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Blood–brain barrier properties of human immunodeficiency virus antiretrovirals

The extent of brain delivery expressed as steady-state brain/blood distribution ratio (log BB) is the most frequently used parameter for characterizing central nervous system exposure of drugs and drug candidates. The aim of the current study was to propose a physicochemical QSAR model for log BB prediction. Model development involved the following steps: (i) A data set consisting of 470 experimental log BB values determined in rodents was compiled and verified to ensure that selected data represented drug disposition governed by passive diffusion across blood–brain barrier. (ii) Available log BB values were corrected for unbound fraction in plasma to separate the influence of drug binding to brain and plasma constituents. (iii) The resulting ratios of total brain to unbound plasma concentrations reflecting brain tissue binding were described by a nonlinear ionization-specific model in terms of octanol/water log P and pK_a. The results of internal and external validation demonstrated good predictive power of the obtained model as both log BB and brain tissue binding strength were predicted with residual mean square error of 0.4 log units. The statistical parameters were similar among training and validation sets, indicating that the model is not likely to be overfitted. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2147–2160, 2011

Poly(lactic acid) (PLA)/chitosan (CS) nanoparticles were prepared by emulsion method for anti-HIV drug delivery applications. The prepared PLA/CS nanoparticles were characterized using DLS, SEM, and FTIR. The hydrophilic antiretroviral drug Lamivudine was loaded into PLA/CS nanoparticles. The encapsulation efficiency and in-vitro drug release behaviour of drug loaded PLA/CS nanoparticles were studied using UV spectrophotometer. In addition, the cytotoxicity of the PLA/CS nanoparticles using MTT assay was also studied. The in-vitro drug release studies showed that drug release rate was lower in the acidic pH when compared to alkaline pH. This may due to repulsion between H⁺ ions and cationic groups present in the polymeric nanoparticles. Drug release rate was found to be higher in the 6% drug loaded formulation when compared to 3% drug loaded formulation. These results indicated that the PLA/CS nanoparticles are a promising carrier system for controlled delivery of anti-HIV drugs.

Neurodevelopmental abnormalities associated with HIV infection have been described since the first reports of pediatric AIDS in the 1980s. Before antiretroviral therapy (ART) became widely available, progressive HIV-1 encephalopathy (PHE) was reported in the US in 13–35% of children with HIV-1 infection and in 35–50% of children with AIDS. Introduction of ART can prevent PHE and reverse PHE present at ART initiation, but a high prevalence of residual problems has been described. Even though 90% of HIV-infected children live in the developing world, few children have access to ART and little is known regarding the neurological manifestations of perinatal HIV infection in those regions.

Mechanisms of pediatric HIV-1 neuropathogenesis and factors associated with neurodevelopmental abnormalities in perinatally infected children are not yet fully understood. Studies have demonstrated that HIV-1 enters the CNS soon after infection and may persist in this compartment over the entire course of HIV-1 infection. The CNS is a distinct viral reservoir, differing from peripheral compartments in target cells and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique environment.

We reviewed the literature on pediatric neuroAIDS and identified gaps in the current knowledge.

The objective of this study was to evaluate the ability of ΔG, the 12 kDa active fragment of ZOT, to increase the brain distribution of MTX and paclitaxel, two commonly used anticancer agents with poor distribution into the brain.

As part of dose estimation of ΔG, [¹⁴C]-sucrose (40 μCi/kg), a hydrophilic paracellular marker, was co-administered with ΔG (0, 400 and 800 μg/kg) with and without protease inhibitors to male Sprague–Dawley rats (n = 3 per group) via an intracarotid cannula. MTX (50 mg/kg) and [³H]-paclitaxel (120 μCi/kg) were co-administered with the effective doses of ΔG determined from the above study via the intracarotid cannula. Animals were euthanized by carbon dioxide asphyxiation at the specified time periods and brain and plasma samples were analyzed for the respective drug.

The brain distribution of [¹⁴C]-sucrose was significantly enhanced at both doses of ΔG. A fold enhancement in the B/P ratios of 1.88 and 2.68 was observed at the 400 and 800 μg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. ΔG significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 μg/kg dose. [³H]-paclitaxel brain AUC_0–60 min was significantly higher in the presence of ΔG (800 μg/kg with PIs) with a 2.5-fold enhancement in brain exposure.

ΔG significantly enhances the brain distribution of MTX (hydrophilic) and paclitaxel (lipophilic) and has the potential to be further developed as adjunct therapy to increase delivery of poorly permeable chemotherapeutic and other CNS targeted compounds.

The blood–brain barrier (BBB) is composed of several components that serve to restrict the passage of compounds between the brain and systemic circulation. The monolayer of endothelial cells comprising the brain capillary is one of the primary components of the BBB. To characterize the properties of this barrier, several in vitro models have been developed. The focus of this review is to present an introduction to the BBB and a brief history of the development of the in vitro models used to investigate the molecular and cellular significance of the barrier. Also presented is a description of the procedures associated with the isolation, culturing, maintenance, and properties of the three most utilized primary culture models: bovine, rat, and porcine. The relevance of the use of astrocyte cocultures with these models is also addressed. Finally, experimental applications of the bovine brain microvessel endothelial cell models and the future of the in vitro models are discussed.

Objectives: This study evaluated the effect of treatment with abacavir/lamivudine/zidovudine versus lamivudine/zidovudine on cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA and clinical manifestations of HIV encephalopathy in children. Study design: HIV-infected children 7 months to 10 years of age (n = 23) were studied. CSF and plasma were obtained at baseline and weeks 8, 16, and 48. Genotype analysis of HIV was attempted at baseline and week 48. Neurologic evaluations were performed at baseline and weeks 16, 32, and 48. Results: At baseline, 83% of children had >2.00 log₁₀ copies/mL HIV RNA in CSF, but only 10% had HIV RNA measurable at week 48. Among children in whom paired genotyping of HIV was possible, 8 of 11 had identical patterns in both CSF and plasma at baseline, whereas at week 48, only 1 of 9 children had similar patterns. Neurologic abnormalities were observed in 83% of children at baseline but only 35% of children at week 48 (P =.004), suggesting a benefit of treatment. Conclusions: Antiretroviral therapy was associated with a decline in CSF HIV RNA and an improvement in neurologic status. The development of genotypic mutations was different in CSF and plasma, suggesting discordant viral evolution. These results suggest that antiretroviral treatment in children should include agents with activity in the CNS. (J Pediatr 2002;141:36-44)