An active transport system in the blood–brain barrier may reduce levodopa availability

Hawkins, Richard A.; Mokashi, Ashwini; Simpson, Ian A.

doi:10.1016/j.expneurol.2005.04.008

Cited by 47 publications

(25 citation statements)

References 26 publications

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“…Though L-DOPA is neutral, the activity of Na + -dependent amino acid transporter, such as System B 0 , may be stimulated as a result of increases in transmembrane potential due to increases in Na + -K + -ATPase activity. These results fit well with recent evidence describing the presence at the level of the blood-brain barrier of Na + -dependent transport of large neutral amino acids and L-DOPA (O'Kane and Hawkins, 2003;Hawkins et al, 2005). Most likely, the Na + -dependent transport of large neutral amino acids and L-DOPA described at the level of the bloodbrain barrier is also presence at the kidney level.…”

Section: Discussionsupporting

confidence: 90%

Increases in transepithelial vectorial Na+ transport facilitates Na+-dependent l-DOPA transport in renal OK cells

2006

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Section: Discussionsupporting

confidence: 90%

Increases in transepithelial vectorial Na+ transport facilitates Na+-dependent l-DOPA transport in renal OK cells

2006

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“…Although some cell line models are available now which have been thoroughly characterized in terms of their transporter functions [181], they have not managed to get broader acceptance in industry, at least in part because of low confidence in their predictivity of the carrier-mediated route for the human situation and the unknown and probably variable efficiency of that route in patients. The complexity of the factors to consider for carrier-mediated drug delivery to become safe and effective in the clinic is high, ranging from continuously changing levels of the circulating endogenous substrates leading to variable and poorly predictable drug-endogenous substrate interactions, to potential disturbances of brain nutrient homeostasis and possible adverse effects on essential brain metabolic functions and even food effects [129,317].…”

Section: Cns Programsmentioning

confidence: 99%

The Role of Blood-Brain Barrier Studies in the Pharmaceutical Industry

Reichel¹

2006

CDM

127

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The blood-brain barrier (BBB) remains one of the greatest challenges for the discovery and development of treatments for CNS disorders, which to this day remains one of the riskiest disease areas in terms of clinical success rates. Although the BBB is currently seen predominantly as a permeability obstacle for CNS drug delivery, it is becoming increasingly clear that the BBB has many more implications for the pharmaceutical industry impacting on CNS pharmacology and pathology, CNS pharmacokinetics and pharmacodynamics, and adverse CNS effects, to name but a few areas. The present review does not intend to summarize the activities in the field of BBB research per se, which has been accomplished by a number of excellent recent reviews, but instead to provide an overview of the role of BBB studies from a pharmaceutical industry perspective. This review will elaborate on the specific needs in terms of BBB-related issues across the different drug discovery and development phases, i.e. target identification and validation, lead generation and optimization, candidate selection and profiling, preclinical development and clinical studies. The specific approaches taken will be discussed in terms of specific requirements, questions to be asked, feasibility, interpretability, and impact. It becomes clear that few of the existing BBB models fully meet the requirements of the industrialized drug discovery process, highlighting the need for an array of new or modified tools and approaches that are more effective in helping make decisions which are more specifically tailored to the various stages of the lengthy process from target to the clinic. In looking at the numerous ongoing activities in the area of BBB research from the drug discovery and development point of view, an attempt has been made to place a stronger emphasis on the applicability of particular techniques and approaches, to identify gaps and areas for future activities. In order to materialize the considerable knowledge gained in recent years, the review is intended to foster an increased awareness of the need to better integrate basic academic research with the specific requirements of the pharmaceutical industry for the search of effective and safe new CNS medicines.

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“…Likewise, l -DOPA and other dopaminergic drugs enter the brain through selective transporters, 15,16 but can also be pumped out of the brain. 17 The transporter functioning is in part dependent from electrolyte gradients across the cell membrane. 17 Of note, disturbed electrolyte homeostasis may parallel systemic infections, and is concomitantly a precipitating factor for akinetic crisis.…”

Section: Altered Dopamine Metabolism and Receptor Signalingmentioning

confidence: 99%

Why is there motor deterioration in Parkinson’s disease during systemic infections-a hypothetical view

Brugger

Erro

Balint

et al. 2015

npj Parkinson's Disease

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Clinicians are well aware of the fact that patients with Parkinson’s disease may significantly deteriorate following a systemic infection or, in its most severe case, may even develop an akinetic crisis. Although this phenomenon is widely observed and has a major impact on the patients’ condition, the knowledge about the underlying mechanisms behind is still sparse. Possible explanations encompass changes in the pharmacodynamics of the dopaminergic drugs, altered dopamine metabolism in the brain, alterations in the dopaminergic transmission in the striatum or an enhancement of neurodegeneration due to remote effects of peripheral inflammatory processes or circulating bacterial toxins. This article provides possible explanatory concepts and may hence support formulating hypothesis for future studies in this field.

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An active transport system in the blood–brain barrier may reduce levodopa availability

Cited by 47 publications

References 26 publications

Increases in transepithelial vectorial Na+ transport facilitates Na+-dependent l-DOPA transport in renal OK cells

Increases in transepithelial vectorial Na+ transport facilitates Na+-dependent l-DOPA transport in renal OK cells

The Role of Blood-Brain Barrier Studies in the Pharmaceutical Industry

Why is there motor deterioration in Parkinson’s disease during systemic infections-a hypothetical view

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