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

Arbeidet som er beskrevet i denne artikkelen ble støttet av en NCI RO1 CA166907 NIDCD RO1-DC 002396 og RO3 DC011621.

Mannlige Wistar rotter ble håndtert i samsvar med National Institutes of Health dyret bruker retningslinjer og en protokoll som er godkjent av Southern Illinois University skolen av medisin laboratorium Animal Care og bruke komiteen. Auditory hjernestammen svar (ABR) ble utført på rotter mens under anestesi før Rusgiften Administrasjonen og 72 h etter for å kontrollere effekten av trans-tympanic narkotika-leveranser.
1. auditiv hjernestammen svar (ABR)
Me...

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Trans-tympanic administrasjon ruten gir lokaliserte levering av narkotika og andre stoffer til sneglehuset som ellers kunne produsere betydelige systemisk bivirkninger hvis administrert systemisk. Dette stoffet administrasjon tillater rask tilgang av narkotika til området av handlingen ved betydelig høyere doser enn kan oppnås gjennom systemisk ruten. Resultatene presenteres her og publisert tidligere viste at trans-tympanic administrasjon av [R] - N - fenyl isopropyl adenosin (R-PIA) beskyttet snegl...

Eksterne hørselen er utsøkt sensitive til stoffer som cisplatin og aminoglycoside antibiotika. Cisplatin er en mye brukt chemotherapeutic agent for behandling av en rekke solide svulster, eggstokkreft, testikler og hode og nakke kreft. Ototoksisitet med bruk av dette stoffet er dose-begrensende og ganske vanlig, påvirker 75-100% av pasienter behandlet1. Andre stoffer, som carboplatin og oxaliplatin, har dukket opp som alternativer til cisplatin2,3,4,5, men nytten er begrenset til noen kreftformer.
Studier har vist den kritiske rollen reaktive oksygen arter (ROS) i formidling av ototoksisitet produsert av cisplatin og aminoglycosides. Studier viste at NOX3 isoformen av NADPH oksidase er hovedkilden til ROS i cochlea, og aktiveres ved cisplatin6,7. Generering av ROS kompromisser økt antioksidant bufring kapasitet på cellene, fører til lipid peroxidation mobilnettet membraner8. Videre øker cisplatin produksjonen av hydroksylradikaler som genererer svært giftige aldehyd 4-hydroxynonenal (4-HNE), en initiator celle død9,10. Basert på disse resultatene, har flere antioksidanter blitt undersøkt for behandling av cisplatin ototoksisitet. Disse inkluderer N-acetyl-cystein (NAC), natrium tiosulfat (m), amifostine og D-metionin. Svært viktig antioksidant terapi er imidlertid at disse antioksidantene kan redusere cisplatin chemotherapeutic effekt når det gis systemisk11 til samspillet av cisplatin med thiol grupper i antioksidant molekyler.
I lys av disse problemene med antioksidant terapi var målet med denne studien å undersøke trans-tympanic ruten å levere antioksidanter og andre stoffer til sneglehuset å redusere hørselstap. Trans-tympanic ruten av narkotika og kort konflikt (si) RNA, beskrevet nedenfor, vises særlig lovende.

<table border="0" cellpadding="0" cellspacing="0" style="width:1025px;" width="1025">
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			<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>
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trans-tympanic drug delivery for the treatment of ototoxicity

Systemisk administrasjonen av beskyttende agenter til å behandle narkotikainduserte ototoksisitet begrenses av muligheten for at disse beskyttende agenter kan forstyrre chemotherapeutic effekten av primære narkotika. Dette gjelder særlig for narkotika cisplatin, handlingene anticancer er svekket av antioksidanter som gir tilstrekkelig beskyttelse mot hørselstap. Andre eksisterende eller potensielle otoprotective agenter kan utgjøre et lignende problem, hvis administrert systemisk. Bruk av ulike biologicals eller beskyttende agenter direkte til sneglehuset ville tillate for høye nivåer av disse agentene lokalt med begrenset systemisk bivirkninger. I denne rapporten viser vi en trans-tympanic metode for levering av ulike legemidler eller biologiske reagenser til sneglehuset, som skal forbedre grunnleggende forskning på cochlea og gir en enkel måte å styre bruken av otoprotective agenter i klinikkene. Denne rapporten viser en metode for trans-tympanic narkotika-leveranser og gir eksempler på hvordan denne teknikken har vært brukt med hell i forsøksdyr for å behandle cisplatin ototoksisitet.

ABR svar målt i rotter på tre dager etter cisplatin administrasjon viste en betydelig høyde i terskler. Heving av disse grensene ble betydelig redusert i rotter administreres med trans-tympanic [R] - N - phenylisopropyladenosine (R-PIA), adenosin en1 reseptor Agonistiske15, før cisplatin. Spesifisiteten av handlingen av R-PIA adenosin en1 reseptor ble demonstrert av observasjon at det var antagonized av 8-Cyclope...

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

Vi presenterer en teknikk for lokaliserte administrasjon av medikamenter gjennom trans-tympanic ruten i sneglehuset. Narkotika-leveranser gjennom denne ruten ville ikke forstyrre anti-kreft effekten av cellegifter som cisplatin.

Trans-Tympanic narkotika-leveranser for behandling av ototoksisitet

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

Research

JoVE Journal

Medicine

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Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain ...