This work was supported by the Korea Ministry of Environment (MOE) as part of the "The advancement of scientific research and technological development in environmental science program (E315-00015-0414-2)."

1. Herstellung von Rohren in der Administration Sets HINWEIS: Gerade die Schneideschritt durchzuführen, die Wirkung von Unterschieden in der Rohrlänge auf Drogen Sorption zu beseitigen. <ol><li> Etikettieren das Ende der Rohre mit dem Rohrtyp (beispielsweise PVC, Polyurethan (PU) und Polyolefin (PO)) einen Marker. </li><li> Entfernen Sie alle abnehmbaren Zubehör, wie Stecker und Nadelabdeckungen. </li><li> ein scharfes Rasiermesser mit einem sauberen Kanten zu gewährleisten, von der Verbindung der Tropfkammer die Rohre bis 1 m Länge geschnitten. </li></ol> 2. Die Verdünnung des Arzneimittels Injections HINWEIS: Verwenden Sie eine Glasflasche (1 l) als Behälter für die injizierten Arzneimittellösung. Führen Sie genau den Verdünnungsschritt. Überprüfen Sie die Zusammensetzung der vermarkteten Arzneimittels und verwenden die gleiche Chargennummer für eine ganze Versuchsanordnung. <ol><li> Label - Flaschen mit dem Medikamentennamen (zB Diazepam oder Tacrolimus). </li><li> Verdünnen Sie die Injektion von Medikamentens mit 5% Dextrose-Lösung, von 5 mg / ml bis 100 &amp; mgr; g / ml für Diazepam Injektionszwecke (2 ml Diazepam Injektions in 100 ml 5% ige Dextrose-Lösung) und 5 mg / ml bis 10 &amp; mgr; g / ml für Tacrolimus Injektionen ( 200 &amp; mgr; l von Tacrolimus Injektion in 100 ml 5% ige Dextrose-Lösung). HINWEIS: Stellen Sie die getesteten Konzentrationen von Arzneimitteln und Lösungsmitteln auf der Basis der klinischen Anwendung. </li><li> Vorsichtig mischen die verdünnten Lösungen in der Flasche durch Verwirbelung homogenen Arzneimittellösungen zu erhalten. </li><li> Sammeln Sie verdünnten Lösungen (1-10 ml) in amber Fläschchen ein Glas mit Messzylinder. </li><li> Überprüfen Sie die Konzentration, wie in Schritt 4 beschrieben. HINWEIS: Verwenden Sie diese Konzentrationen von Medikamenten, die als Konzentrationen an den Ausgangspunkten. </li></ol> 3. Kinetische Sorption Studie mit einer Infusionspumpe HINWEIS: Überprüfen Sie die Rohrabhängige Strömungsgeschwindigkeit eine Pumpe vor der Sorption Test aufgrund der Härte von Rohren verwendet wird. Die Proben werden in genauen Zeitpunkte und die Verwendung glass Flaschen und Fläschchen, um zusätzliche Medikament Sorption während der Lagerung zu verhindern. Führen Sie den Test , wie in Abbildung 2 dargestellt. Schützen Sie die Medikamentenlösung gegen Licht, wenn das Medikament Lichtempfindlichkeit hat. Führen Sie die Versuche in dreifacher Ausfertigung. <ol><li> Luftblasen ohne Anlegen vorzubelasten eine verdünnte Lösung des Arzneimittels in das Röhrchen unter Verwendung einer Spritze. <ol><li> Ein Ende des Röhrchens mit einer Spritze. </li><li> Legen Sie das andere Ende des Rohrs in die Flaschen abgefüllt Arzneimittellösung. </li><li> Ziehen Sie den Spritzenkolben zurück, bis das Rohr vollständig mit der Arzneimittellösung gefüllt ist. </li></ol></li><li> Installieren Sie das Rohr in einer Infusionspumpe. <ol><li> Öffnen Sie die Tür der Infusionspumpe und drücken Sie den Entriegelungshebel. </li><li> Legen Sie die vorinstallierte Rohr in die Infusionspumpe und halten Sie sie gerade. </li><li> Entfernen Sie die Spritze am Ende des Rohres nach der Installation. </li><li> Setzen Sie das Ende des Rohres in einem chemisch resistenten Borosilikatglas Meßzylinder das Medikament solut zu sammelnIonen, nachdem sie das Rohr durchläuft. </li></ol></li><li> Stellen Sie die Durchflussrate basierend auf der Art des Röhrchens in dem Verabreichungsset (PVC, PU, oder PO) und das Arzneimittel (beispielsweise 1 ml / min für Diazepam und 10 ml / h für Tacrolimus). </li><li> Sammeln von Proben in amber Vials zu verschiedenen Zeitpunkten, bei Raumtemperatur. <ol><li> Sammeln Sie 1-ml Diazepam Proben bei 0,05, 0,30, 0,55 und 1,05 h. </li><li> Sammeln Sie 10-ml Tacrolimus Proben bei 1,05, 2,05, 3,05 und 4,05 h. </li></ol></li></ol> 4. Analyse der Droge mit Hochleistungs-Flüssigkeits-Chromatographie (HPLC) HINWEIS: Empfohlene HPLC - Methoden zur Wirkstoffanalyse sind in der Literatur 1, 8 beschrieben, 9. Verwenden Sie die Tandem - Massenspektrometrie (MS / MS) und Immunoassay nach der Probenvorbereitung als alternative Verfahren 10, 11. Führen Sie die Versuche in dreifacher Ausfertigung.<ol><li> Wiegen Sie die Medikamente und lösen sie in organischen Lösungsmitteln in einer Konzentration von 1 mg / ml als Stammlösungen. <ol><li> Verwenden von Methanol als Lösungsmittel für Diazepam Stammlösung aufgrund der geringen Löslichkeit von Diazepam in 5% Dextrose. </li><li> Verwenden Sie Acetonitril als Lösungsmittel für Tacrolimus-Stammlösung aufgrund der geringen Löslichkeit von Tacrolimus in 5% Dextrose. </li></ol></li><li> Standardlösungen, indem die Stammlösungen zu verdünnen. <ol><li> Verdünnen Sie Diazepam-Stammlösungen mit Methanol auf 0,3125, 0,625, 1,25, 2,5, 5,0, 10,0 und 20,0 g / mL. </li><li> Verdünnte Tacrolimus-Stammlösungen mit 5% Dextrose auf 2,5, 5,0, 10,0, 15,0 und 20,0 g / mL. </li></ol></li><li> Analysieren Standards unter Verwendung des HPLC - Verfahren mit UV - Nachweis 1, 8, 9. HINWEIS: Verwenden Sie ein geeignetes Nachweisverfahren (UV, Fluoreszenz, etc.) für die Arzneimittelanalyse. <ol><li> Injizieren 10 &amp; mgr; l standards in ein HPLC - System mit UV - Detektion mit einer Säule 18 C ausgestattet (1,5 mm × 250 mm, 5 um). Siehe Tabelle 1 für Analysebedingungen. </li><li> Bestätigen Sie die Spezifität und Linearität 1, 8, 9. <ol><li> Spezifität, zur Überwachung der Medikamenten Peak ( das heißt, ob sie von anderen Peaks im Chromatogramm wurde abgetrennt) , um das Medikament zu identifizieren. </li><li> Bestätigen Linearität im Kalibrierbereich (dh, ob der Peakfläche Ergebnisse auf die Konzentrationen direkt proportional sind). </li></ol></li><li> Erhalten Sie Kalibrierungskurven. <ol><li> Erstellen Graphen basierend auf Konzentration gegen die Peakflächenwert von Chromatogramme der Standards 1, 8, 9. </li><li> Erhalten lineare Regressionsgleichungen mit R 2 für die Kalibrierungskurven (zB </em&gt; Y = ax + b, x: Konzentration des Wirkstoffs, y: Peakfläche) 1, 8, 9. </li></ol></li></ol></li><li> Verdünnen Sie die Proben aus der Sorption Studie mit Methanol für Diazepam oder 5% Dextrose für Tacrolimus als angemessen, so dass sie innerhalb der Kalibrierungsbereich fallen und injizieren direkt 10 &amp; mgr; l der verdünnten Probe in das HPLC-System. </li></ol> 5. Berechnung der Arzneimittelkonzentration und Sorption Stufe <ol><li> Berechnen Sie die Arzneimittelkonzentrationen der Proben unter Verwendung von Kalibrierungskurven (unbekannt x und y bekannt). </li><li> Berechne die Sorption Ebenen der Medikamente die folgende Gleichung verwendet: <img alt="Gleichung 1" src="/files/ftp_upload/55086/55086eq1.jpg" /> wobei S: Sorption Ebene (%) Co: Arzneimittelkonzentration nach der Verdünnung der Einspritzungen (ug / ml) Cp: ​​Arzneimittelkonzentration geleitet durch die Rohre (ug / ml) </li></ol>

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The authors have nothing to disclose.

Drug Sorption Verabreichungssets ist eine Ursache der unerwarteten einen Arzneimittelverlust bei der intravenösen Medikamentenabgabe. Während Sorption, sind Arzneimittel zur Polymermaterialien der Rohre in der frühen Phase der Infusion im allgemeinen unterteilt; nach der Sorption Gleichgewicht erreicht ist, wird die zugeführte Menge an Wirkstoff 1 stabilisiert. Die Sorption Ebenen Medikamente sollten ausgewertet und minimiert werden. untersucht, wie eine Pumpe Verfahren und eine Tropfmethode ...

Verwaltungssätze werden von einer Spitze, einer Tropfkammer, Rohre, Luer-Adapter (Stecker) zusammengesetzt ist, und einer Nadelabdeckung zum Schutz. Andere Zusätze, wie beispielsweise ein Rückschlagventil der Atemwege, einer Regelklemme, einer in-line-Filter, ein Y-Rohr mit der Kappe (eine Einspritzöffnung) und einer Nadel, kann auch auf Verabreichungssets angebracht werden. Drug Sorption an Rohren ist ein kritisches Thema bei der Bereitstellung von injizierbaren Arzneimitteln 1. Sorption beschreibt die Adsorption eines Arzneimittels an die Polymeroberfläche und die Absorption eines Arzneimittels in der Polymermatrix 2. Drug Sorption an Röhren in Verabreichungssets können unvorhersehbare Schwierigkeiten einen Arzneimittelverlust und macht es schwierig, die gelieferte Wirkstoffkonzentration zu steuern. Drug Sorption an polymeren Rohren ist daher ein Haupthindernis für die präzise Übertragung von injizierbaren Medikamenten in den Körper. Allerdings gibt es keine Standardverfahren oder regulatorischen Vorgaben für die Bewertung der Drogen Sorption an Rohren in Verabreichungssets. <html> Die Niveaus der Arzneimittel Sorption an Rohren in Verabreichungssets wurden Verfahren 1 unter Verwendung von verschiedenen Evaluierungs berichtet, 2, 3, 4, 5. Prüfverfahren und Modellsubstanzen sind Schlüsselfaktoren bei der Sorption Auswertung. Die Pumpe Methode 1, 3 und Tropfmethode 4, 5 wurden Sorptionstests weit verbreitet. Im allgemeinen sollte die Pumpe Verfahren in dem Fall von Medikamenten mit geringen Konzentrationen und niedrigen Strömungsgeschwindigkeiten wie die Infusionsbedingungen verwendet werden. Unter Verwendung verschiedener Bewertungsverfahren haben viele Studien von Medikamenten Sorption für Polyvinylchlorid (PVC) berichtet - und Nicht-PVC-Basis Rohre in Verabreichungssets 1, 2, 3,&gt; 5. Viele sorptive Medikamente können zur Untersuchung ausgewählt werden, ob die Rohre des Verabreichungssets Arzneimittel Sorption Potential haben oder nicht. Diazepam (1a) 1, 2, Tacrolimus (Abbildung 1b) 5, Nitroglyzerin 2 und Cyclosporin A 3 sind repräsentative Arzneimittel mit hoher Sorption in PVC- und Nicht-PVC-Basis Rohre. Für die Bewertung der Arzneimittel Sorption an den Rohren, Prüfbedingungen wie Strömungsrate und die Arzneimittelkonzentration auf die klinische Verwendung der ausgewählten Medikamente auf Basis 1, 6, 7. Im Falle von Diazepam, wurde mit einer Strömungsgeschwindigkeit von 1 ml / min zu imitieren die anfängliche Dosis für die Behandlung von Status epilepticus 1 eine hohe Konzentration von 100 ug / ml verwendet. Für Tacrolimus, eine Konzentration von 10 ug / mlwurde mit einer Strömungsgeschwindigkeit von 10 ml / h geliefert. Dextrose-Lösung (5%) wurde zur Verdünnung der Arzneimittelinjektionszwecke verwendet und Rohrlänge wurde auf 1 m befestigt. Glasflaschen und Fläschchen sollten während des Experiments und Lagerung zusätzliche Sorption zu verhindern, verwendet werden. In dieser Studie haben wir eine kinetische Sorption Studie mit dem Modell Drogen, Diazepam und Tacrolimus, ein Pumpenverfahren. Spezifische Details dieses Protokolls von Rohrvorbereitung zur Sorption Auswertung wurden zuvor beschrieben. Die Methoden zur Beurteilung der Arzneimittel Sorption wurden bereits verwendet worden Drogen Eigenschaften für Injektionen zu bestätigen und die klinische Anwendung von Injektionen mit Verabreichungssets auf eine Fall-zu-Fall - Basis 1, 2, 3, 4, 5, 6, 7 zu empfehlen. Dieses Protokoll kann als Standard verwendet werden,Verfahren für die Sorption Auswertung der Verabreichungssets. Die internationalen Standards für die Beurteilung der Medikamenten Sorption an Rohren kann notwendig sein, um die Sicherheit und Wirksamkeit der Arzneimittelabgabe zu gewährleisten.

<table>
	<tbody>
		<tr>
			<td>PVC IV sets</td>
			<td>Becton Dickinson 
			(BD) Co. Ltd. (Franklin Lakes, NJ, USA)</td>
			<td></td>
			<td>Internal diameter: 2.54 mm</td>
		</tr>
		<tr>
			<td>PU IV sets</td>
			<td>Tianjin Hanaco Medical (THM) Co.Ltd. 
			(Tianjin, China)</td>
			<td></td>
			<td>Non-PVC 
			Internal diameter: 2.54 mm</td>
		</tr>
		<tr>
			<td>Non-PVC Polyolefin IV sets</td>
			<td>Polyscientech, Co. Ltd (Anseong, Korea)</td>
			<td></td>
			<td>Non-PVC [PE elastomer/PP elastomer/PB elastomer(25/50/25, weight ratio) blend] 
			Internal diameter: 2.54 mm</td>
		</tr>
		<tr>
			<td>Syringe</td>
			<td>Korea Vaccine Co. Ltd. (Seoul, Korea)</td>
			<td>KOVAX-SYRINGE 1 mL 26G 1/2&#34;</td>
			<td></td>
		</tr>
		<tr>
			<td>Daewon diazepam injection</td>
			<td>Daewon Pharma. Co. Ltd. (Hwaseong, Gyunggi, Korea)</td>
			<td></td>
			<td>1 mg/mL, total 2 mL 
			Batch No.: P003 
			Composition: diazepam, propylene glycol, ethanol, benzyl alcohol, sodium benzoate, bezoic acid, water for injection</td>
		</tr>
		<tr>
			<td>Tacrobel injection</td>
			<td>Chong Keun Dang, Co. Ltd. (Seoul, Korea)</td>
			<td></td>
			<td>5 mg/mL, total 1 mL 
			Batch No.: AG002 
			Composition: tacrolimus hydrate, polyoxyl 60 hydrogenated castor oil (HCO-60), dehydrated alcohol</td>
		</tr>
		<tr>
			<td>5% Dextrose</td>
			<td>JW Pharmaceutical (Seoul, Korea)</td>
			<td>500 mL</td>
			<td></td>
		</tr>
		<tr>
			<td>5% Dextrose</td>
			<td>Daehan Pharmaceutical (Seoul, Korea)</td>
			<td>200 mL</td>
			<td>Bottle (glass)</td>
		</tr>
		<tr>
			<td>Amber vials</td>
			<td></td>
			<td>20 mL</td>
			<td>Glass</td>
		</tr>
		<tr>
			<td>Terumo infusion pump</td>
			<td>Terumo (Medical Corp., USA)</td>
			<td>TE-135</td>
			<td></td>
		</tr>
		<tr>
			<td>HPLC system with UV detector</td>
			<td>Agilent (Santa Clara, CA, USA)</td>
			<td>Agilent 1260</td>
			<td></td>
		</tr>
		<tr>
			<td>CAPCELL PAK C18 column&#160;</td>
			<td>Shiseido (Japan)</td>
			<td>90404</td>
			<td>1.5 mm x 250 mm, 5 &#956;m</td>
		</tr>
		<tr>
			<td>Diazepam</td>
			<td></td>
			<td></td>
			<td>From Daewon Pharma. Co., Ltd.</td>
		</tr>
		<tr>
			<td>Tacrolimus</td>
			<td>Teva Czech industries&#160; (Czech Republic)</td>
			<td></td>
			<td>From Chong Keun Dang, Co. Ltd.</td>
		</tr>
		<tr>
			<td>Acetonitrile</td>
			<td>Burdick and Jackson Co., Ltd. (MI, USA)</td>
			<td>3/1/9017</td>
			<td></td>
		</tr>
		<tr>
			<td>Methanol</td>
			<td>Burdick and Jackson Co. Ltd. (MI, USA)</td>
			<td>AH230-4</td>
			<td></td>
		</tr>
		<tr>
			<td>Water</td>
			<td>Burdick and Jackson Co. Ltd. (MI, USA)</td>
			<td>3/1/4218</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium dihydrogen phosphate</td>
			<td>Sigma (St. Louis, MO, USA)</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Phosphoric acid</td>
			<td>Sigma (St. Louis, MO, USA)</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

evaluation of drug sorption to pvc- and non-pvc-based tubes in administration sets using a pump

Verwaltung Sets sind Liefer Werkzeuge für die direkte Anwendung von Medikamenten in den Körper und einer Spitze zusammengesetzt, eine Tropfkammer, Rohre, Luer-Adapter (Stecker), einer Nadelabdeckung zum Schutz und anderes Zubehör. Drug Sorption an Rohren von Verabreichungssets ist ein kritisches Thema in Bezug auf Sicherheit und Wirksamkeit. Obwohl Drogen Sorption in der Qualität eines Verabreichungsset ein wichtiger Faktor ist, gibt es keine Standard-Bewertungsverfahren für die Regulierung der Arzneimittel Sorption an den Rohren. Hier beschreiben wir ein Bewertungsprotokoll für Arzneimittel Sorption an Rohren Verabreichungssets. Rohre aus Polyvinylchlorid (PVC) - und Nicht-PVC-basierten Polymermaterialien wurden auf 1 m Länge geschnitten. Diazepam und Tacrolimus wurden als Modell Drogen verwendet werden. Bei der kinetischen Sorption Studie wählten wir die Wirkstoffkonzentration und Strömungsgeschwindigkeit auf der Grundlage der klinischen Verwendung dieser Medikamente. Nach der Verdünnung jedes Arzneimittels in einer Glasflasche wurde die verdünnte Arzneimittellösung durch Rohre zugeder Verwaltung setzt eine Pumpe. Proben wurden in bernsteinfarbene Phiolen zu geeigneten Zeitpunkten gesammelt, und die Arzneimittel wurden HOCHLEISTUNGSFLÜSSIGKEITSCHROMATOGRAPHIE analysiert. Wirkstoffkonzentrationen und Sorption Ebenen Rohre der Verabreichungssets wurden berechnet. Akzeptable Kriterien die Qualität der Verwaltung setzt, um sicherzustellen, werden empfohlen.

Die Sorption an Rohren in der Verabreichungsset kinetisch wurde das Modell Drogen überwacht unter Verwendung von Diazepam (Abbildung 1a) und Tacrolimus (Abbildung 1b), und die Pumpe - Methode (Abbildung 2). Verdünnte Medikament (2a) durch PVC- und Nicht-PVC-Basis Rohre (2b) mit einer festen Strömungsgeschwindigkeit geleitet einer Infusionspumpe (Abbildung 2c) verwendet wird . Die Glas...

Watch this Scientific Journal Video about Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump at JoVE.com

Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump

Wir berichten über ein Verfahren zur Auswertung Drogen Sorption einer Pumpe und Modell Medikamente (Diazepam und Tacrolimus) verwendet wird. Nach der Arzneimittelanalyse HOCHLEISTUNGSFLÜSSIGKEITSCHROMATOGRAPHIE, Wirkstoffkonzentrationen und Sorption Ebenen in den Rohren des Verabreichungssets verwendet werden berechnet.

Evaluierung der Drogen Sorption zu PVC- und Nicht-PVC-Basis Tubes in Verabreichungssets mit einer Pumpe

Administration sets are delivery tools for the direct application of drugs into the body and are composed of a spike, a drip chamber, tubes, Luer adapters ...

evaluation-drug-sorption-to-pvc-non-pvc-based-tubes-administration

Research

JoVE Journal

Medicine

10.5K Aufrufe.  Yonsei University.  Wir berichten über ein Verfahren zur Auswertung Drogen Sorption einer Pumpe und Modell Medikamente (Diazepam und Tacrolimus) verwendet wird. Nach der Arzneimittelanalyse HOCHLEISTUNGSFLÜSSIGKEITSCHROMATOGRAPHIE, Wirkstoffkonzentrationen und Sorption Ebenen in den Rohren des Verabreichungssets verwendet werden berechnet. 

Serie: Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump

Evaluation of Cancer Stem Cell Migration Using Compartmentalizing Microfluidic Devices and Live Cell Imaging

In the last 40 years, the United States invested over 200 billion dollars on cancer research, resulting in only a 5% decrease in death rate. A major obstacle for improving patient outcomes is the poor understanding of mechanisms underlying cellular migration associated with aggressive cancer cell invasion, metastasis and therapeutic resistance1. Glioblastoma Multiforme (GBM), the most prevalent primary malignant adult brain tumor2, exemplifies this difficulty. Despite standard surgery, radiation and chemotherapies, patient median survival is only fifteen months, due to aggressive GBM infiltration into adjacent brain and rapid cancer recurrence2. The interactions of aberrant cell migratory mechanisms and the tumor microenvironment likely differentiate cancer from normal cells3. Therefore, improving therapeutic approaches for GBM require a better understanding of cancer cell migration mechanisms. Recent work suggests that a small subpopulation of cells within GBM, the brain tumor stem cell (BTSC), may be responsible for therapeutic resistance and recurrence. Mechanisms underlying BTSC migratory capacity are only starting to be characterized1,4.
Due to a limitation in visual inspection and geometrical manipulation, conventional migration assays5 are restricted to quantifying overall cell populations. In contrast, microfluidic devices permit single cell analysis because of compatibility with modern microscopy and control over micro-environment6-9.
We present a method for detailed characterization of BTSC migration using compartmentalizing microfluidic devices. These PDMS-made devices cast the tissue culture environment into three connected compartments: seeding chamber, receiving chamber and bridging microchannels. We tailored the device such that both chambers hold sufficient media to support viable BTSC for 4-5 days without media exchange. Highly mobile BTSCs initially introduced into the seeding chamber are isolated after migration though bridging microchannels to the parallel receiving chamber. This migration simulates cancer cellular spread through the interstitial spaces of the brain. The phase live images of cell morphology during migration are recorded over several days. Highly migratory BTSC can therefore be isolated, recultured, and analyzed further. 
Compartmentalizing microfluidics can be a versatile platform to study the migratory behavior of BTSCs and other cancer stem cells. By combining gradient generators, fluid handling, micro-electrodes and other microfluidic modules, these devices can also be used for drug screening and disease diagnosis6. Isolation of an aggressive subpopulation of migratory cells will enable studies of underlying molecular mechanisms.

A compartmentalizing microfluidic device for investigating cancer stem cell migration is described. This novel platform creates a viable cellular microenvironment and enables microscopic visualization of live cell locomotion. Highly motile cancer cells are isolated to study molecular mechanisms of aggressive infiltration, potentially leading to more effective future therapies.

Evaluation of Cancer Stem Cell Migration Mit Abschottung Mikrofluidiksysteme und Live Cell Imaging

In the last 40 years, the United States invested over 200 billion dollars on cancer research, resulting in only a 5% decrease in death rate. A major ...

Forschung

Medizin

Femoral Arterial and Venous Catheterization for Blood Sampling, Drug Administration and Conscious Blood Pressure and Heart Rate Measurements

In multiple fields of study, access to the circulatory system in laboratory studies is necessary. Pharmacological studies in rats using chronically implanted catheters permit a researcher to effectively and humanely administer substances, perform repeated blood sampling and assists in conscious direct measurements of blood pressure and heart rate. Once the catheter is implanted long-term sampling is possible. Patency and catheter life depends on multiple factors including the lock solution used, flushing regimen and catheter material. This video will demonstrate the methodology of femoral artery and venous catheterization of the rat. In addition the video will demonstrate the use of the femoral venous and arterial catheters for blood sampling, drug administration and use of the arterial catheter in taking measurements of blood pressure and heart rate in a conscious freely-moving rat. A tether and harness attached to a swivel system will allow the animal to be housed and have samples taken by the researcher with minimal disruption to the animal. To maintain patency of the catheter, careful daily maintenance of the catheter is required using lock solution (100 U/ml heparinized saline), machine-ground blunt tip syringe needles and the use of syringe filters to minimize potential contamination. With careful aseptic surgical techniques, proper catheter materials and careful catheter maintenance techniques, it is possible to sustain patent catheters and healthy animals for long periods of time (several weeks).

Chronic catheterization of blood vessels in the rat is often required for administration of substances, obtain blood sample over a period of time or for direct conscious blood pressure measurements. Femoral arterial catheterization of the rat and corresponding measurements of blood pressure in the conscious animal will be demonstrated.

Femoral arterielle und venöse Katheterisierung zur Blutentnahme, Drug Administration und Conscious Blutdruck und Herzfrequenz-Messungen

In multiple fields of study, access to the circulatory system in laboratory studies is necessary. Pharmacological studies in rats using chronically ...

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%1-3, the majority of cases being monocular2. Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.
Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself4,5 . Amblyopia is characterized by both monocular and binocular deficits6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions8. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia9,10 .
Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations.
In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15.

Amblyopia is a developmental disorder of the visual cortex that is often accompanied by strong suppression of one eye. We present a new technique for measuring and treating interocular suppression in patients with amblyopia that can be deployed using virtual reality goggles or a portable iPod Touch device.

Die Messung und Behandlung von Unterdrückung in Amblyopie

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current ...

Intranasal Administration of CNS Therapeutics to Awake Mice

Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects1. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport2. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials3.
Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models 4-6 and deferoxamine in Alzheimer's mouse models. 7,8
The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible.

A method to intranasally administer drugs to awake mice for the purpose of targeting the brain is described. This method allows for repeat dosing over long periods using intranasal administration of drug without anesthesia, and nose-to-brain delivery with minimal systemic exposure.

Intranasale Verabreichung von CNS Therapeutics Awake Mäuse

Intranasal administration is a method of delivering  therapeutic agents to the central nervous system (CNS). It is  non-invasive and allows large ...

Evaluation of a Novel Laser-assisted Coronary Anastomotic Connector - the Trinity Clip - in a Porcine Off-pump Bypass Model

To simplify and facilitate beating heart (i.e., off-pump), minimally invasive coronary artery bypass surgery, a new coronary anastomotic connector, the Trinity Clip, is developed based on the excimer laser-assisted nonocclusive anastomosis technique. The Trinity Clip connector enables simplified, sutureless, and nonocclusive connection of the graft to the coronary artery, and an excimer laser catheter laser-punches the opening of the anastomosis. Consequently, owing to the complete nonocclusive anastomosis construction, coronary conditioning (i.e., occluding or shunting) is not necessary, in contrast to the conventional anastomotic technique, hence simplifying the off-pump bypass procedure. Prior to clinical application in coronary artery bypass grafting, the safety and quality of this novel connector will be evaluated in a long-term experimental porcine off-pump coronary artery bypass (OPCAB) study. In this paper, we describe how to evaluate the coronary anastomosis in the porcine OPCAB model using various techniques to assess its quality. Representative results are summarized and visually demonstrated.

This paper describes a novel nonocclusive coronary anastomotic connector in a porcine off-pump coronary artery bypass (OPCAB) model. This easy-to-use coronary connector has intrinsic potential to facilitate minimally invasive OPCAB surgery.

Evaluierung eines neuartigen Lasergestützte Koronare Anastomotische Steckverbinder - Dreifaltigkeit Clip - in einem Schweine Off-Pumpe Bypass-Modell

To simplify and facilitate beating heart (i.e., off-pump), minimally invasive coronary artery bypass surgery, a new coronary anastomotic connector, the ...

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United States. Tacrolimus is a narrow therapeutic index drug and as such requires therapeutic drug monitoring and dose adjustment based on its whole blood trough concentrations. To facilitate home therapeutic drug and adherence monitoring, the collection of dried blood spots is an attractive concept. After a finger stick, the patient collects a blood drop on filter paper at home. After the blood is dried, it is mailed to the analytical laboratory where tacrolimus is quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in combination with a simple manual protein precipitation step and online column extraction.
For tacrolimus analysis, a 6-mm disc is punched from the saturated center of the blood spot. The blood spot is homogenized using a bullet blender and then proteins are precipitated with methanol/0.2 M ZnSO4 containing the internal standard D2,13C-tacrolimus. After vortexing and centrifugation, 100 &#181;l of supernatant is injected into an online extraction column and washed with 5 ml/min of 0.1 formic acid/acetonitrile (7:3, v:v) for 1 min. Hereafter, the switching valve is activated and the analytes are back-flushed onto the analytical column (and separated using a 0.1% formic acid/acetonitrile gradient). Tacrolimus is quantified in the positive multi reaction mode (MRM) using a tandem mass spectrometer.
The assay is linear from 1 to 50 ng/ml. Inter-assay variability (3.6%-6.1%) and accuracy (91.7%-101.6%) as assessed over 20 days meet acceptance criteria. Average extraction recovery is 95.5%. There are no relevant carry-over, matrix interferences and matrix effects. Tacrolimus is stable in dried blood spots at RT and at +4 &#176;C for 1 week. Extracted samples in the autosampler are stable at +4 &#176;C for at least 72 hr.

Here we describe a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay to quantify the immunosuppressant tacrolimus in dried blood spots using a simple manual protein precipitation step and online column extraction.

Die Quantifizierung des Immunsuppressivums Tacrolimus auf Getrocknetes Blut mittels LC-MS / MS

The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United ...

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling molecules that affect multiple organs; they modulate gut motility and hormone production, and alter vascular tone, glucose metabolism, lipid metabolism, and energy utilization. Changes in fecal bile acids may alter the gut microbiome and promote colon pathology including cholerrheic diarrhea and colon cancer. Key regulators of fecal bile acid composition are the small intestinal Apical Sodium-dependent Bile Acid Transporter (ASBT) and fibroblast growth factor-19 (FGF19). Reduced expression and function of ASBT decreases intestinal bile acid up-take. Moreover, in vitro data suggest that some FDA-approved drugs inhibit ASBT function. Deficient FGF19 release increases hepatic bile acid synthesis and release into the intestines to levels that overwhelm ASBT. Either ASBT dysfunction or FGF19 deficiency increases fecal bile acids and may cause chronic diarrhea and promote colon neoplasia. Regrettably, tools to measure bile acid malabsorption and the actions of drugs on bile acid transport in vivo are limited. To understand the complex actions of bile acids, techniques are required that permit simultaneous monitoring of bile acids in the gut and metabolic tissues. This led us to conceive an innovative method to measure bile acid transport in live animals using a combination of proton (1H) and fluorine (19F) magnetic resonance imaging (MRI). Novel tracers for fluorine (19F)-based live animal MRI were created and tested, both in vitro and in vivo. Strengths of this approach include the lack of exposure to ionizing radiation and translational potential for clinical research and practice.

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

Tools to diagnose bile acid malabsorption and measure bile acid transport in vivo are limited. An innovative approach in live animals is described that utilizes combined proton (1H) plus fluorine (19F) magnetic resonance imaging; this novel methodology has translational potential to screen for bile acid malabsorption in clinical practice.

Mit Multi-fluorierten Bile Acids und<em&gt; In Vivo</em&gt; Magnetic Resonance Imaging Maßnahme Gallensäure-Transport

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling ...

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain barrier. However, there have been few reports regarding not only the quantitative analysis but also optimal administration conditions and dosing regimens for investigations of nose-to-brain delivery. The limited progress in research on nose-to-brain pathway mechanisms using rodents represents a significant impediment in terms of designing nose-to-brain delivery systems for candidate drugs.
To gain some headway in this regard, we developed and evaluated two novel methods of stable intranasal administration under inhalation anesthesia for experimental animals. We also describe a method for the evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radio-labeled [14C]-inulin (molecular weight: 5,000) as a model substrate of water-soluble macromolecules.
Initially, we developed a pipette-based intranasal administration protocol using temporarily openable masks, which enabled us to perform reliable administration to animals under stable anesthesia. Using this system, [14C]-inulin could be delivered to the brain with little experimental error.
We subsequently developed an intranasal administration protocol entailing reverse cannulation from the airway side through the esophagus, which was developed to minimize the effects of mucociliary clearance (MC). This technique led to significantly higher levels of [14C]-inulin, which was quantitatively detected in the olfactory bulb, cerebrum, and medulla oblongata, than the pipette method. This appears to be because retention of the drug solution in the nasal cavity was substantially increased by active administration using a syringe pump in a direction opposite to the MC into the nasal cavity.
In conclusion, the two methods of intranasal administration developed in this study can be expected to be extremely useful techniques for evaluating pharmacokinetics in rodents. The reverse cannulation method, in particular, could be useful for evaluating the full potential of nose-to-brain delivery of drug candidates.

Here, we describe two novel methods of stable intranasal administration under inhalation anesthesia with minimal physical stress for experimental animals. We also describe a method for quantitative evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radiolabeled [14C]-inulin as a model substrate of water-soluble macromolecules.

Neuartige Methoden für intranasale Verabreichung unter Inhalation Anästhesie auszuwertende Nase zu Gehirn Drug Delivery

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

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.

The chronic administration of isoproterenol via an implanted osmotic pump has been used widely to mimic advanced heart failure in mice. Here, we describe detailed methods in surgical mini-pump implantation for the continuous isoproterenol administration over 3 weeks, as well as, echocardiographic assessment for the successful model creation.

Implantation einer Isoproterenol Mini-Pumpe zur Induzieren von Herzinsuffizienz bei Mäusen

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics ...

Evaluation of Cerebral Blood Flow Autoregulation in the Rat Using Laser Doppler Flowmetry

When investigating the body&#39;s mechanisms for regulating cerebral blood flow, a relative measurement of microcirculatory blood flow can be obtained using laser Doppler flowmetry (LDF). This paper demonstrates a closed skull preparation that allows cerebral blood flow to be assessed without penetrating the skull or installing a chamber or cerebral window. To evaluate autoregulatory mechanisms, a model of controlled blood pressure reduction via graded hemorrhage can be utilized while simultaneously employing LDF. This enables the real time tracking of the relative changes in the blood flow in response to reductions in arterial blood pressure produced by the withdrawal of circulating blood volume. This paradigm is a valuable approach to study cerebral blood flow autoregulation during reductions in arterial blood pressure and, with minor modifications in the protocol, is also valuable as an experimental model of hemorrhagic shock. In addition to evaluating autoregulatory responses, LDF can be used to monitor the cortical blood flow when investigating metabolic, myogenic, endothelial, humoral, or neural mechanisms that regulate cerebral blood flow and the impact of various experimental interventions and pathological conditions on cerebral blood flow.

This article demonstrates the use of laser Doppler flowmetry to evaluate the ability of the cerebral circulation to autoregulate its blood flow during reductions in arterial blood pressure.

Auswertung der zerebralen Blutfluss-Autoregulation in der Ratte mit Laser-Doppler-Flowmetrie

When investigating the body&#39;s mechanisms for regulating cerebral blood flow, a relative measurement of microcirculatory blood flow can be obtained ...