Translational research in central nervous system drug discovery

Hurko, Orest; Ryan, John L.

doi:10.1602/neurorx.2.4.671

Cited by 87 publications

(62 citation statements)

References 133 publications

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“…Advantages to this test selection include a direct correlate to known clinical side effects of this drug class, i.e. reaction time, and also a congruency between the 5-CSRTT and human attention tasks, including the clinical variant of this task (see Robbins 2002;Day et al 2008), which identifies a translational medicine approach to early clinical evaluation of novel AEDs (Hurko and Ryan 2005). Profiles in these tests were compared with efficacy in seizure tests conducted in the same species, to assess the relationship between AED efficacy and any cognitive effect.…”

Section: Introductionmentioning

confidence: 99%

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

et al. 2009

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These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.

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Section: Introductionmentioning

confidence: 99%

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

et al. 2009

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“…Also, short-term favorable effects may reverse over longer-term application, demonstrating that results after chronic treatment may differ from acute effects, as the CNS may respond to treatment in a very complex mode [3]. Another persisting problem is to identify an appropriate dose and schedule in the clinical trial which is both efficacious and safe, this difficulty being further aggravated if the drug candidate has a very narrow therapeutic window, and validated biomarkers are not at hand [4] [5]. Last but not least, the vasculature of the brain which forms the socalled blood-brain barrier (BBB) may serve as formidable obstacle to the entry of drugs into the brain causing CNS exposure to be insufficient for efficacy [6 -8].…”

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confidence: 99%

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

Reichel

2009

Chemistry & Biodiversity

158

133

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Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood-brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic.

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“…Nevertheless, less well-validated biomarkers can be useful if imperfect tools for internal decision-making before investment in more expensive clinical trials with registrable endpoints. Different Biomarkers could be used to address key questions along the decisionmaking path [Hurko and Ryan, 2005;Feuerstein, 2007;Feuerstein et al, 2008a,b …”

Section: How Translational Medicine Approaches Can Add Valuementioning

confidence: 99%

Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

Wan¹,

Hurko²,

Day³

et al. 2009

Drug Development Research

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Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of age-related dementia. Currently available pharmacologic therapies, including acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, only treat symptoms and do not address the underlying neurodegeneration. In addition to potentially improve the accuracy of diagnosis, biomarkers serve important roles for the development of putative disease-modifying drugs for AD. In this article, we review the existing and emerging areas of biomarker research and development for AD. Biochemical biomarkers in cerebrospinal fluid have been used to provide a link to disease pathology and may provide important proof of concept data for several classes of emerging therapeutics. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or radioligands binding to amyloid plaque are discussed. Appropriate uses of these biomarkers in the context of the development of disease-modifying therapies are discussed. Drug Dev Res 70 : 60-69, 2009.

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Translational research in central nervous system drug discovery

Cited by 87 publications

References 133 publications

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

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