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Myotonia Therapy Through Nav Channel...

Chen, Pearl Beier.

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Myotonia Therapy Through Nav Channel Slow Inactivation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Myotonia Therapy Through Nav Channel Slow Inactivation./
作者:	Chen, Pearl Beier.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	146 p.
附註:	Source: Dissertation Abstracts International, Volume: 79-09(E), Section: B.
Contained By:	Dissertation Abstracts International79-09B(E).
標題:	Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10682079
ISBN:	9780355972405

Myotonia Therapy Through Nav Channel Slow Inactivation.
Chen, Pearl Beier.

Myotonia Therapy Through Nav Channel Slow Inactivation. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 146 p.

Source: Dissertation Abstracts International, Volume: 79-09(E), Section: B.

Thesis (Ph.D.)--University of California, Davis, 2018.

Myotonia is a heritable defect in muscle relaxation that has been described for well over a century. It is caused by a reduced chloride conductance due to mutations in the gene encoding the skeletal muscle chloride channel, CLCN1, or increased sodium channel activity from mutations in the gene encoding the skeletal muscle sodium channel, SCN4A. Patients with myotonia present with muscle stiffness after initiating movement and difficulty relaxing myotonic muscles. In addition to the ramifications of compromised motor performance, myotonia patients also report depression, substance abuse and suicidal ideation. FDA-approved therapy is non-existent, forcing patients to rely on off-label alternatives originally intended to treat cardiac arrhythmia and epilepsy. Treatment-emergent adverse effects, incomplete control and waning of the therapeutic effect with repeated use further complicate the situation. Pharmacological intervention, therefore, is imperative to reduce the risk of accidents as well as to limit dangerous self-medication.

ISBN: 9780355972405Subjects--Topical Terms:

518431
Physiology.

Myotonia Therapy Through Nav Channel Slow Inactivation.
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500 $a Adviser: Michael A. Rogawski.
502 $a Thesis (Ph.D.)--University of California, Davis, 2018.
520 $a Myotonia is a heritable defect in muscle relaxation that has been described for well over a century. It is caused by a reduced chloride conductance due to mutations in the gene encoding the skeletal muscle chloride channel, CLCN1, or increased sodium channel activity from mutations in the gene encoding the skeletal muscle sodium channel, SCN4A. Patients with myotonia present with muscle stiffness after initiating movement and difficulty relaxing myotonic muscles. In addition to the ramifications of compromised motor performance, myotonia patients also report depression, substance abuse and suicidal ideation. FDA-approved therapy is non-existent, forcing patients to rely on off-label alternatives originally intended to treat cardiac arrhythmia and epilepsy. Treatment-emergent adverse effects, incomplete control and waning of the therapeutic effect with repeated use further complicate the situation. Pharmacological intervention, therefore, is imperative to reduce the risk of accidents as well as to limit dangerous self-medication.
520 $a The goal of this study was to establish a drug screen program toward FDA-approved myotonia therapy. While classical Nav channel blockers such as mexiletine modulate fast inactivation, we sought to also target Na v channel slow inactivation, a natural safety switch that is activated during periods of prolonged cellular excitation to reduce the pool of available Nav channels. Lacosamide (LCM), one of the most prescribed and successful antiepileptic drug worldwide, was later discovered to target Na v channels and enhance slow inactivation (P. L. Sheets et al., 2008). Preliminary studies conducted in our lab discovered that LCM was extremely effective in terminating myotonic hyperactivity in isolated muscle. Based on LCM's success in vitro, we identified 3 other FDA-approved compounds (ranolazine, zonisamide and licarbazepine) suspected of modulating slow inactivation as well as 4 proprietary compounds derived from LCM. These proprietary compounds were developed by Dr. Harold Kohn, the father of LCM, and demonstrated the highest anticonvulsant activity (>35-fold) by slow inactivation enhancement out of the many proprietary compounds developed. By pharmacologically enhancing Nav channel slow inactivation instead of interfering with core channel function (mexiletine), we proposed that these slow inactivation enhancers (SIEs) provide better drug performance and improved tolerability in treating myotonia.
520 $a We began testing of our SIEs on isolated skeletal muscle to determine their antimyotonic properties in vitro (Chapter II). These results were compared to mexiletine and carbamazepine, two well-known Na v channel blockers that increase fast inactivation activity. Myotonia was quantified by measuring the muscle's time to relaxation, in which myotonic muscle exhibited delayed relaxation time. Antimyotonic activity was exhibited when an SIE significantly reduces muscle relaxation time.
520 $a Based on our in vitro results, we identified LCM and ranolazine (RNZ) with the most potent antimyotonic properties for testing in an in vivo myotonia model (Chapter III). To that end, we develop a new in vivo myotonia model by injecting 9-anthracenecarboxylic acid (9-AC), a ClC-1 blocker capable of inducing myotonia, into mice. This new, chemically induced in vivo myotonia model can be a direct alternative to the available genetically myotonic mouse models, which are difficult to breed. By injecting LCM and RNZ into the chemically induced myotonia model, our in vivo results confirmed the force myography findings, although LCM was found to be highly toxic at higher dosages.
520 $a Because our SIEs have been FDA-approved for epilepsy and cardiac problems, they were screened to identify any CNS toxicity and cardiac safety issues present at dosages clinically relevant in treating myotonia (Chapter IV). We presented methods utilizing in vitro cardiotoxicity assay based on iPSC-derived cardiomyocytes and in silico blood-brain-barrier (BBB) analysis to determine BBB permeability and, by extension, CNS toxicity. Our results indicated cardiotoxicity at high concentrations and moderate-to-high permeability for all our compounds of interest, with NGT-125 showing the lowest BBB permeability and RNZ demonstrating a safe cardiac profile.
520 $a Finally, we biophysically characterized the action of zonisamide (ZNS), a compound of interest, on skeletal muscle Nav1.4 channels in order to discover how the drug alters Nav1.4 gating. We used whole-cell voltage clamp recording to examine heterologously expressed Nav1.4 channel behavior in the presence and absence of ZNS (Chapter V). By elucidating the drug's mechanism of action in Nav channel block, we determined that ZNS primarily mediated Nav1.4 activity in a concentration- and use-dependent manner by reducing steady-state availability and enhancing fast inactivation, while slow inactivation was unaffected. Based on our experiments, there appear to be a correlation between a compound's SIE properties and its antimyotonic efficacy, such that RNZ, LCM and NGT-125, the most successful candidates, were SIEs. (Abstract shortened by ProQuest.).
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