publishedin vitroandin vivodata. The effect of theCYP2B6c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above thein vitrotoxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above thein vitrotoxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of theCYP2B6genotype, particularly in those with impaired blood-brain barrier integrity.

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