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. Preparação de Tubos em conjuntos de administração NOTA: Precisamente executar o passo de corte para eliminar o efeito de diferenças no comprimento do tubo na absorção de fármaco. <ol><li> Rotular a extremidade dos tubos com o tipo de tubo (por exemplo, PVC, poliuretano (PU), e de poliolefina (PO)), utilizando um marcador. </li><li> Retire todos os acessórios removíveis, tais como conectores e tampas de seringas. </li><li> Usando uma lâmina de barbear afiada para assegurar arestas limpas, cortou os tubos a 1 m de comprimento, a partir da ligação da câmara de gotejamento. </li></ol> 2. A diluição da droga injecções NOTA: Utilizar um frasco de vidro (1 L) como um recipiente para a solução de droga injectada. Realizar a etapa de diluição com precisão. Verificar a composição do medicamento comercializado e usar o mesmo número de lote para todo um conjunto experimental. <ol><li> Garrafas Label com os nomes de medicamentos (por exemplo, diazepam ou tacrolimus). </li><li> Diluir a injeção de drogass com uma solução de dextrose a 5%, a partir de 5 mg / ml a 100 ug / mL para injectáveis ​​diazepam (2 mL de injecção de diazepam em solução de dextrose a 100 mL de 5%) e de 5 mg / mL a 10 ug / mL para injectáveis ​​tacrolimus ( 200 ul de injecção tacrolimus em 100 ml de solução de dextrose a 5%). NOTA: Configurar as concentrações testadas de drogas e solventes com base no uso clínico. </li><li> Misture delicadamente as soluções diluídas na garrafa por agitação para obter soluções de drogas homogêneos. </li><li> Colete soluções diluídas (1-10 ml) em frascos âmbar, utilizando um cilindro de vidro graduado. </li><li> Verificar a concentração, tal como descrito no passo 4. Observação: usar essas concentrações de fármacos como concentrações nos pontos de partida. </li></ol> 3. Kinetic sorção estudo utilizando uma bomba de infusão NOTA: confirmar a taxa de fluxo dependente do tubo utilizando uma bomba antes do teste de sorção devido à dureza de tubos. Coletar amostras em momentos precisos e uso ABLgarrafas ss e frascos para evitar absorção de droga adicional, durante o armazenamento. A efectuar o teste, como mostrado na Figura 2. Proteger a solução de um fármaco contra a luz, se a droga tem fotossensibilidade. Execute as experiências em triplicado. <ol><li> Sem criar bolhas de ar, pré-carregar uma solução diluída do medicamento para dentro do tubo utilizando uma seringa. <ol><li> Conectar uma extremidade do tubo a uma seringa. </li><li> Colocar a outra extremidade do tubo para dentro da solução do fármaco engarrafada. </li><li> Puxar para trás o êmbolo da seringa até que o tubo é completamente preenchida com a solução de fármaco. </li></ol></li><li> Instalar o tubo para uma bomba de infusão. <ol><li> Abra a porta da bomba de infusão e empurre a alavanca de liberação. </li><li> Insira o tubo pré-carregado na bomba de infusão e mantê-lo em linha reta. </li><li> Remover a seringa no final do tubo após instalação. </li><li> Coloque a extremidade do tubo em um vidro de borosilicato resistente a produtos químicos cilindro graduado para recolher a droga solutião depois de passar através do tubo. </li></ol></li><li> Definir a taxa de fluxo com base no tipo de tubo no conjunto de administração (PVC, PU, ou PO) e da droga (por exemplo, 1 ml / min para o diazepam e 10 ml / h para o tacrolimus). </li><li> Recolha de amostras em frascos âmbar a vários pontos de tempo, à temperatura ambiente. <ol><li> Recolha de 1 ml amostras diazepam em 0,05, 0,30, 0,55, e 1,05 h. </li><li> Colete 10 ml amostras de tacrolimus a 1,05, 2,05, 3,05, e 4,05 h. </li></ol></li></ol> 4. Análise de fármaco utilizando-cromatografia líquida de alta resolução (HPLC) NOTA: Recomenda métodos de HPLC para análise de drogas são descritos em referências 1, 8, 9. Use espectrometria de massa em tandem (MS / MS) e imunoensaio após a preparação das amostras como métodos alternativos 10, 11. Execute as experiências em triplicado.<ol><li> Pesar as drogas e os dissolvem em solventes orgânicos a uma concentração de 1 mg / mL como soluções de reserva. <ol><li> Use metanol como um solvente para a solução estoque diazepam, devido à baixa solubilidade do diazepam em 5% de dextrose. </li><li> Utilizar acetonitrilo como um solvente para a solução estoque tacrolimus devido à baixa solubilidade do tacrolimus em 5% de dextrose. </li></ol></li><li> Prepare soluções padrão por diluição das soluções stock. <ol><li> Dilui-se soluções de reserva diazepam com metanol a 0,3125, 0,625, 1,25, 2,5, 5,0, 10,0, e 20,0 ug / mL. </li><li> Dilui-se soluções de reserva de tacrolimus com 5% de dextrose a 2,5, 5,0, 10,0, 15,0, e 20,0 ug / mL. </li></ol></li><li> Analisar padrões usando o método de HPLC com detecção por UV 1, 8, 9. NOTA: Use um método de detecção adequado (UV, a fluorescência, etc.) para análise de drogas. <ol><li> Injectar 10 ml de stanpa- num sistema de HPLC com detecção por UV equipado com uma coluna C 18 (1,5 mm x 250 mm, 5 um). Ver Tabela 1 para as condições de análise. </li><li> Confirmar a especificidade e linearidade 1, 8, 9. <ol><li> Para especificidade, monitorar o pico do fármaco (isto é, se foi separado de outros picos no cromatograma) para identificar a droga. </li><li> Confirmar linearidade na gama de calibração (isto é, se os resultados de área de pico são directamente proporcional às concentrações). </li></ol></li><li> Obtenção de curvas de calibração. <ol><li> Criar gráficos com base na concentração versus valor área do pico de cromatogramas das normas 1, 8, 9. </li><li> Obter equações de regressão linear com R 2 para as curvas de calibração (por exemplo, </em&gt; Y = ax + b, x: concentração de droga, y: área do pico) 1, 8, 9. </li></ol></li></ol></li><li> Diluir as amostras do estudo de sorção com metanol para diazepam ou dextrose a 5% para o tacrolimus, conforme apropriado, para que eles fiquem dentro do intervalo de calibração e injetar diretamente 10 mL de amostra diluída para o sistema de HPLC. </li></ol> 5. Cálculo da concentração da droga e sorção Nível <ol><li> Calcular as concentrações de droga das amostras utilizando as curvas de calibração (desconhecido X e Y conhecida). </li><li> Calcular os níveis de sorção das drogas usando a seguinte equação: <img alt="equação 1" src="/files/ftp_upload/55086/55086eq1.jpg" /> onde S: nível de sorção (%) Co: concentração da droga após a diluição das preparações injectáveis ​​(ug / ml) Cp: ​​concentração de droga passou através dos tubos (ug / ml) </li></ol>

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The authors have nothing to disclose.

sorção droga para conjuntos de administração é uma causa de perda de droga inesperada na entrega de drogas intravenosas. Durante a adsorção, as drogas são geralmente particionado para materiais poliméricos dos tubos na fase de início da infusão; após sorção equilíbrio é alcançado, a quantidade administrada de droga é estabilizada 1. Os níveis de sorção de drogas deve ser avaliado e minimizado. Vários métodos de avaliação para a sorção de drogas têm sido estudadas, tais...

conjuntos de administração são compostas de um ponto, uma câmara conta-gotas, tubos, adaptadores Luer (conectores), e uma cobertura de agulha de protecção. Outros acessórios, tais como uma válvula de verificação das vias aéreas, uma braçadeira de regulação, de um filtro em linha, um Y-tubo com tampa (uma porta de injecção), e uma agulha, também pode ser ligado a conjuntos de administração. Sorção droga para tubos é uma questão crítica na entrega de drogas injetáveis 1. Sorção descreve a adsorção de um fármaco para a superfície do polímero e a absorção de uma droga na matriz polimérica 2. sorção droga para tubos em conjuntos de administração provoca perda de fármaco e imprevisível torna mais difícil controlar a concentração de fármaco administrado. sorção droga para tubos poliméricos é, portanto, um grande impedimento para a transferência precisa de drogas injetáveis ​​no corpo. No entanto, não existem métodos padrão ou diretrizes regulatórias para a avaliação da sorção de droga para tubos em conjuntos de administração. <html> Os níveis de sorção de drogas para tubos em conjuntos de administração têm sido relatados vários métodos de avaliação usando 1, 2, 3, 4, 5. métodos de ensaio e drogas modelo são fatores-chave na avaliação de sorção. O método da bomba 1, 3 e gotejamento método 4, 5 têm sido amplamente utilizados para testes de sorção. Em geral, o método da bomba deve ser usado no caso de drogas com baixas concentrações e as taxas de fluxo baixas como as condições de infusão. Usando vários métodos de avaliação, muitos estudos de sorção de drogas têm sido relatados para o cloreto de polivinila (PVC) - e os tubos não baseados em PVC na administração define 1, 2, 3,&gt; 5. Muitas drogas adsorventes podem ser seleccionados para investigar se os tubos dos conjuntos de administração têm potencial de sorção de drogas ou não. Diazepam (Figura 1a) 1, 2, tacrolimus (Figura 1b) 5, nitroglicerina 2, 3 e ciclosporina A são drogas representativas com elevada adsorção na de PVC e tubos não à base de PVC. Para a avaliação da sorção de droga para os tubos, as condições de teste, tais como a taxa de fluxo e a concentração de fármaco são baseados na utilização clínica dos medicamentos escolhidos 1, 6, 7. No caso de o diazepam, uma elevada concentração de 100 ug / ml foi utilizado a uma taxa de fluxo de 1 mL / min para imitar a dose inicial para o tratamento de um estado de mal epiléptico. Para o tacrolimus, uma concentração de 10 ug / mLfoi libertado a uma taxa de fluxo de 10 mL / h. Solução de dextrose (5%) foi utilizado para a diluição da injecção de drogas, e comprimento do tubo foi fixado em 1 m. garrafas e frascos de vidro devem ser usadas para prevenir a adsorção adicional durante a experiência e armazenamento. Neste estudo, foi realizado um estudo de sorção cinética com a droga modelo, diazepam e tacrolimus, usando um método de bomba. Os detalhes específicos do presente protocolo, desde a preparação tubo para avaliação de sorção, foram descritos anteriormente. Os métodos para a avaliação da sorção de drogas já foram utilizados para confirmar as propriedades de drogas para injecções e recomendar o uso clínico de injeções com conjuntos de administração, caso a caso a caso 1, 2, 3, 4, 5, 6, 7. Este protocolo pode ser utilizado como um padrãotécnica para a avaliação de sorção de conjuntos de administração. As normas internacionais para a avaliação da sorção de droga para tubos podem ser necessárias para garantir a segurança e eficácia da entrega da droga.

<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

conjuntos de administração são ferramentas de entrega para a aplicação direta de drogas no corpo e são compostas de um pico, uma câmara de gotejamento, tubos, adaptadores Luer (conectores), uma tampa de agulha para a proteção e outros acessórios. sorção droga para tubos de conjuntos de administração é uma questão crítica em termos de segurança e eficácia. Apesar de sorção de drogas é um fator importante para a qualidade de um conjunto de administração, não há métodos de avaliação standard para a regulação da absorção de droga para os tubos. Aqui, descrevemos um protocolo de avaliação para sorção droga para tubos de conjuntos de administração. Os tubos feitos de cloreto de polivinilo (PVC) - e materiais poliméricos não baseados em PVC foram cortadas a 1 m de comprimento. O diazepam e o tacrolimus foram usadas como drogas modelo. No estudo de sorção cinética, foram selecionados a taxa de concentração da droga e do fluxo com base no uso clínico dessas drogas. Após a diluição da droga em cada uma garrafa de vidro, a solução de fármaco diluída foi entregue através de tubosde administração define usando uma bomba. As amostras foram recolhidas em frascos âmbar a pontos de tempo apropriados e as drogas foram analisados ​​por cromatografia líquida de alto desempenho. As concentrações de fármaco e os níveis de sorção para os tubos dos conjuntos de administração foram calculados. critérios aceitáveis ​​para assegurar a qualidade dos conjuntos de administração são recomendados.

A sorção para os tubos no conjunto de administração foi monitorizada cineticamente usando as drogas modelo, diazepam (Figura 1A) e de tacrolimus (Figura 1b), e o método de bomba (figura 2). Diluído droga (Figura 2a) foi passada através de tubos de PVC e não à base de PVC (Figura 2b), a uma taxa de fluxo fixa utilizando uma bomba de infusão (Figura 2c). O frasco de vidro foi lig...

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

Relata-se um método para avaliação de sorção de drogas usando uma bomba e modelo drogas (diazepam e tacrolimus). Após análise de drogas usando cromatografia líquida de alto desempenho, as concentrações de fármaco e os níveis de sorção nos tubos de conjuntos de administração são calculados.

Avaliação de Drogas sorção a de PVC e Tubos em Administração Não-PVC com base em conjuntos utilizando uma bomba

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 visualizações.  Yonsei University.  Relata-se um método para avaliação de sorção de drogas usando uma bomba e modelo drogas (diazepam e tacrolimus). Após análise de drogas usando cromatografia líquida de alto desempenho, as concentrações de fármaco e os níveis de sorção nos tubos de conjuntos de administração são calculados. 

Vídeo: 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.

Avaliação do Câncer de Migração Stem Cell Usando compartimentar dispositivos microfluídicos e imagens de células vivas

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 ...

Medicina

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.

Cateterismo arterial e venoso femoral para coleta de sangue, Drug Administration e Pressão Arterial Consciente e Medidas de freqüência cardíaca

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.

A Medição e Tratamento de Supressão de ambliopia

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.

A administração intranasal de Terapêutica do SNC para Ratos Awake

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.

Avaliação de uma nova Laser-assistida Coronary Anastomotic Connector - Trindade Clip - em um modelo de Bypass Porcina Off-bomba

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.

Quantificação do imunossupressor tacrolimus em manchas de sangue seco utilizando 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.

Utilizando os ácidos biliares e multi-fluorados<em&gt; In Vivo</em&gt; Magnetic Resonance Imaging medir Bile transporte do ácido

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.

Novos métodos para a Administração Intranasal sob anestesia por inalação para avaliar a entrega da droga de nariz-de-Brain

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.

Implante de uma Minibomba isoproterenol para induzir insuficiência cardíaca em camundongos

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.

Avaliação da autoregulação do fluxo sanguíneo cerebral no rato usando fluimetria de laser

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