RESUMEN
BACKGROUND: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). METHODS: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. RESULTS: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. CONCLUSIONS: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation.
Asunto(s)
Doxiciclina/administración & dosificación , Electrocardiografía , Metaloproteinasas de la Matriz/sangre , Infarto del Miocardio/terapia , Reperfusión Miocárdica/métodos , Inhibidor Tisular de Metaloproteinasa-1/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Administración Oral , Anciano , Antibacterianos/administración & dosificación , Angiografía Coronaria , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Estudios Prospectivos , Inhibidores de Proteasas/uso terapéutico , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Remodelación VentricularRESUMEN
Taking advantage of click chemistry, we synthesized triazole-containing RGD peptidomimetics capable of binding to αvß3 integrin with diverse potency, and selected (125)I-labeled compounds proved to interact in vitro and in vivo with αvß3 integrin expressed by melanoma cells. Two (125)I-compounds containing either 2-aminobenzimidazole or 2-aminopyridine groups as the arginine bioisostere with the capacity to selectively bind cells of highly expressing αvß3 melanoma xenografts were found using micro-SPECT imaging studies.
Asunto(s)
Integrinas/química , Sondas Moleculares , Neovascularización Patológica/diagnóstico , Oligopéptidos/química , Tomografía Computarizada de Emisión de Fotón Único/métodos , Triazoles/química , Animales , Xenoinjertos , Humanos , Ligandos , Melanoma/diagnóstico por imagen , Ratones , Modelos Moleculares , Oligopéptidos/síntesis químicaRESUMEN
AIMS: Experimental studies suggest that doxycycline attenuates post-infarction remodelling and exerts protective effects on myocardial ischaemia/reperfusion injury. However, the effects of the drug in the clinical setting are unknown. The aim of this study was to examine the effect of doxycycline on left ventricular (LV) remodelling in patients with acute ST-segment elevation myocardial infarction (STEMI) and LV dysfunction. METHODS AND RESULTS: Open-label, randomized, phase II trial. Immediately after primary percutaneous coronary intervention, patients with STEMI and LV ejection fraction < 40% were randomly assigned to doxycycline (100 mg b.i.d. for 7 days) in addition to standard therapy, or to standard care. The echo LV end-diastolic volumes index (LVEDVi) was determined at baseline and 6 months. (99m)Tc-Sestamibi-single-photon emission computed tomography infarct size and severity were assessed at 6 months. We calculated a sample size of 110 patients, assuming that doxycycline may reduce the increase in the LVEDVi from baseline to 6 months > 50% compared with the standard therapy (statistical power > 80% with a type I error = 0.05). The 6-month changes in %LVEDVi were significant smaller in the doxycycline group than in the control group [0.4% (IQR: -16.0 to 14.2%) vs.13.4% (IQR: -7.9 to 29.3%); P = 0.012], as well as infarct size [5.5% (IQR: 0 to 18.8%) vs. 10.4% (IQR: 0.3 to 29.9%) P = 0.052], and infarct severity [0.53 (IQR: 0.43-0.62) vs. 0.44 (IQR: 0.29-0.60), P = 0.014], respectively. CONCLUSION: In patients with acute STEMI and LV dysfunction, doxycycline reduces the adverse LV remodelling for comparable definite myocardial infarct size (NCT00469261).
Asunto(s)
Cardiotónicos/administración & dosificación , Doxiciclina/administración & dosificación , Infarto del Miocardio/terapia , Disfunción Ventricular Izquierda/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Adulto , Anciano , Análisis de Varianza , Angiografía Coronaria , Progresión de la Enfermedad , Esquema de Medicación , Ecocardiografía , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Radiofármacos , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
In this paper, using a hybrid small-animal Micro SPECT/CT imaging system, we report that a new (125)I-Cilengitide-like RGD-cyclopentapeptide, containing d-morpholine-3-carboxylic acid, interacts in vivo with α(v)ß(3) integrin expressed by melanoma cells. Images clearly show that the (125)I-compound has the capacity to monitor the growth of a melanoma xenograft. Indeed, retention of the labeled ligand in the tumor mass has a good tumor/background ratio, and a significant reduction of its uptake was observed after injection of unlabeled ligand. These results suggest that the use of (125)I-labeled morpholine-based RGD-cyclopentapeptides targeting α(v)ß(3) positive tumors may play a role in future therapeutic strategies.
Asunto(s)
Integrina alfaVbeta3/metabolismo , Sondas Moleculares/síntesis química , Morfolinas/síntesis química , Neovascularización Patológica/diagnóstico por imagen , Oligopéptidos/síntesis química , Péptidos Cíclicos/síntesis química , Radiofármacos/síntesis química , Adhesión Celular , Movimiento Celular , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Radioisótopos de Yodo , Ligandos , Melanoma/diagnóstico por imagen , Modelos Moleculares , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Morfolinas/química , Morfolinas/farmacocinética , Imagen Multimodal , Trasplante de Neoplasias , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/farmacología , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular , Tomografía Computarizada por Rayos X , Trasplante HeterólogoRESUMEN
A click chemistry approach was applied for the discovery of triazole-based arginine-glycine-aspartate (RGD) mimetics by Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction, which showed binding affinity properties toward α(v)ß(3)/α(v)ß(5) integrins. Biological assays showed compound 18 capable of binding α(v)ß(3) integrin with nanomolar affinity according to a two-sites model, and molecular modeling studies revealed a peculiar π-stacking interaction between the triazole ring and Tyr178 side chain. Accordingly, compound 18 inhibited the adhesion of integrin-expressing human melanoma cells to RGD-containing proteins of the extracellular matrix, such as vitronectin, fibronectin, and osteopontin, and also angiogenesis in in vitro and in vivo experimental models. The relevant biological effects exerted by compound 18 suggest its potential application as an antiangiogenic agent in the diagnosis and therapy of tumors where α(v)ß(3) integrin expression is up-regulated.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Melanoma/irrigación sanguínea , Melanoma/patología , Neovascularización Patológica/patología , Oligopéptidos/metabolismo , Fenilpropionatos/síntesis química , Receptores de Vitronectina/metabolismo , Triazoles/síntesis química , Alquinos/síntesis química , Alquinos/química , Alquinos/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Azidas/síntesis química , Azidas/química , Azidas/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Ligandos , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Imitación Molecular , Neovascularización Patológica/tratamiento farmacológico , Fenilpropionatos/química , Fenilpropionatos/farmacología , Unión Proteica , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Two c[RGDfX] cyclopeptides, having either L- or D-morpholine-3-COOH (Mor) as the X amino acid were developed as ligands for alpha(v)beta(3)/alpha(v)beta(5) integrins. Biological assays showed only d-Mor-containing cyclopentapeptide capable to bind alpha(v)beta(3) integrin with a low nanomolar affinity according to a two-site model, thus revealing a connection between the configuration of Mor and the preferred binding to alpha(v)beta(3) integrin. Conformational analysis showed different structural preferences for the two peptides induced by the two enantiomeric cyclic amino acids, suggesting a role of the stereochemistry of Mor on the overall peptide conformation and on the presentation of the pharmacophoric Arg and Asp side chains.
Asunto(s)
Integrina alfaVbeta3/metabolismo , Oligopéptidos/metabolismo , Péptidos Cíclicos/metabolismo , Receptores de Vitronectina/metabolismo , Sitios de Unión , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Morfolinas/química , Morfolinas/metabolismo , Oligopéptidos/química , Péptidos Cíclicos/química , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
BACKGROUND: The relationship among plasma brain natriuretic peptide (BNP), markers of extracellular matrix (ECM) remodeling, and left ventricular (LV) dilation after reperfused acute myocardial infarction is poorly known. METHODS AND RESULTS: Echocardiogram, plasma BNP, and ECM degradation markers (serum amino-terminal telopeptide of type I procollagen and type III procollagen and carboxy-terminal telopeptide of type I procollagen [ICTP]) were evaluated in 34 patients at days 1, 3, and 30 after first reperfused acute myocardial infarction. At 1 month, infarct size and severity and LV volume were measured by sestamibi gated single photon emission computed tomography. Patients were stratified according to day 3 BNP levels into 2 groups: group 1 (n = 17) had BNP values over the median value, and group 2 (n = 17) had BNP values under the median value. Infarct size and severity were similar in the 2 groups. LV volumes increased in group 1 but decreased in group 2 (P < .01). BNP values, LV volume/mass index, and infarct size were independent predictors of 1-month LV dilation (beta = .58 [P = .001], beta = .41 [P = .01], and beta = .32 [P = .03], respectively). Levels of serum amino-terminal propeptide of type I procollagen and type III procollagen were similar in both groups. The level of ICTP increased significantly in group 1 only, and after 3 days, it was higher (P < .01) than in group 2. In group 1 ICTP significantly interacted with the relationship between BNP release and serial changes in LV volumes (F = 4.87, P = .03). CONCLUSIONS: ICTP is related to elevated BNP level independently of infarct size and severity and interacts with the relationship between BNP and LV dilation. BNP levels could play a role in LV remodeling by favoring ECM degradation.
Asunto(s)
Colágeno/metabolismo , Infarto del Miocardio/metabolismo , Péptido Natriurético Encefálico/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Remodelación Ventricular , Anciano , Ecocardiografía/métodos , Electrocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/patología , Péptidos/química , Estudios Prospectivos , Factores de RiesgoRESUMEN
The embodiment of 4-aminoproline residues (Amp) into the arginine-glycine-aspartate (RGD) sequence led to the discovery of a novel class of high-affinity alpha Vbeta 3/alpha Vbeta 5 integrin binders [IC 50 h (alpha Vbeta 3) 0.03-5.12 nM; IC 50 h (alpha Vbeta 5) 0.88-154 nM]. A total of eight cyclopeptides of type cyclo-[-Arg-Gly-Asp-Amp-], 5- 12, were assembled by a standard solid-phase peptide synthesis protocol that involved the C2-carboxyl and C4-amino functionalities of the proline scaffolds, leaving the N (alpha)-nuclear site untouched. Functionalization of this vacant proline site with either alkyl or acyl substituents proved feasible, with significant benefit to the integrin binding capabilities of the ligands. Notably, six out of eight cyclopeptide inhibitors, 5- 7 and 9- 11, showed moderate yet significant selectivity toward the alpha Vbeta 3 receptor. The three-dimensional structure in water was determined by NMR techniques and molecular dynamics calculations. Docking studies to the X-ray crystal structure of the extracellular segment of integrin alpha Vbeta 3 complexed with reference compound 1 were also performed on selected analogues to highlight the structural features required for potent ligand binding affinity.
Asunto(s)
Integrina alfaVbeta3/efectos de los fármacos , Integrinas/efectos de los fármacos , Oligopéptidos/farmacología , Prolina/análogos & derivados , Prolina/química , Receptores de Vitronectina/efectos de los fármacos , Sitios de Unión , Cristalografía por Rayos X , Humanos , Integrina alfaVbeta3/química , Integrinas/química , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Estructura Molecular , Oligopéptidos/química , Receptores de Vitronectina/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The aim of the study is to investigate the relation between plasma brain natriuretic peptide (BNP), collagen type I turnover, and left ventricular (LV) remodeling after primary angioplasty. Echo-Doppler, BNP, carboxy-terminal telopeptide of procollagen type I (ICTP), C-terminal propeptide of procollagen type I (PICP), and their ratio PICP/ICTP (as an index of coupling between the synthesis and degradation of collagen type I) were evaluated at days 1 and 3 and months 1 and 6 after primary angioplasty in 56 consecutive patients with a first large acute myocardial infarction (AMI). During the 6 months after AMI, a direct relation was shown between BNP and ICTP (day 1, r = 0.54, p = 0.000; day 3, r = 0.64, p = 0.000; month 1, r = 0.64, p = 0.000; month 6, r = 0.41, p = 0.005) and BNP and PICP/ICTP (day 1, r = -0.54, p = 0.003; day 3, r = -0.58, p = 0.000; month 1, r = -0.50, p = 0.000; month 6, r = -0.30, p = 0.043), but not between BNP and PICP. Using analysis of covariance, relations between BNP and ICTP and PICP/ICTP were independent from infarct size. Patients with LV remodeling had significantly higher plasma ICTP and BNP levels and lower PICP/ICTP than patients without LV remodeling. Day-1 ICTP independently predicted 6-month remodeling (exp beta = 2.14, 95% confidence interval 1,120 to 3,550, p = 0.01). In conclusion, a relation exists between plasma BNP collagen type I turnover and LV remodeling after reperfused AMI.
Asunto(s)
Infarto del Miocardio/sangre , Infarto del Miocardio/terapia , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Remodelación Ventricular/fisiología , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón , Colágeno Tipo I , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Péptidos , Estudios Prospectivos , Factores de Tiempo , UltrasonografíaRESUMEN
CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with additional heteroatoms at positions 3 and 6. The compounds were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [3H]WIN35,428 and [3H]citalopram as specific radioligands, respectively. Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Tropanos/síntesis química , Animales , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Células CHO , Línea Celular , Citalopram/farmacología , Cocaína/análogos & derivados , Cocaína/farmacología , Cricetinae , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Tropanos/química , Tropanos/farmacologíaRESUMEN
The correlation between Doppler deceleration time (DT) and brain natriuretic peptide (BNP) and their predictive value for detecting left ventricular (LV) remodeling in patients who are treated with primary percutaneous intervention for infarction and LV dysfunction are unknown. Fifty-six patients (64 +/- 12 years of age; 11 women) who had a first ST-segment elevation myocardial infarction and systolic dysfunction that was successfully treated with direct primary coronary intervention underwent 2-dimensional Doppler echocardiographic and plasma BNP evaluation at days 1 and 3 and 1 and 6 months after the index infarction. Repeat coronary angiograms were obtained at 1 and 6 months. Because of previous consistent evidence, 3 days after the index infarction was the time point of comparison between BNP and DT values. Echocardiographic LV remodeling was defined as an increase in end-diastolic volume index above baseline values of 2 x SD. Ventricular remodeling occurred in 20 patients (36%). Multivariate analyses that included BNP level, Doppler DT, echocardiographic measurements of systolic function, peak creatine kinase, and anterior infarct location showed Doppler DT to be the only predictor of LV remodeling (odds ratio 0.963, 95% confidence interval 0.936 to 0.990, p = 0.008). The optimal cutoff for DT in the prediction of 6-month LV remodeling was <136 ms (sensitivity 75%, specificity 97%, accuracy 81%, area under receiver-operating characteristic curve 0.90). Thus, in patients who have a first ST-segment elevation myocardial infarction and LV systolic dysfunction that is successfully treated with primary percutaneous coronary intervention, Doppler-derived DT 3 days after index infarction is more effective than BNP level in detecting patients who are at higher risk for 6-month LV remodeling.