Drug Delivery to the Brain by Blood-Brain Barrier Circumvention and Drug Modification

Greig, Nigel H.

doi:10.1007/978-1-4613-0701-3_12

Cited by 48 publications

(21 citation statements)

References 178 publications

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“…However, recent studies indicate the BMVEC of the BBB form a dynamic interface between the blood and the brain that can be in¯uenced by drug regimens (Bartus et al, 1996;Greig, 1989) and endogenous factors such as bradykinin (Hurst and Clark, 1998) bile salts (Greenwood et al, 1991) and cytokines (Mark and Miller, 1999). Changes in BBB function are observed in several neurological disorders associated with immune responses (i.e.…”

Section: Introductionmentioning

confidence: 99%

Immunobiology of the blood-brain barrier

Miller¹

1999

J Neurovirol

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The brain microvessel endothelial cells (BMVEC) that form the blood-brain barrier are uniquely positioned to in¯uence immune responses within the central nervous system. As the biological interface separating the blood from the brain extracellular¯uid, BMVEC regulate the entry of leukocytes into the brain. In addition, through the release of various soluble factors that affect immune responses, BMVEC may modulate immune responses in the brain. This review addresses the interplay between the immune system and the blood-brain barrier as it relates to the regulation of CNS defense and immunity.

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Section: Introductionmentioning

confidence: 99%

Immunobiology of the blood-brain barrier

Miller¹

1999

J Neurovirol

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“…However, interventional methods do have their drawbacks. Such non-specific opening of the barrier by either mechanism allows the entry of toxins and unwanted molecules, potentially resulting in significant damage (Greig, 1989). The primary disadvantage is the requirement of extremely invasive neurosurgery, thus limiting their potential.…”

Section: Nanodelivery Of Therapeutics To Central Nervous System (Cns)mentioning

confidence: 99%

Nanotechnology Based Targeted Drug Delivery: Current Status and Future Prospects for Drug Development

Sharma¹,

Singh²

2011

Drug Discovery and Development - Present and Future

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“…Use of small molecules that directly target transport proteins to overcome BBB restrictions eliminates the need for the drug to be biotransformed in brain and linking to antibodies. Lipidization can result in an undesirable pharmacokinetic profile (Greig, 1989). We have proposed to use BBB transport proteins such as the choline transporter as brain drug delivery vectors for polar drugs (Metting et al, 1998); this approach has been successful with regard to the amino acid transporter and the transport of L-DOPA and gabapentin into brain (Smith, 1993).…”

Section: Cns Drug Delivery Via the Choline Transporter 1271mentioning

confidence: 99%

“…The BBB presents drug permeation restrictions similar to a continuous cell membrane, allowing lipid-soluble molecule transport across the membrane, whereas molecules that are hydrophilic, charged, protein bound, or of large molecular weight have restricted permeation (Smith, 1990). Attempts have been made to increase brain drug delivery across the BBB either by increasing a drug's lipid solubility or by caus-ing a temporary "opening" of the BBB (Greig, 1989) using osmotic methods or specific solutes including RMP-7. Additional methods used to augment brain drug delivery include direct brain or cerebrospinal fluid injection, intracarotid infusion to maximize brain arterial concentrations, inhibition of active removal from brain, or blocking drug metabolism (Smith, 1993).…”

mentioning

confidence: 99%

Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter

Allen¹,

Lockman²,

Roder³

et al. 2002

J Pharmacol Exp Ther

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Cigarette smoking is strongly implicated in the development of cardiovascular disorders. Recently identified nicotinium analogs may have therapeutic benefit as smoking cessation therapies but may have restricted entry into the central nervous system by the blood-brain barrier (BBB) due to their physicochemical properties. Using the in situ perfusion technique, lobeline, choline, and nicotinium analogs were evaluated for binding to the BBB choline transporter. Calculated apparent K i values for the choline transporter were 1., 393 M lobeline, and Ն1000 M Nmethylnicotinium iodide. Nicotine and N-methylpyridinium iodide, however, do not apparently interact with the BBB choline transporter. Given NONI's apparent K i value determined in this study and its ability to inhibit nicotine-evoked dopamine release from superfused rat brain slices, potential brain entry of NONI via the BBB choline transporter was evaluated. [3 H]NONI exhibited a BBB transfer coefficient value of ϳ1.6 ϫ 10 Ϫ3 ml/s/g and a K m of ϳ250 M. Unlabeled choline addition to the perfusion fluid reduced [ 3 H]NONI brain uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI facilitates brain entry via the BBB choline transporter. Thus, NONI may have utility as a smoking cessation agent, given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally, and to be distributed to brain via the BBB choline transporter.

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Drug Delivery to the Brain by Blood-Brain Barrier Circumvention and Drug Modification

Cited by 48 publications

References 178 publications

Immunobiology of the blood-brain barrier

Immunobiology of the blood-brain barrier

Nanotechnology Based Targeted Drug Delivery: Current Status and Future Prospects for Drug Development

Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter

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