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Deguchi, Yoshiaki; Inabe, Kazimori; Tomiyasu, Koichi; Nozawa, Kenji; Yamada, Shizuo; Kimura, Ryohei

doi:10.1023/a:1016263032765

Cited by 71 publications

(17 citation statements)

References 17 publications

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“…Therefore, the brain extracellular concentration may not be equal to the CSF concentration, when active transporters are involved in the brain distribution. For example, the concentrations of probenecid and salicylate were 2-to 3-fold higher in CSF than in the brain extracellular brain concentrations (ECF) in rats [187]. The lower extracellular brain concentrations of probenecid and salicylate might be due to efflux transport from the brain to plasma, probably mediated by the monocarboxylic acid transport system at the BBB.…”

Section: Other Methods For Unbound Drug Measurementmentioning

confidence: 98%

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.

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Section: Other Methods For Unbound Drug Measurementmentioning

confidence: 98%

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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“…C17.2 is an immortalized mouse neural progenitor cell line established by retroviral-mediated transduction of the avian myc oncogene into mitotic progenitor cells of neonatal mouse cerebellum, and an important model system in studies of neural regeneration. [9] , [11] , [12] , [59] – [67] C17.2 NSCs have shown the ability to successfully integrate into the central nervous system of animals used as disease models for Parkinson’s, stroke and Alzheimer’s. [9] – [12] Both in vivo and in vitro studies also demonstrate that C17.2 NSCs undergo neuronal cell differentiation under nutrient depletion, [11] , [12] , [59] – [61] , [64] which makes them an appropriate cellular model for this work.…”

Section: Introductionmentioning

confidence: 99%

Maintenance and Neuronal Cell Differentiation of Neural Stem Cells C17.2 Correlated to Medium Availability Sets Design Criteria in Microfluidic Systems

2014

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BackgroundNeural stem cells (NSCs) play an important role in developing potential cell-based therapeutics for neurodegenerative disease. Microfluidics has proven a powerful tool in mechanistic studies of NSC differentiation. However, NSCs are prone to differentiate when the nutrients are limited, which occurs unfavorable by fast medium consumption in miniaturized culture environment. For mechanistic studies of NSCs in microfluidics, it is vital that neuronal cell differentiation is triggered by controlled factors only. Thus, we studied the correlation between available cell medium and spontaneous neuronal cell differentiation of C17.2 NSCs in standard culture medium, and proposed the necessary microfluidic design criteria to prevent undesirable cell phenotype changes.Methodology/Principal FindingsA series of microchannels with specific geometric parameters were designed to provide different amount of medium to the cells over time. A medium factor (MF, defined as the volume of stem cell culture medium divided by total number of cells at seeding and number of hours between medium replacement) successfully correlated the amount of medium available to each cell averaged over time to neuronal cell differentiation. MF smaller than 8.3×104 µm3/cell⋅hour produced significant neuronal cell differentiation marked by cell morphological change and significantly more cells with positive β-tubulin-III and MAP2 staining than the control. When MF was equal or greater than 8.3×104 µm3/cell⋅hour, minimal spontaneous neuronal cell differentiation happened relative to the control. MF had minimal relation with the average neurite length.Significance MFs can be controlled easily to maintain the stem cell status of C17.2 NSCs or to induce spontaneous neuronal cell differentiation in standard stem cell culture medium. This finding is useful in designing microfluidic culture platforms for controllable NSC maintenance and differentiation. This study also offers insight about consumption rate of serum molecules involved in maintaining the stemness of NSCs.

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“…25,44 On the other hand, its distribution is restricted because baclofen is effluxed by the organic anion transporters. 24,25 The pharmaceutical is a racemic mixture, but it was resolved and the (R)-(-)-enantiomer is substantially more active than the other enantiomer. 45 For example, (R)-(-)-baclofen inhibits binding of [ 3 H]baclofen to GABA B receptors in cat cerebellum with IC 50 = 0.015 µM but (S)-(+)-baclofen inhibits with IC 50 = 1.77 µM in this assay (100-fold difference in potency).…”

Section: Agonists and Antagonistsmentioning

confidence: 99%

“…23 Despite its FDA approval for the treatment of muscle spasticity and a growing number of off-label and potential uses, baclofen is far from an ideal drug molecule. Baclofen has low penetration into the brain, 24 a property which may be ascribed to transport out of the brain via the organic acid transporter. 25 Additionally, baclofen has a short duration of action, a narrow therapeutic window, and a rapid tolerance.…”

Section: Introductionmentioning

confidence: 99%

Activation of the γ-Aminobutyric Acid Type B (GABA_B) Receptor by Agonists and Positive Allosteric Modulators

et al. 2015

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Since the discovery of the GABA(B) agonist and muscle relaxant baclofen, there have been substantial advancements in the development of compounds that activate the GABA(B) receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure-activity data apply to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and structure-activity relationships are less well-defined; however, multiple classes of molecules have been discovered. The recent report of the X-ray structure of the GABA(B) receptor with bound agonists and antagonists provides new insights for the development of compounds that bind the orthosteric site of this receptor. From a therapeutic perspective, these data have enabled efforts in drug discovery in areas of addiction-related behavior, the treatment of anxiety, and the control of muscle contractility.

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Abstract: The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.

Cited by 71 publications

References 17 publications

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Maintenance and Neuronal Cell Differentiation of Neural Stem Cells C17.2 Correlated to Medium Availability Sets Design Criteria in Microfluidic Systems

Activation of the γ-Aminobutyric Acid Type B (GABA_B) Receptor by Agonists and Positive Allosteric Modulators

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Untitled

Abstract: The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.

Cited by 71 publications

References 17 publications

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Maintenance and Neuronal Cell Differentiation of Neural Stem Cells C17.2 Correlated to Medium Availability Sets Design Criteria in Microfluidic Systems

Activation of the γ-Aminobutyric Acid Type B (GABAB) Receptor by Agonists and Positive Allosteric Modulators

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Activation of the γ-Aminobutyric Acid Type B (GABA_B) Receptor by Agonists and Positive Allosteric Modulators