Name: trans-tympanic drug delivery for the treatment of ototoxicity
Uploaded: 2018-03-16T12:30:00
Description: Watch this Scientific Journal Video about Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity at JoVE.com

Het werk in dit artikel beschreven werd gesteund door een NCI RO1 CA166907, NIDCD RO1-DC 002396 en RO3 DC011621.

Mannelijke Wistar ratten werden behandeld in overeenstemming met het National Institutes of Health dier gebruiken richtlijnen en een protocol goedgekeurd door de Southern Illinois University School van geneeskunde Laboratory Animal Care en Comité gebruiken. Auditieve brainstem response (ABR) werd uitgevoerd op ratten terwijl onder verdoving vóór drug administration en 72 uur na om te controleren of het effect van de trans-tympanic drug levering.
1. auditieve Brainstem Response (ABR)
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<ol>
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De route van de trans-tympanic administratie zorgt voor gelokaliseerde levering van drugs en andere agenten aan het slakkenhuis die significante systemische bijwerkingen als systemisch toegediend anders kon produceren. Deze wijze van toediening van de drug biedt snelle toegang van drugs op de site van actie bij aanzienlijk hogere doseringen dan zou kunnen worden bereikt door de systemische route. Resultaten hier gepresenteerd en gepubliceerd eerder toonden aan dat trans-tympanic beheer van [R] - N - fenyl isopro...

Het perifere auditieve systeem is prachtig gevoelig voor drugs zoals cisplatine en aminoglycoside antibiotica. Cisplatine is een veel gebruikte chemotherapeutische agent voor de behandeling van een verscheidenheid van solide tumoren, zoals ovariële testiculaire en hoofd en nek kanker. Ototoxiciteit ervaren met het gebruik van deze drug is dosis-beperken en vrij gemeenschappelijk,1treft 75-100 procent van de patiënten behandeld. Andere drugs, zoals carboplatin en oxaliplatin, opgedoken als alternatieven voor cisplatine2,,3,,4,5, maar het nut ervan is beperkt tot een paar kankers.
Vroege studies hebben de kritische rol van reactieve zuurstof soorten (ROS) in het bemiddelen van de ototoxiciteit geproduceerd door cisplatine en aminoglycosiden aangetoond. Latere studies is gebleken dat de NOX3 isovorm van NADPH oxidase de primaire bron van ROS in het slakkenhuis is, en wordt geactiveerd door cisplatine6,7. De generatie van ROS compromissen verhoogde de antioxidant buffercapaciteit van cellen, wat leidt tot lipide peroxidatie van cellulaire membranen8. Bovendien, cisplatine verhoogt de productie van hydroxyl radicalen die zeer toxische aldehyde 4-hydroxynonenal (4-HNE), initiator van9,10van de dood van de cel genereren. Op basis van deze bevindingen, verschillende antioxidanten onderzocht voor de behandeling van cisplatine ototoxiciteit. Het gaat hierbij om N-acetyl-cysteïne (NAC), natrium thiosulfate (STS), amifostine en D-methionine. Een grote zorg van antioxidant therapie is echter dat deze antioxidanten cisplatine chemotherapeutische werkzaamheid bij toediening systemisch11 door de interactie van cisplatine met thiol-groepen in de antioxidant moleculen kunnen verminderen.
Met het oog op deze problemen met antioxidant therapie was het doel van deze studie om de trans-tympanic route antioxidanten en andere drugs te leveren aan het slakkenhuis om verlies van het gehoor te controleren. De trans-tympanic route van drugs- en korte inmenging (si) RNA, hieronder beschreven, lijkt veelbelovend.

<table border="0" cellpadding="0" cellspacing="0" style="width:1025px;" width="1025">
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		<tr height="19">
			<td height="19" style="height:19px;width:423px;">Ketathesia (100 mg/ml) 10 ml</td>
			<td style="width:192px;">Henry Schein</td>
			<td style="width:127px;">56344</td>
			<td style="width:284px;">Controlled substance&#160;</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">AnaSed Injection/Xylazine (20 mg/ml) 20 ml</td>
			<td>Henry Schein</td>
			<td>33197</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">2.5 mm disposable ear specula</td>
			<td>Welch Allyn</td>
			<td>52432</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Surgical Scope</td>
			<td>Zeiss</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">29 G X 1/2 insulin syringe</td>
			<td>Fisher Scientific</td>
			<td>14-841-32&#160;</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">cis-Diammineplatinum(II) dichloride</td>
			<td>Sigma Aldrich</td>
			<td>P4394</td>
			<td>TOXIC - wear proper PPE</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Harvard 50-7103 Homeothermic Blanket Control Unit</td>
			<td>Harvard Apparatus</td>
			<td>Series 863</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Excel International 21 G X 3/4 butterfly needle</td>
			<td>Fisher</td>
			<td>14-840-34&#160;</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">BSP Single Speed Syringe Pump</td>
			<td>Brain Tree Sci, Inc</td>
			<td>BSP-99</td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;">Pulse Sound Measurement System</td>
			<td>Bruel &#38; Kjaer</td>
			<td>Pulse 13 software</td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;">High-Frequency Module</td>
			<td>Bruel &#38; Kjaer</td>
			<td>3560C</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">1/8&#8243; Pressure-field Microphone &#8212;-Type 4138</td>
			<td>Bruel &#38; Kjaer</td>
			<td>bp2030</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">High Frequency Transducer</td>
			<td>Intelligent Hearing System</td>
			<td>M014600</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Opti-Amp Power Transmitter</td>
			<td>Intelligent Hearing System</td>
			<td>M013010P</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">SmartEP ABR System</td>
			<td>Intelligent Hearing System</td>
			<td>M011110</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Disposable Subdermal EEG Electrodes</td>
			<td>CareFusion</td>
			<td>019-409700</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">16% Formaldehyde, Methanol-free</td>
			<td>Fisher Scientific</td>
			<td>28908</td>
			<td>TOXIC - wear proper PPE&#160;</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">7 mL Borosilicate Glass Scintillation Vial</td>
			<td>Fisher Scientific</td>
			<td>03-337-26</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">EDTA</td>
			<td>Fisher Scientific</td>
			<td>BP118-500</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Sucrose</td>
			<td>Fisher Scientific</td>
			<td>S5-500</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Tissue Plus OCT Compound</td>
			<td>Fisher Scientific</td>
			<td>4585</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">CryoMolds (15 mm x 15 mm x 5mm)</td>
			<td>Fisher Scientific</td>
			<td>22-363-553</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Microscope Slides (25mm x 75mm)</td>
			<td>MidSci</td>
			<td>1354W</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Coverslips (22 x 22 x 1)</td>
			<td>Fisher Scientific</td>
			<td>12-542-B</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Poly-L-Lysine Solution (0.01%)</td>
			<td>EMD Millipore</td>
			<td>A-005-C</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">HM525 NX Cryostat</td>
			<td>Thermo Fischer Scientific</td>
			<td>956640</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">MX35 Premier Disposable Low-Profile Microtome Blades</td>
			<td>Thermo Fischer Scientific</td>
			<td>3052835</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Wheaton&#8482;&#160;Glass 20-Slide Staining Dish with Removable Rack</td>
			<td>Fisher Scientific</td>
			<td>08-812</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Super Pap Pen Liquid Blocker</td>
			<td>Ted Pella, Inc.</td>
			<td>22309</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Normal Donkey Serum</td>
			<td>Jackson Immuno Research</td>
			<td>017-000-121</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">TritonX-100</td>
			<td>Acros</td>
			<td>21568</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">BSA</td>
			<td>Sigma Aldrich</td>
			<td>A7906</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Phospho-Stat1 (Ser727) antibody</td>
			<td>Cell Signaling</td>
			<td>9177</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">VR1 Antibody (C-15)</td>
			<td>Santa Cruz</td>
			<td>sc-12503</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">DyLight 488 Donkey anti Rabbit</td>
			<td>Jackson Immuno Research</td>
			<td>711-485-152</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">DyLight 488 Donkey anti Goat</td>
			<td>Jackson Immuno Research</td>
			<td>705-485-003</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Rhodamine (TRTIC) Donkey anti Rabbit</td>
			<td>Jackson Immuno Research</td>
			<td>711-025-152</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">ProLong&#174; Diamond Antifade Mountant w/ DAPI</td>
			<td>Thermo Fisher</td>
			<td>P36971</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">(&#8722;)-N6-(2-Phenylisopropyl)adenosine</td>
			<td>Sigma Aldrich</td>
			<td>P4532</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">8-Cyclopentyl-1,3-dipropylxanthine</td>
			<td>Sigma Aldrich</td>
			<td>C101</td>
			<td></td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">siRNA pSTAT1</td>
			<td>Qiagen</td>
			<td>Custome Made</td>
			<td>Kaur et al. 201120</td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">siRNA NOX3</td>
			<td>Qiagen</td>
			<td>Custome Made</td>
			<td>Kaur et al. 201120</td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">Scrambled Negative Control siRNA</td>
			<td>Qiagen</td>
			<td>1022076</td>
			<td>Kaur et al. 201120</td>
		</tr>
	</tbody>
</table>

trans-tympanic drug delivery for the treatment of ototoxicity

De systemische toediening van beschermende middelen voor de behandeling van drug-geïnduceerde ototoxiciteit wordt beperkt door de mogelijkheid dat deze beschermende middelen zou kunnen met de chemotherapeutische werkzaamheid van de primaire drugs interfereren. Dit geldt met name voor de drug cisplatine, wiens antikanker acties zijn verzwakt door anti-oxidanten die adequate bescherming tegen verlies van het gehoor biedt. Andere huidige of potentiële otoprotective agenten kunnen opleveren een soortgelijk probleem, als systemisch toegediend. De toepassing van verschillende biologicals of beschermende middelen rechtstreeks naar het slakkenhuis zou voor hoge niveaus van deze agenten lokaal met beperkt systemische bijwerkingen. In dit verslag tonen wij een trans-tympanic methode van de levering van verschillende drugs of biologische reagentia aan het slakkenhuis, die moet verbeteren van fundamenteel wetenschappelijk onderzoek op het slakkenhuis en bieden een eenvoudige manier van het leiden van het gebruik van otoprotective stoffen in de klinieken. Dit verslag een methode van levering van de trans-tympanic drug gedetailleerd en bevat voorbeelden van hoe deze techniek is gebruikt met succes in proefdieren te behandelen cisplatine ototoxiciteit.

ABR reacties gemeten bij ratten op drie dagen volgende cisplatine administratie een aanzienlijke verhoging in drempels toonde. Hoogte van deze drempels was aanzienlijk verminderd bij ratten toegediend met trans-tympanic [R] - N - phenylisopropyladenosine (R-PIA), adenosine een1 receptor agonist15, vóór cisplatine. Het specifieke karakter van het optreden van R-PIA op de adenosine receptor van een1 werd aangetoond d...

Watch this Scientific Journal Video about Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity at JoVE.com

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity

Presenteren we een techniek gelokaliseerde beheer van drugs via de trans-tympanic route in het slakkenhuis. Drug bezorging via deze route zou niet interfereren met de anti-kanker werkzaamheid van het chemotherapeutische geneesmiddelen zoals cisplatine.

Trans-Tympanic Drug Delivery voor de behandeling van ototoxiciteit

The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could ...

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