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1.
Br J Clin Pharmacol ; 88(4): 1655-1666, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34240449

RESUMEN

AIM: Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. METHODS: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax ) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8. RESULTS: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax and partial AUC through Weeks 4 and 8. CONCLUSION: MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Imágenes de Resonancia Magnética Multiparamétrica , Adulto , Dicetopiperazinas , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Inyecciones Intramusculares , Cinética , Masculino , Piridonas , Voluntarios
2.
J Pharmacol Exp Ther ; 370(3): 786-795, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30936291

RESUMEN

Autosomal dominant polycystic kidney disease (ADPKD) is a leading monogenetic cause of end-stage renal disease with limited therapeutic repertoire. A targeted drug delivery strategy that directs a small molecule to renal niches around cysts could increase the safety margins of agents that slow the progression of ADPKD but are poorly tolerated due to extrarenal toxicity. Herein, we determined whether previously characterized lysine-based and glutamic acid-based megalin-binding peptides can achieve renal-specific localization in the juvenile cystic kidney (JCK) mouse model of polycystic kidney disease and whether the distribution is altered compared with control mice. We performed in vivo optical and magnetic resonance imaging studies using peptides conjugated to the VivoTag 680 dye and demonstrated that megalin-interacting peptides distributed almost exclusively to the kidney cortex in both normal and JCK mice. Confocal analysis demonstrated that the peptide-dye conjugate distribution overlapped with megalin-positive renal proximal tubules. However, in the JCK mouse, the epithelium of renal cysts did not retain expression of the proximal tubule markers aquaporin 1 and megalin, and therefore these cysts did not retain peptide-dye conjugates. Furthermore, human kidney tumor tissues were evaluated by immunohistochemistry and revealed significant megalin expression in tissues from patients with renal cell carcinoma, raising the possibility that these tumors could be treated using this drug delivery strategy. Taken together, our data suggest that linking a small-molecule drug to these carrier peptides could represent a promising opportunity to develop a new platform for renal enrichment and targeting in the treatment of ADPKD and certain renal carcinomas.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Riñón/efectos de los fármacos , Péptidos/administración & dosificación , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Animales , Acuaporina 1/metabolismo , Colorantes , Diseño de Fármacos , Epitelio/metabolismo , Ácido Glutámico/química , Humanos , Corteza Renal/diagnóstico por imagen , Corteza Renal/metabolismo , Neoplasias Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Lisina/química , Imagen por Resonancia Magnética , Ratones , Péptidos/química , Péptidos/farmacocinética , Enfermedades Renales Poliquísticas/diagnóstico por imagen , Distribución Tisular
3.
Heart Lung Circ ; 28(3): 495-504, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29277546

RESUMEN

BACKGROUND: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. METHODS: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10µM indoxyl sulphate (IS) or 10ng/ml transforming growth factor ß1 (TGFß1) for 48hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2hours before being stimulated with 100nM AngII for 60hours, 10µM IS, 10ng/ml interleukin 1ß (IL-1ß) or tumour necrosis factor α (TNFα) for 48hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. RESULTS: Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1ß- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFß1-stimulated NCF collagen synthesis and AngII- and TGFß1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. CONCLUSIONS: Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.


Asunto(s)
Cardiomegalia/genética , Colágeno/biosíntesis , Regulación del Desarrollo de la Expresión Génica , MAP Quinasa Quinasa Quinasa 5/genética , Miocitos Cardíacos/patología , ARN/genética , Animales , Animales Recién Nacidos , Cardiomegalia/metabolismo , Cardiomegalia/patología , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , MAP Quinasa Quinasa Quinasa 5/biosíntesis , Miocitos Cardíacos/metabolismo , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Transducción de Señal
4.
Toxicol Pathol ; 44(1): 51-60, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26516164

RESUMEN

To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established.


Asunto(s)
Sistema Biliar/fisiopatología , Gadolinio DTPA/farmacocinética , Lipidosis/fisiopatología , Hígado/fisiopatología , Imagen por Resonancia Magnética/métodos , Fosfolípidos/metabolismo , Amiodarona/toxicidad , Animales , Sistema Biliar/metabolismo , Sistema Biliar/patología , Lipidosis/inducido químicamente , Lipidosis/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley
5.
Cardiovasc Diabetol ; 12: 148, 2013 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-24125539

RESUMEN

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.


Asunto(s)
Cardiotónicos/farmacología , Péptido 1 Similar al Glucagón/farmacología , Inmunoconjugados/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Fragmentos de Péptidos/farmacología , Albúmina Sérica/inmunología , Anticuerpos de Dominio Único/farmacología , Animales , Cardiotónicos/administración & dosificación , Cardiotónicos/sangre , Cardiotónicos/farmacocinética , Modelos Animales de Enfermedad , Exenatida , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/farmacocinética , Receptor del Péptido 1 Similar al Glucagón , Inmunoconjugados/administración & dosificación , Inmunoconjugados/sangre , Inmunoconjugados/farmacocinética , Inyecciones Subcutáneas , Masculino , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/farmacocinética , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/agonistas , Receptores de Glucagón/genética , Anticuerpos de Dominio Único/administración & dosificación , Anticuerpos de Dominio Único/sangre , Ponzoñas/farmacología , Función Ventricular Izquierda/efectos de los fármacos
6.
J Cardiovasc Pharmacol ; 61(4): 291-301, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23232840

RESUMEN

Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.


Asunto(s)
Aorta/efectos de los fármacos , Ciclohexilaminas/farmacología , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Piperidinas/farmacología , Triazinas/farmacología , Animales , Aorta/patología , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Constricción Patológica , Modelos Animales de Enfermedad , Fibrosis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Remodelación Ventricular/efectos de los fármacos
7.
Birth Defects Res ; 115(14): 1284-1293, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37140214

RESUMEN

OBJECTIVES: The objective of this study was to examine the fetal skeletons using both alizarin red stain and micro-computed tomography (CT) images; investigate differences, and to determine if the conclusions of the study were the same regardless of the examination method. METHODS: A candidate drug was given orally by gavage to pregnant New Zealand White rabbits on gestation day (GD) 7 to GD 19 (mating = GD 0) at doses of 0 (control), 0.02, 0.5, 5, and 15 mg/kg/day. Maternal toxicity was evident at ≥0.02 mg/kg/day. The 199 fetal skeletons (totaling 50,546 skeletal elements) obtained at cesarean delivery on GD29 were first stained with Alizarin Red S, then imaged by a Siemens Inveon micro-CT scanner. All fetal skeletons were examined by both methods, without knowledge of dose group, and the results were compared. RESULTS: In total, 33 types of skeletal abnormalities were identified. There was 99.8% concordance of results comparing stain to micro-CT. Ossification of the middle phalanx of the forepaw digit 5 showed the greatest difference between the two methods. CONCLUSION: Overall, micro-CT imaging is a realistic, and robust alternative to skeletal staining to examine fetal rabbit skeletons in developmental toxicity studies.


Asunto(s)
Huesos , Cesárea , Embarazo , Femenino , Conejos , Animales , Microtomografía por Rayos X/métodos , Huesos/diagnóstico por imagen , Coloración y Etiquetado
8.
Mol Imaging Biol ; 25(3): 528-540, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36266600

RESUMEN

PURPOSE: The presence and functional competence of intratumoral CD8+ T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8+ T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting. Here, we took advantage of immuno-PET imaging using 89Zr-IAB42M1-14, anti-mouse CD8 minibody, to characterize CD8+ T-cell tumor infiltration dynamics following ICOS (inducible T-cell co-stimulator) agonist antibody treatment alone and in combination with PD-1 blocking antibody in a model of mammary carcinoma. PROCEDURES: Female BALB/c mice with established EMT6 tumors received 10 µg, IP of either IgG control antibodies, ICOS agonist monotherapy, or ICOS/PD-1 combination therapy on days 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 and 48 h post IV dose of 89Zr IAB42M1-14. In addition to 89Zr-IAB42M1-14 uptake in tumor and tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images to identify treatment effects. Imaging mass cytometry (IMC) and immunohistochemistry (IHC) was performed at end of study. RESULTS: 89Zr-IAB42M1-14 uptake in the tumor was observed by day 11 and was preceded by an increase in the TDLN as early as day 4. The spatial distribution of 89Zr-IAB42M1-14 was more uniform in the drug treated vs. control tumors, which had spatially distinct tracer uptake in the periphery relative to the core of the tumor. IMC analysis showed an increased percentage of cytotoxic T cells in the ICOS monotherapy and ICOS/PD-1 combination group compared to IgG controls. Additionally, temporal radiomics analysis demonstrated early predictiveness of imaging features. CONCLUSION: To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8+ T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8+ T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Animales , Ratones , Femenino , Linfocitos T CD8-positivos/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptor de Muerte Celular Programada 1 , Neoplasias/patología , Tomografía de Emisión de Positrones/métodos , Inmunoglobulina G , Línea Celular Tumoral , Proteína Coestimuladora de Linfocitos T Inducibles
9.
Magn Reson Med ; 67(1): 191-200, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21671268

RESUMEN

The temporal evolution of heart failure and associated pulmonary congestion in rodent heart failure models has not yet been characterized simultaneously and noninvasively. In this study, MRI was used to assess the serial progression of left-ventricular dysfunction and lung congestion in mice following myocardial infarction (MI). Cardiac and lung (1) H MRI was performed at baseline and every 3 days up to 13 days postsurgery in sham and MI mice. Respiratory parameters and terminal lung mechanics were assessed followed by histological analysis. MRI revealed that the MI induced significant pulmonary congestion/edema as detected by increased MRI signal intensity and was associated with increased lung volume and reduced cardiac contractility. Pulmonary function was also depressed in MI-mice, reflected by a reduced tidal volume and a low minute ventilation rate. Additionally, MI significantly increased lung resistance, markedly reduced lung compliance and total lung capacity and significantly increased lung weights by 57%. Significant correlations were observed between the MRI measured lung congestion, lung volume, ejection fraction, and lung wet-weight parameters. This study demonstrates that MRI may be of significant value in evaluating therapies aimed at primary intervention for lung congestion and secondary prevention of unfavorable cardiac remodeling.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Edema Pulmonar/patología , Edema Pulmonar/fisiopatología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/fisiología , Animales , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Edema Pulmonar/complicaciones , Disfunción Ventricular Izquierda/complicaciones
10.
J Control Release ; 352: 199-210, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36084816

RESUMEN

Liposomes are promising targeted drug delivery systems with the potential to improve the efficacy and safety profile of certain classes of drugs. Though attractive, there are unique analytical challenges associated with the development of liposomal drugs including human dose prediction given these are multi-component drug delivery systems. In this study, we developed a multimodal imaging approach to provide a comprehensive distribution assessment for an antibacterial drug, GSK2485680, delivered as a liposomal formulation (Lipo680) in a mouse thigh model of bacterial infection to support human dose prediction. Positron emission tomography (PET) imaging was used to track the in vivo biodistribution of Lipo680 over 48 h post-injection providing a clear assessment of the uptake in various tissues and, importantly, the selective accumulation at the site of infection. In addition, a pharmacokinetic model was created to evaluate the kinetics of Lipo680 in different tissues. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was then used to quantify the distribution of GSK2485680 and to qualitatively assess the distribution of a liposomal lipid throughout sections of infected and non-infected hindlimb tissues at high spatial resolution. Through the combination of both PET and MALDI IMS, we observed excellent correlation between the Lipo680-radionuclide signal detected by PET with the GSK2485680 and lipid component signals detected by MALDI IMS. This multimodal translational method can reduce drug attrition by generating comprehensive biodistribution profiles of drug delivery systems to provide mechanistic insight and elucidate safety concerns. Liposomal formulations have potential to deliver therapeutics across a broad array of different indications, and this work serves as a template to aid in delivering future liposomal drugs to the clinic.


Asunto(s)
Enfermedades Transmisibles , Liposomas , Animales , Ratones , Humanos , Liposomas/química , Distribución Tisular , Antibacterianos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Tomografía de Emisión de Positrones , Imagen Multimodal , Lípidos
11.
Front Immunol ; 13: 1081156, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36713458

RESUMEN

The goal of this study was to utilize a multimodal magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging approach to assess the local innate immune response in skeletal muscle and draining lymph node following vaccination in rats using two different vaccine platforms (AS01 adjuvanted protein and lipid nanoparticle (LNP) encapsulated Self-Amplifying mRNA (SAM)). MRI and 18FDG PET imaging were performed temporally at baseline, 4, 24, 48, and 72 hr post Prime and Prime-Boost vaccination in hindlimb with Cytomegalovirus (CMV) gB and pentamer proteins formulated with AS01, LNP encapsulated CMV gB protein-encoding SAM (CMV SAM), AS01 or with LNP carrier controls. Both CMV AS01 and CMV SAM resulted in a rapid MRI and PET signal enhancement in hindlimb muscles and draining popliteal lymph node reflecting innate and possibly adaptive immune response. MRI signal enhancement and total 18FDG uptake observed in the hindlimb was greater in the CMV SAM vs CMV AS01 group (↑2.3 - 4.3-fold in AUC) and the MRI signal enhancement peak and duration were temporally shifted right in the CMV SAM group following both Prime and Prime-Boost administration. While cytokine profiles were similar among groups, there was good temporal correlation only between IL-6, IL-13, and MRI/PET endpoints. Imaging mass cytometry was performed on lymph node sections at 72 hr post Prime and Prime-Boost vaccination to characterize the innate and adaptive immune cell signatures. Cell proximity analysis indicated that each follicular dendritic cell interacted with more follicular B cells in the CMV AS01 than in the CMV SAM group, supporting the stronger humoral immune response observed in the CMV AS01 group. A strong correlation between lymph node MRI T2 value and nearest-neighbor analysis of follicular dendritic cell and follicular B cells was observed (r=0.808, P<0.01). These data suggest that spatiotemporal imaging data together with AI/ML approaches may help establish whether in vivo imaging biomarkers can predict local and systemic immune responses following vaccination.


Asunto(s)
Infecciones por Citomegalovirus , Fluorodesoxiglucosa F18 , Ratas , Animales , Vacunación , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones , Citomegalovirus , Inmunidad Innata , Músculo Esquelético/diagnóstico por imagen , Imagen Multimodal , Ganglios Linfáticos/diagnóstico por imagen
12.
Arterioscler Thromb Vasc Biol ; 30(2): 253-9, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19965779

RESUMEN

UNLABELLED: Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model. METHODS AND RESULTS: Apolipoprotein E(-/-) mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (P<0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (P<0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (P<0.05). CONCLUSIONS: An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.


Asunto(s)
Antiinflamatorios/farmacología , Enfermedades de la Aorta/dietoterapia , Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Imagen por Resonancia Magnética , Naftiridinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Animales , Antiinflamatorios/farmacocinética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Medios de Contraste , Dextranos , Grasas de la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Óxido Ferrosoférrico , Humanos , Inmunohistoquímica , Bombas de Infusión Implantables , Macrófagos/inmunología , Macrófagos/patología , Nanopartículas de Magnetita , Ratones , Ratones Noqueados , Ratones Transgénicos , Naftiridinas/farmacocinética , Peritonitis/inmunología , Peritonitis/prevención & control , Receptores CCR2/genética , Receptores CCR2/metabolismo , Factores de Tiempo
13.
Life Sci ; 272: 119267, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33631173

RESUMEN

AIMS: Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. MAIN METHODS: IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. KEY FINDINGS: IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor ß receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. SIGNIFICANCE: ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.


Asunto(s)
Endotelio/metabolismo , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , MAP Quinasa Quinasa Quinasa 5/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Células Endoteliales/metabolismo , Endotelio/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Indicán/efectos adversos , Indicán/farmacología , MAP Quinasa Quinasa Quinasa 5/fisiología , Masculino , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Vasodilatación/efectos de los fármacos
14.
J Cardiovasc Pharmacol ; 56(2): 147-55, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20714241

RESUMEN

BACKGROUND: Hypoxia inducible factors (HIFs) are transcription factors that are regulated by HIF-prolyl 4-hydroxylases (PHDs) in response to changes in oxygen tension. Once activated, HIFs play an important role in angiogenesis, erythropoiesis, proliferation, cell survival, inflammation, and energy metabolism. We hypothesized that GSK360A, a novel orally active HIF-PHD inhibitor, could facilitate local and systemic HIF-1 alpha signaling and protect the failing heart after myocardial infarction (MI). METHODS AND RESULTS: GSK360A is a potent (nanomolar) inhibitor of HIF-PHDs (PHD1>PHD2 = PHD3) capable of activating the HIF-1 alpha pathway in a variety of cell types including neonatal rat ventricular myocytes and H9C2 cells. Male rats treated orally with GSK360A (30 mg x kg x d) had a sustained elevation in circulating levels of erythropoietin and hemoglobin and increased hemoxygenase-1 expression in the heart and skeletal muscle. In a rat model of established heart failure with systolic dysfunction induced by ligation of left anterior descending coronary artery, chronic treatment with GSK360A for 28 days prevented the progressive reduction in ejection fraction, ventricular dilation, and increased lung weight, which were observed in the vehicle-treated animals, for up to 3 months. In addition, the microvascular density in the periinfarct region was increased (>2-fold) in GSK360A-treated animals. Treatment was well tolerated (survival was 89% in the GSK360A group vs. 82% in the placebo group). CONCLUSIONS: Chronic post-myocardial infarction treatment with a selective HIF PHD inhibitor (GSK360A) exerts systemic and local effects by stabilizing HIF-1 alpha signaling and improves long-term ventricular function, remodeling, and vascularity in a model of established ventricular dysfunction. These results suggest that HIF-PHD inhibitors may be suitable for the treatment of post-MI remodeling and heart failure.


Asunto(s)
Vasos Coronarios/efectos de los fármacos , Glicina/análogos & derivados , Factor 1 Inducible por Hipoxia/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Quinolonas/farmacología , Remodelación Ventricular/efectos de los fármacos , Animales , Línea Celular , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Glicina/farmacología , Hemodinámica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley
15.
Int J Cardiol ; 310: 128-136, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32305147

RESUMEN

BACKGROUND: Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. METHODS: Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. RESULTS: G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. CONCLUSION: Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.


Asunto(s)
Síndrome Cardiorrenal , Disfunción Ventricular Izquierda , Animales , Síndrome Cardiorrenal/tratamiento farmacológico , Fibrosis , Hipertrofia Ventricular Izquierda , MAP Quinasa Quinasa Quinasa 5 , Masculino , Ratas , Ratas Sprague-Dawley
16.
Arterioscler Thromb Vasc Biol ; 28(2): 265-71, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18162612

RESUMEN

OBJECTIVE: Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation. The purpose of this study was to noninvasively evaluate USPIO uptake in aorta of apoE-/- mice and to determine the effects of Angiotensin II (Ang II) infusion and chronic antiinflammatory treatment with a p38 MAPK inhibitor on this uptake. METHODS AND RESULTS: ApoE-/- mice were administered saline or Ang II (1.44 mg/kg/d) for 21 days. In vivo MRI assessment of USPIO uptake in the aortic arch was observed in all animals. However, although the Ang II group had significantly higher absolute iron content (increased 103%, P<0.001) in the aortic arch compared with the saline group, the p38 MAPK inhibitor (SB-239063, 150 mg/kg/d) treatment group did not (increased 6%, NS). The in vivo MRI signal intensity was significantly correlated to the absolute iron content in the aortic arch. Histological evaluation of the aortic root lesion area showed colocalization of USPIO with macrophages and a reduction in USPIO but not macrophage content with SB-239063 treatment. CONCLUSIONS: The present study demonstrates that noninvasive assessment of USPIO uptake, as a marker for inflammation in murine atherosclerotic plaque, is feasible and that p38 MAPK inhibition attenuates the uptake of USPIO in aorta of Ang II-infused apoE-/- mice.


Asunto(s)
Aorta/patología , Óxido Ferrosoférrico , Imidazoles/farmacología , Angiografía por Resonancia Magnética/métodos , Nanopartículas del Metal , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Animales , Apolipoproteínas E/genética , Aterosclerosis/diagnóstico , Medios de Contraste/farmacocinética , Inhibidores Enzimáticos/farmacología , Estudios de Factibilidad , Óxido Ferrosoférrico/farmacocinética , Inflamación/diagnóstico , Masculino , Ratones , Ratones Noqueados , Vasoconstrictores/administración & dosificación
17.
J Pharmacol Exp Ther ; 325(2): 466-74, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18287212

RESUMEN

Peroxisome proliferator-activated receptor (PPAR)-delta is a transcription factor that belongs to the PPAR family. PPAR-delta is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of PPAR-delta protects the heart from ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia. A highly selective PPAR-delta agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]acetic acid (GW0742), was administered for 7 days at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with GW0742 reduced serum levels of cardiac troponin-I and infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with GW0742 up-regulated gene expression involved in cardiac fatty acid oxidation, increased fat use in the heart, and reduced serum levels of free fatty acids. The enhanced cardiac expression of interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by GW0742. Treatment with GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac caspase-3 activity by 61% (both p < 0.01 versus vehicle). GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition, GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of PPAR-delta protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.


Asunto(s)
Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , PPAR delta/agonistas , Tiazoles/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Citocinas/genética , Modelos Animales de Enfermedad , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Corazón/fisiopatología , Cetonas/metabolismo , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Daño por Reperfusión Miocárdica/sangre , Daño por Reperfusión Miocárdica/fisiopatología , PPAR delta/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Zucker , Troponina I/sangre
18.
Birth Defects Res ; 110(3): 276-298, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29159925

RESUMEN

OBJECTIVES: In our laboratory we evaluated the use of micro-computed tomography (micro-CT) using a high resolution acquisition protocol and fetuses obtained on Gestation Day (GD) 29 (mating = GD 0). METHODS: To show concordance between traditional Alizarin Red S stain and micro-CT skeletal examination methods, 103 fetuses from 19 untreated Dutch belted rabbits were obtained by cesarean section and stored frozen. The fetuses were thawed, imaged and examined digitally by micro-CT, then stained and re-examined using traditional methods. RESULTS: A total of 12 individual malformations and 35 unique variations were detected by both methods. Differences in the extent of ossification were found in only 51 of 26,196 bones while 99.8% of the observations were identical. Of the 51 differences, 31 were an unossified fifth medial phalanx of the forepaw indicating that very low-density skeletal bones may be visible by Alizarin Red stain but not by micro-CT scan. To establish this methodology under pharmaceutical testing conditions, we obtained and imaged by micro-CT Alizarin Red S stained abnormal fetal rabbit skeletons previously exposed to a drug candidate associated with craniofacial malformations in humans. All of the types of skeletal abnormalities first identified by staining were also detected by micro-CT examination. Representative images of these 66 different fetal skeletal abnormalities were characterized, and compiled to illustrate visual concordance between micro-CT scanned and traditional Alizarin Red S stained skeletons. CONCLUSION: Micro-CT imaging is an accurate, reliable and robust method that can be used as an alternative to stain when examining fetal rabbit skeletons in developmental toxicity studies.


Asunto(s)
Antraquinonas/química , Huesos , Feto , Coloración y Etiquetado , Microtomografía por Rayos X/métodos , Animales , Huesos/anomalías , Huesos/diagnóstico por imagen , Huesos/embriología , Feto/anomalías , Feto/diagnóstico por imagen , Feto/embriología , Conejos
19.
PLoS One ; 13(5): e0197213, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29771932

RESUMEN

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic. CONCLUSION: Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.


Asunto(s)
Medios de Contraste , Gadolinio DTPA , Hígado , Imagen por Resonancia Magnética , Animales , Transporte Biológico Activo/efectos de los fármacos , Biomarcadores/metabolismo , Medios de Contraste/farmacocinética , Medios de Contraste/farmacología , Evaluación Preclínica de Medicamentos , Gadolinio DTPA/farmacocinética , Gadolinio DTPA/farmacología , Hígado/diagnóstico por imagen , Hígado/metabolismo , Masculino , Ratas , Ratas Wistar
20.
J Control Release ; 268: 102-112, 2017 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-29042321

RESUMEN

Long-Acting Parenterals (LAPs) have been used in the clinic to provide sustained therapeutic drug levels at a target site, and thereby reducing the frequency of dosing required. In an effort to understand the factors associated with long-acting cabotegravir (GSK1265744 LAP) pharmacokinetic variability, the current study was designed to investigate the temporal relationship between intramuscular (IM) or subcutaneous (SC) drug depot morphology and distribution kinetics with plasma pharmacokinetics. Therefore, a multi-modal molecular imaging (MRI & MALDI IMS) approach was employed to examine the temporal GSK1265744 LAP biodistribution in rat following either IM or SC administration. Serial MRI was performed immediately post drug administration, and then at day 1 (24h post), 2, 3, 4, 7, and 14. In a separate cohort of rats, an MRI contrast agent, Feraheme® (USPIO), was administered 2days post IM drug injection in order to investigate the potential involvement of macrophages trafficking to the GSK1265744 LAP and Vehicle depot sites. The GSK1265744 LAP depot volume increased rapidly by day 2 in the IM injected rats (~3-7 fold) compared with a ~1 fold increase in the SC injected rats. In addition, the USPIO contrast agent labeled macrophages were shown to be present in the depot region of the GSK1265744 LAP injected gastrocnemius while the Vehicle injected gastrocnemius appeared to show reduced uptake. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) of muscle and abdominal tissue sections identified the drug content primarily within the depot. Co-registration of the GSK1265744 ion images with immunohistochemical images established that the drug was taken up by macrophages associated with the depot. Linear regression analysis demonstrated that the drug depot characteristics including volume, surface area, and perimeter assessed by MRI at day 2 correlated with early time point plasma drug concentrations. In summary, a multimodal molecular imaging approach was used to identify the drug depot location and volumetric/physiologic changes in both IM and SC locations following GSK1265744 LAP administration. The IM depot volume increased rapidly to a maximum volume at 2days post-GSK1265744 LAP administration, while the Vehicle depot did not suggesting that the active drug substance and/or related particle was a key driver for drug depot evolution. The depot expansion was associated with an increase in macrophage infiltration and edema in and around the depot region and was correlated to plasma drug concentration at early time points (0-4days). Consequently, molecular imaging approaches may be used in patients to help understand the biodistribution of GSK1265744 LAP and its associated pharmacokinetics.


Asunto(s)
Piridonas/administración & dosificación , Piridonas/farmacocinética , Animales , Medios de Contraste/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Óxido Ferrosoférrico/administración & dosificación , Inyecciones Intramusculares , Inyecciones Subcutáneas , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Imagen por Resonancia Magnética , Masculino , Imagen Multimodal , Piridonas/sangre , Ratas Sprague-Dawley , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Distribución Tisular
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