The blood-brain barrier: Bottleneck in brain drug development

Pardridge, William M.

doi:10.1007/bf03206638

Cited by 416 publications

(586 citation statements)

References 70 publications

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“…Indeed, both small molecules and macromolecular agents potentially useful for the treatment of neurologic diseases do not penetrate the intact BBB (Pardridge, 2005;Meairs and Alonso, 2007). Experimental studies indicate that ultrasound might be useful for local delivery of drugs to the brain because of its ability to transiently open the BBB (Hynynen et al, 2001;McDannold et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Reorganization of Gap Junctions after Focused Ultrasound Blood–Brain Barrier Opening in the Rat Brain

Alonso

Reinz

Jenne

et al. 2010

J Cereb Blood Flow Metab

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Ultrasound-induced opening of the blood-brain barrier (BBB) is an emerging technique for targeted drug delivery to the central nervous system. Gap junctions allow transfer of information between adjacent cells and are responsible for tissue homeostasis. We examined the effect of ultrasoundinduced BBB opening on the structure of gap junctions in cortical neurons, expressing Connexin 36, and astrocytes, expressing Connexin 43, after focused 1-MHz ultrasound exposure at 1.25 MPa of one hemisphere together with intravenous microbubble (Optison, Oslo, Norway) application. Quantification of immunofluorescence signals revealed that, compared with noninsonicated hemispheres, small-sized Connexin 43 and 36 gap-junctional plaques were markedly reduced in areas with BBB breakdown after 3 to 6 hours (34.02 ± 6.04% versus 66.49 ± 2.16%, P = 0.02 for Connexin 43; 33.80 ± 1.24% versus 36.77 ± 3.43%, P = 0.07 for Connexin 36). Complementing this finding, we found significant increases in large-sized gap-junctional plaques (5.76 ± 0.96% versus 1.02 ± 0.84%, P = 0.05 for Connexin 43; 5.62 ± 0.22% versus 4.65 ± 0.80%, P = 0.02 for Connexin 36). This effect was reversible at 24 hours after ultrasound exposure. Western blot analyses did not show any change in the total connexin amount. These results indicate that ultrasound-induced BBB opening leads to a reorganization of gap-junctional plaques in both neurons and astrocytes. The plaque-size increase may be a cellular response to imbalances in extracellular homeostasis after BBB leakage.

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Section: Introductionmentioning

confidence: 99%

Reorganization of Gap Junctions after Focused Ultrasound Blood–Brain Barrier Opening in the Rat Brain

Alonso

Reinz

Jenne

et al. 2010

J Cereb Blood Flow Metab

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“…Despite its enormous surface area, the BBB lacks intercellular cleft and fenestrae and significantly restricts the entry of solutes to the brain from the periphery. Its low permeability is attributed, in large part, to BMVEC, which forms tight junctions and have low pinocytic activity [17,83,84]. Some relatively lipophilic and low molecular weight substances can transport across the BMVEC by passive diffusion.…”

Section: Barriers To Cns Drug Deliverymentioning

confidence: 99%

“…This is not a simple task. Indeed, the BBB represents a significant impediment for drug delivery due to its structure and functional complexities [17]. Entry of low molecular weight compounds and biomacromolecules are significantly restricted in entering the brain and include imaging contrast agents, drugs, nucleic acids, and proteins representing a major bottleneck in the development of efficacious and safe treatment and diagnostic modalities.…”

Section: Introductionmentioning

confidence: 99%

“…Although extensive reviews on drug delivery to the brain have emerged in recent years [17,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] none describes the recent and significant works that employ cell and polymer-based nanomaterials in CNS delivery. In this regard, balanced discussions are made to describe disease processes and needs together with new research efforts made in nanomedicine.…”

Section: Introductionmentioning

confidence: 99%

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Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Kabanov

Gendelman

2007

Progress in Polymer Science

242

138

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Neurodegenerative and infectious disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population's age. Alzheimer's disease alone currently affects 4.5 million Americans, and more than $100 billion is spent per year on medical and institutional care for affected people. Such numbers will double in the ensuing decades. Currently disease diagnosis for all disorders is made, in large measure, on clinical grounds as laboratory and neuroimaging tests confirm what is seen by more routine examination. Achieving early diagnosis would enable improved disease outcomes. Drugs, vaccines or regenerative proteins present "real" possibilities for positively affecting disease outcomes, but are limited in that their entry into the brain is commonly restricted across the blood-brain barrier. This review highlights how these obstacles can be overcome by polymer science and nanotechnology. Such approaches may improve diagnostic and therapeutic outcomes. New developments in polymer science coupled with cell-based delivery strategies support the notion that diseases that now have limited therapeutic options can show improved outcomes by advances in nanomedicine.

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“…Additionally, when the targeted site of action lies within the CNS, the BBB represents a relevant barrier for the access of compounds to the target organ and it is frequently responsible for the relatively low success rate in discovery and development of CNS drugs (Partridge, 2005). For instance, in vitro it was demonstrated that BIA 2-024 had a higher potency to bind to sodium channels and modulate sodium entry than CBZ.…”

mentioning

confidence: 99%

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: New set of data for predictive in silico ADME models

et al. 2013

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Please cite this article as: Fortuna, A., Alves, G., Soares-da-Silva, P., Falcão, A., Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models, Epilepsy Research (2013), http://dx.doi.org/10.1016/j.eplepsyres. 2013.08.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractIn silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programs. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models.For this purpose, a single dose of each compound (1.4 mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12 h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure.The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC 0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (> 0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05-0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma-protein bound fraction (> 90%) herein revealed for the first time.The comparative ...

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The blood-brain barrier: Bottleneck in brain drug development

Cited by 416 publications

References 70 publications

Reorganization of Gap Junctions after Focused Ultrasound Blood–Brain Barrier Opening in the Rat Brain

Reorganization of Gap Junctions after Focused Ultrasound Blood–Brain Barrier Opening in the Rat Brain

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: New set of data for predictive in silico ADME models

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