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1.
Dev Med Child Neurol ; 2023 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-37990438

RESUMEN

AIM: To investigate the prevalence and clinical manifestations of reading, writing, and mathematics disorders in children with cerebral palsy (CP). We explored how the clinical profile of these children differed from those with specific learning disorders (SLDs), taking into account several factors, particularly IQ scores, neuropsychological aspects, and the presence of a visual impairment. METHOD: A prospective cross-sectional study was conducted in 42 children with CP (mean age 9 years 8 months; SD = 2 years 2 months) and 60 children with SLDs (mean age 10 years; SD = 1 year 7 months). Clinical characteristics, neuromotor and cognitive profiles, neuropsychological aspects (speech performance, academic skills, visual attention, phonological awareness, working memory), and signs of visual impairment (visual acuity, contrast sensitivity, visual field, oculomotor functions) were assessed. A machine learning approach consisting of a random forest algorithm, where the outcome was the diagnosis and the covariates were the clinical variables collected in the sample, was used for the analyses. RESULTS: About 59% of the children with CP had reading, writing, or mathematics disorders. Children with CP with learning disorders had a low performance IQ, normal phonological awareness, and working memory difficulties, whereas children with SLDs had normal performance IQ, impaired phonological awareness, and mild working memory difficulties. There were no differences in verbal IQ between the two groups. INTERPRETATION: Learning disorders are frequently associated with CP, with different clinical characteristics, compared with SLDs. Assessment of academic skills is mandatory in these children, even if the IQ is normal. At school age, specific interventions to promote academic skills in children with CP could be a major rehabilitative goal.

2.
Eur J Nucl Med Mol Imaging ; 47(11): 2633-2638, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32249345

RESUMEN

PURPOSE: To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl2 in the daily clinical practice. MATERIALS: We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl2 immediately after progressing during an AA treatment line in everyday clinical practice. RESULTS: We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl2 as second- or third-line treatment. [223Ra]RaCl2 treatment was well-tolerated; there were only four cases of grade 3 anaemia, two cases of grade 3 leukopenia and one case of grade 3 neutropenia. The overall fracture rate is 2.1%; one fracture was recorded during the course of [223Ra]RaCl2 treatment, and one was recorded 1 month after its end. The fractures both occurred at metastatic sites. Median OS from [223Ra]RaCl2 start was more than 14 months regardless of the treatment line when [223Ra]RaCl2 was administered. CONCLUSION: The findings of this study show that the treatment with [223Ra]RaCl2 immediately after AA was active and safe with a very low risk of a fracture. Thus, the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including [223Ra]RaCl2 in the therapeutic algorithm.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Acetato de Abiraterona/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radio (Elemento)/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento
3.
Bioconjug Chem ; 21(5): 928-39, 2010 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-20402465

RESUMEN

(99m)Tc(N)-DBODC5 is a cationic mixed compound under clinical investigation as potential myocardial imaging agent. In spite of this, analogously to the other cationic (99m)Tc-agents, presents a relatively low first-pass extraction. Thus, modification of (99m)Tc(N)-DBODC(5) direct to increase its first-pass extraction keeping unaltered the favorable imaging properties would be desirable. This work describes the synthesis and biological evaluation of a series of novel cationic (99m)Tc-nitrido complexes, of general formula [(99m)TcN(DTC-Ln)(PNP)](+) (DTC-Ln= alicyclic dithiocarbamates; PNP = diphosphinoamine), as potential radiotracers for myocardial perfusion imaging. The synthesis of cationic (99m)Tc-(N)-complexes were accomplished in two steps. Biodistribution studies were performed in rats and compared with the distribution profiles of (99m)Tc(N)-DBODC5 and (99m)Tc-Sestamibi. The metabolisms of the most promising compounds were evaluated by HPLC methods. Biological studies revealed that most of the complexes have a high initial and persistent heart uptake with rapid clearance from nontarget tissues. Among tested compounds, 2 and 12 showed improved heart uptake with respect to the gold standard (99m)Tc-complexes with favorable heart-to-liver and slightly lower heart-to-lung ratios. Chromatographic profiles of (99m)Tc(N)-radioactivity extracted from tissues and fluids were coincident with the native compound evidencing remarkable in vivo stability of these agents. This study shows that the incorporation of alicyclic dithiocarbamate in the [(99m)Tc(N)(PNP)](+) building block yields to a significant increase of the heart uptake at early injection point suggesting that the first-pass extraction fraction of these novel complexes may be increased with respect to the other cationic (99m)Tc-agents keeping almost unaltered the favorable target/nontarget ratios.


Asunto(s)
Corazón/diagnóstico por imagen , Compuestos de Organotecnecio/química , Animales , Femenino , Humanos , Compuestos de Organotecnecio/metabolismo , Compuestos de Organotecnecio/farmacocinética , Unión Proteica , Cintigrafía , Ratas , Ratas Sprague-Dawley , Suero/metabolismo , Tiocarbamatos/química , Tiocarbamatos/metabolismo , Tiocarbamatos/farmacocinética , Imagen de Cuerpo Entero/métodos
4.
J Nucl Med ; 49(8): 1336-44, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18632814

RESUMEN

UNLABELLED: 99mTc(N)-DBODC5 is the lead compound of a new series of monocationic 99mTc(N)-based potential myocardial imaging agents that exhibit original biodistribution properties. This study was addressed to elucidate the mechanisms of distribution, retention, and elimination of this promising 99mTc(N)-agent. METHODS: The sex-related in vitro and in vivo stability and the subcellular distribution of 99mTc(N)-DBODC5 were investigated. Studies were performed by considering binding to the serum proteins; stability in rat serum, human serum, and rat liver homogenates; and the chemical integrity of the complex after extraction from rat tissues such as heart, liver, and kidney, as well as from intestinal fluids and urine. The effect of cyclosporin A on the in vivo pharmacokinetic properties of 99mTc(N)-DBODC5 was also evaluated. Subcellular distribution of 99mTc(N)-DBODC5 in ex vivo rat heart was determined by standard differential centrifugation techniques. RESULTS: No significant in vitro serum protein binding and no notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was evidenced. In vivo experiments showed that sex affects the pharmacokinetic profile of the 99mTc(N)-complexes including metabolism and excretion. Chromatographic profiles of 99mTc(N)-radioactivity extracted from tissues and fluids of female rats were always coincident with the control. Conversely, a small percentage of metabolized species was detected by high-performance liquid chromatography in liver extracts of male rats. Furthermore, administration of cyclosporin A caused a significant reduction of lung, liver, and kidney washout along with a considerable variation in activity distribution in the intestinal tract in both male and female rats, thus indicating a possible implication of Pgp transporters in determining the biologic behavior of 99mTc(N)-DBODC5. However, this phenomenon was more pronounced in females. Subcellular distribution studies showed that 86.3% +/- 7.4% of 99mTc(N)-DBODC5 was localized into mitochondrial fraction as a result of the interaction with the negative membrane potential. CONCLUSION: Evidence showing that the new 99mTc(N)-myocardial tracers behave as multidrug resistance-associated protein P-glycoprotein substrates, combined with their selective mitochondrial accumulation, strongly supports the possibility that diagnostic application of 99mTc(N)-DBODC5 can be extended to tumor imaging and noninvasive multidrug resistance studies.


Asunto(s)
Radiofármacos/metabolismo , Animales , Proteínas Sanguíneas/metabolismo , Ciclosporina/farmacología , Femenino , Masculino , Miocardio/metabolismo , Compuestos Organofosforados/metabolismo , Compuestos Organofosforados/farmacocinética , Compuestos de Organotecnecio/metabolismo , Compuestos de Organotecnecio/farmacocinética , Unión Proteica , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución Tisular
5.
Inorg Chem ; 47(24): 11972-83, 2008 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19007158

RESUMEN

The reactivity of bulky alkylphosphino-thiol ligands (PSH) toward nitride-M(V, VI) (M = Tc/Re) precursors was investigated. Neutral five-coordinate monosubstituted complexes of the type [M(N)(PS)Cl(PPh(3))] (Tc1-4, Re1-2) were prepared in moderate to high yields. It was found that these [M(N)(PS)Cl(PPh(3))] species underwent ligand-exchange reactions under mild conditions when reacted with bidentate mononegative ligands having soft donor atoms such as dithiocarbamates (NaL(n)) to afford stable dissymmetrical mixed-substituted complexes of the type [M(N)(PS)(L(n))] (Tc5,8-10, Re5-9) containing two different bidentate chelating ligands bound to the [M[triple bond]N](2+) moiety. In these reactions, the dithiocarbamate replaced the two labile monodentate ligands (Cl and PPh(3)) leaving the [M(N)(PS)](+) building block intact. In the above reactions, technetium and rhenium were found to behave in a similar way. Instead, under more drastic conditions, reactions of PSH with [M(N)Cl(2)(PPh(3))(2)] gave a mixture of monosubstituted [M(N)(PS)Cl(PPh(3))] and bis-substituted species [M(N)(PS)(2)] (Tc11-14) in the case of technetium, whereas only monosubstituted [M(N)(PS)Cl(PPh(3))] complexes were recovered for rhenium. All isolated products were characterized by elemental analysis, IR and multinuclear ((1)H, (13)C, and (31)P) NMR spectroscopies, ESI MS spectrometry, and X-ray crystal structure determination of the representative monosubstituted [Tc(N)(PStbu)Cl(PPh(3))] (Tc4) and mixed-substituted [Re(N)(PScy)(L(3))] (Re7) and [Re(N)(PSiso)(L(4))] (Re9) complexes. The latter rhenium complexes represent the first example of a square-pyramidal nitrido Re species with the basal plane defined by a PS(3) donor set. Monosubstituted [M(N)(PS)Cl(PPh(3))] species bearing the substitution-inert [M(N)(PS)](+) moieties act as suitable building blocks proposed for the construction of new classes of dissymmetrical nitrido compounds with potential application in the development of essential and target specific (99m)Tc and (188)Re radiopharmaceuticals for imaging and therapy, respectively.


Asunto(s)
Fosfinas/química , Fosfinas/síntesis química , Renio/química , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/síntesis química , Tecnecio/química , Encéfalo/diagnóstico por imagen , Cristalografía por Rayos X/métodos , Corazón/diagnóstico por imagen , Humanos , Ligandos , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Conformación Molecular , Tomografía de Emisión de Positrones/métodos , Radiografía , Radiofármacos/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Tiocarbamatos/química , Tomografía Computarizada de Emisión de Fotón Único/métodos
6.
Nucl Med Biol ; 34(5): 511-22, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17591551

RESUMEN

Using the avidin-biotin system as model, we investigate here the effective application of [Tc(N)L(PNP)](+/0) technology (L=N-functionalized cysteine [O(-),S(-)]; PNP=aminodiphosphine) to the preparation of target-specific radiopharmaceuticals. A series of (99m)Tc-nitrido complexes containing functionalized biotin ligands was prepared and their biological profile was determined. To minimize the steric and the electronic influences of the Tc-carrying complex on the biotin-avidin receptor interaction, the following N-functionalized cysteine-biotin derivatives were synthesized: (1) Biot-CysOSH; (2) Biot-Abu-CysOSH; (3) Biot-Abz-CysOSH; (4) Biot-l-(Ac)Lys-CysOSH; (5) Biot-d-(Ac)Lys-CysOSH; (6) Biot-Glu-CysOSH. The asymmetrical nitrido-Tc(V) (99g/99m)Tc(N)(Biot-X-CysOS)(PNP3) (X=spacer) complexes, where PNP3 was N,N-bis-[(dimethoxypropyl)phosphinoethyl] methoxy-ethylamine, were obtained by simultaneous addition of PNP3 and the relevant biotinylated ligand to a solution containing a (99m)Tc-nitrido precursor (yields >95%). In all cases, a mixture of syn- and anti isomers was observed. In vitro challenge experiments with glutathione and cysteine indicated that no transchelation reactions occurred. Assessment of the in vitro binding to avidin of the complexes revealed that only the complexes containing Biot-Abu-CysOS and Biot-Glu-CysOS ligand maintained a good affinity for the concentrator. Stability studies carried out in human and mouse plasma as well as in rat and mouse liver homogenate evidenced a rapid enzymatic degradation for the (99m)Tc(N)(Biot-Abu-CysOS)(PNP3) complex, whereas the (99m)Tc(N)(Biot-Glu-CysOS)(PNP3) one was stable in all conditions. Tissue biodistribution in normal Balb/C mice of the most stable candidate showed a rapid clearance both from the blood and the other tissues. The activity was eliminated both through the hepatobiliary system and the urinary tract.


Asunto(s)
Avidina/metabolismo , Biotina/farmacocinética , Tecnecio/farmacocinética , Animales , Biotina/química , Biotinilación/métodos , Cisteína/química , Cisteína/farmacocinética , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Masculino , Tasa de Depuración Metabólica , Metales/química , Metales/farmacocinética , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Biblioteca de Péptidos , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas , Tecnecio/química , Distribución Tisular
7.
Nucl Med Biol ; 38(3): 399-415, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21492789

RESUMEN

We report on an efficient procedure for the preparation of [(188)Re(N)(PNP)]-based complexes (where PNP is diphosphinoamine) useful in the development of target-specific radiopharmaceuticals. The radiochemical yield of the compounds was optimized considering such reaction parameters as nature of the nitrido nitrogen donor, reaction times and pH level. The chemical identity of the (188)Re agents was determined by high-performance liquid chromatography comparison with the corresponding well-characterized cold Re compounds. (188)Re(N) mixed compounds have been evaluated with regard to stability toward transchelation with GSH and degradation by serum enzymes. The clearance of selected radiocompounds from normal tissues and their in vivo stability were evaluated in rats by biodistribution and imaging studies. [(188)Re(N)(cys ∼)(PNP)](+/0) mixed-ligand compounds were efficiently prepared in aqueous solution from perrhenate using a multistep procedure based on the preliminary formation of the labile (188)Re(III)-EDTA species, which easily undergo oxidation/ligand exchange reaction to afford the [(188)Re(V) ≡ N](2+) core in the presence of dithiocarbazate. The final mixed-ligand compounds were obtained, at 100 °C, by adding the two bidentate ligands to the buffered [(188)Re(V) ≡ N](2+) solution (pH 3.2-3.6). However, a relatively high amount of cys ∼ ligand was required to obtain a quantitative radiochemical yield. The complexes were stable toward reoxidation to perrhenate and ligand exchange reactions. In vivo studies showed rapid distribution and elimination of the complexes from the body. No specific uptakes in sensitive tissues/organs were detected. A positive correlation of the distribution of the complexes estimated with biodistribution studies (%ID) and with micro-SPECT semiquantification imaging analysis (standard uptake values) was observed. These results support the possibility of applying [(188)Re(N)(PNP)] technology to the preparation of target-specific agents.


Asunto(s)
Cisteína/química , Fosfinas/síntesis química , Fosfinas/metabolismo , Radioisótopos/química , Radiofármacos/síntesis química , Radiofármacos/metabolismo , Renio/química , Animales , Ligandos , Masculino , Fosfinas/farmacocinética , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Tomografía Computarizada de Emisión de Fotón Único
8.
J Pept Sci ; 13(4): 211-9, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17269133

RESUMEN

The radiolabeling of the natural octapeptide CCK8, derivatized with a cysteine residue (Cys-Gly-CCK8), by using the metal fragment [99mTc(N)(PNP3)]2+ (PNP3 = N,N-bis(dimethoxypropylphosphinoethyl)methoxyethylamine) is reported. The [99mTc(N)(NS-Cys-Gly-CCK8)(PNP3)]+ complex was obtained according to two methods (one-step or two-step procedure) that gave the desired compound in high yield. The complex is stable in aqueous solution and in phosphate buffer. In vitro challenge experiments with an excess of cysteine and glutathione indicate that no transchelation reactions occur, confirming the high thermodynamic stability and kinetic inertness of this compound. Stability studies carried out in human and mouse serum, as well as in mouse liver homogenates, show that the radiolabeled compound remains intact for prolonged incubation at 37 degrees C. Binding properties give Kd (19.0 +/- 4.6 nmol/l) and Bmax (approximately 10(6) sites/cell) values in A431 cells overexpressing the CCK2-R. In vivo evaluation of the compound shows rapid and specific targeting to CCK2-R, a fourfold higher accumulation compared to nonreceptor expressing tumors.


Asunto(s)
Colecistoquinina/química , Colecistoquinina/metabolismo , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Receptor de Colecistoquinina B/análisis , Animales , Tampones (Química) , Colecistoquinina/farmacocinética , Humanos , Marcaje Isotópico/métodos , Ratones , Ratones Desnudos , Biología Molecular/métodos , Fragmentos de Péptidos/farmacocinética , Radiofármacos/química , Receptor de Colecistoquinina B/genética , Receptor de Colecistoquinina B/metabolismo , Distribución Tisular , Trasplante Heterólogo
9.
Bioconjug Chem ; 17(2): 419-28, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16536474

RESUMEN

A general procedure is presented for the preparation of a new class of nitrido asymmetrical Tc-99m complexes containing two different bidentate ligands bound to the same [Tc(N)]2+ core that could be used to design either essential or target specific imaging agents. This procedure is based on the chemical properties of a new monosubstituted [Tc(N)(R2PS)Cl(PPh3)] species composed of a TcN multiple bond and an ancillary phosphine thiol ligand (R2PSH). This intermediate readily reacts with bidentate mononegative ligands (S--Y) containing soft pi-donor coordinating atoms to give neutral pentacoordinate asymmetrical complexes of the type [Tc(N)(R2PS)(S--Y)]. The ability of several bidentate ligands containing different combination of heteroatoms (S, N, O) to form complexes with the [Tc(N)(R2PS)]+ building block was investigated. It was found that mononegative dithiocarbamate (DTC) or cysteine carboxyl derivate ligands promptly react with the monosubstituted species to form the final mixed compound in high yield. Preliminary biodistribution data in rats of some representative [Tc(N)(R2PS)(DTC)] compounds revealed an interesting initial brain uptake (in the range 0.20 +/- 0.01% ID/g and 0.91 +/- 0.06% ID/g), indicating their ability to cross in and out of the intact BBB. In these complexes the dithiocarbamate, or more generally the bidentate ligand (S--Y), can be designed to carry a functional group or a bioactive molecule, which could be involved in a trapping mechanism to increase brain retention for longer time intervals. These results could be conveniently utilized to devise a new procedure for the production of a novel class of brain perfusion and/or brain receptor imaging agents.


Asunto(s)
Encéfalo/metabolismo , Ligandos , Compuestos de Nitrógeno/química , Compuestos de Organotecnecio , Compuestos de Sulfhidrilo/química , Tecnecio/química , Animales , Barrera Hematoencefálica/fisiología , Encéfalo/anatomía & histología , Cisteína/metabolismo , Diagnóstico por Imagen , Femenino , Glutatión/metabolismo , Marcaje Isotópico , Estructura Molecular , Compuestos de Nitrógeno/síntesis química , Compuestos de Nitrógeno/metabolismo , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/metabolismo , Ratas , Compuestos de Sulfhidrilo/metabolismo , Tecnecio/metabolismo
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