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1.
Regul Toxicol Pharmacol ; 70(1): 413-29, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25078890

RESUMEN

An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk. They are included on toxicology studies to assess whether effects observed during dosing persist or reverse once treatment ends. The group devised a questionnaire to collect information on the use of recovery animals in general regulatory toxicology studies to support first-in-human studies. Questions focused on study design, the rationale behind inclusion or exclusion and the impact this had on internal and regulatory decisions. Data on 137 compounds (including 53 biologicals and 78 small molecules) from 259 studies showed wide variation in where, when and why recovery animals were included. An analysis of individual study and programme design shows that there are opportunities to reduce the use of recovery animals without impacting drug development.


Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Modelos Animales , Toxicología/métodos , Animales , Humanos , Cooperación Internacional , Proyectos de Investigación , Encuestas y Cuestionarios , Factores de Tiempo
2.
Cancer Chemother Pharmacol ; 67(4): 775-81, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20532886

RESUMEN

PURPOSE: In this preclinical study, we examined the biodistribution of hypericin formulated as its water-soluble PVP-hypericin complex in the different layers (urothelium, submucosa, muscle) of a normal rat bladder and a rat bladder bearing a malignant urothelium composed of syngeneic AY-27 tumor cells. The results were compared with the biodistribution of hexaminolevulinate (HAL)-induced protoporphyrin IX (PpIX). METHODS: Freshly prepared PVP-hypericin and HAL solutions were instilled in both normal as well as tumor-bearing rat bladders. Following instillation, bladders were removed and snap frozen in liquid nitrogen. Fluorescence of PVP-hypericin or PpIX-induced HAL was measured in the bladder layers and quantified using image analysis software. RESULTS: The results of these experiments show that PVP-hypericin (30 µM) accumulated about 3.5-fold more in malignant urothelial tissue when compared to normal urothelium, whereas PpIX accumulated to the same extent in malignant and normal urothelium, both after intrabladder instillation of 8 or 16 mM HAL. Besides, PVP-hypericin and PpIX accumulated selectively in the urothelium with a tumor-to-muscle ratio of 30.6 for PVP-hypericin and 3.7-8.3 for 16 and 8 mM HAL, respectively. CONCLUSIONS: This study shows that PVP-hypericin appears to have great potential as a photodynamic agent against non-muscle-invasive bladder cancers after intravesical administration, with a limited risk of affecting the deeper layers of the bladder.


Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Perileno/análogos & derivados , Povidona/química , Protoporfirinas/farmacocinética , Neoplasias de la Vejiga Urinaria/patología , Ácido Aminolevulínico/farmacología , Animales , Antracenos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Femenino , Fluorescencia , Perileno/administración & dosificación , Perileno/farmacocinética , Fotoquimioterapia/métodos , Ratas , Ratas Endogámicas F344 , Solubilidad , Distribución Tisular
3.
J Biomed Opt ; 16(1): 018001, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21280926

RESUMEN

Polyvinylpyrrolidone (PVP)-hypericin is a potent photosensitizer that is used in the urological clinic to photodiagnose with high-sensitivity nonmuscle invasive bladder cancer (NMIBC). We examined the differential accumulation and therapeutic effects of PVP-hypericin using spheroids composed of a human urothelial cell carcinoma cell line (T24) and normal human urothelial (NHU) cells. The in vitro biodistribution was assessed using fluorescence image analysis of 5-µm cryostat sections of spheroids that were incubated with PVP-hypericin. The results show that PVP-hypericin accumulated to a much higher extent in T24 spheroids as compared to NHU spheroids, thereby reproducing the clinical situation. Subsequently, spheroids were exposed to different PDT regimes with a light dose ranging from 0.3 to 18 J∕cm2. When using low fluence rates, only minor differences in cell survival were seen between normal and malignant spheroids. High light fluence rates induced a substantial difference in cell survival between the two spheroid types, killing ∼80% of the cells present in the T24 spheroids. It was concluded that further in vivo experiments are required to fully evaluate the potential of PVP-hypericin as a phototherapeutic for NMIBC, focusing on the combination of the compound with methods that enhance the oxygenation of the urothelium.


Asunto(s)
Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Perileno/análogos & derivados , Povidona/química , Esferoides Celulares/efectos de los fármacos , Urotelio/efectos de los fármacos , Urotelio/metabolismo , Antracenos , Carcinoma de Células Transicionales/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Perileno/farmacocinética , Perileno/uso terapéutico , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Esferoides Celulares/patología , Distribución Tisular , Urotelio/patología
4.
Blood ; 100(1): 347-9, 2002 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-12070048

RESUMEN

A hyperdiploid karyotype is found in 30% of B-cell precursor acute lymphoblastic leukemias in childhood. The time of nondisjunction of chromosomes leading to hyperdiploidy during leukemogenesis is unknown. We used the 3 clonotypic immunoglobulin heavy chain (IgH) gene rearrangements as molecular markers for each of the 3 chromosomes 14 in a case with hyperdiploid acute lymphoblastic leukemia to define the order of events-namely, somatic recombination and nondisjunction of chromosomes-during leukemia development. A partial sequence homology of the incomplete DJ(H) rearrangement with 1 of the 2 nonfunctional VDJ(H) rearrangements suggests that the doubling of chromosomes had occurred after this DJ(H) rearrangement and thus during early B-cell differentiation. The occurrence of the nondisjunction of chromosomes as well as ongoing rearrangement processes in utero were confirmed by the presence of all 3 IgH rearrangements in neonatal blood spots, providing the first evidence that hyperdiploidy formation is an early event in leukemogenesis in these leukemias.


Asunto(s)
Transformación Celular Neoplásica/genética , Poliploidía , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Edad de Inicio , Preescolar , Cromosomas Humanos Par 14 , Reordenamiento Génico , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cariotipificación , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología
5.
Blood ; 99(12): 4386-93, 2002 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-12036866

RESUMEN

We performed sensitive polymerase chain reaction-based minimal residual disease (MRD) analyses on bone marrow samples at 9 follow-up time points in 71 children with T-lineage acute lymphoblastic leukemia (T-ALL) and compared the results with the precursor B-lineage ALL (B-ALL) results (n = 210) of our previous study. At the first 5 follow-up time points, the frequency of MRD-positive patients and the MRD levels were higher in T-ALL than in precursor-B-ALL, reflecting the more frequent occurrence of resistant disease in T-ALL. Subsequently, patients were classified according to their MRD level at time point 1 (TP1), taken at the end of induction treatment (5 weeks), and at TP2 just before the start of consolidation treatment (3 months). Patients were considered at low risk if TP1 and TP2 were MRD negative and at high risk if MRD levels at TP1 and TP2 were 10(-3) or higher; remaining patients were considered at intermediate risk. The relative distribution of patients with T-ALL (n = 43) over the MRD-based risk groups differed significantly from that of precursor B-ALL (n = 109). Twenty-three percent of patients with T-ALL and 46% of patients with precursor B-ALL were classified in the low-risk group (P =.01) and had a 5-year relapse-free survival (RFS) rate of 98% or greater. In contrast, 28% of patients with T-ALL were classified in the MRD-based high-risk group compared to only 11% of patients with precursor B-ALL (P =.02), and the RFS rates were 0% and 25%, respectively (P =.03). Not only was the distribution of patients with T-ALL different over the MRD-based risk groups, the prognostic value of MRD levels at TP1 and TP2 was higher in T-ALL (larger RFS gradient), and consistently higher RFS rates were found for MRD-negative T-ALL patients at the first 5 follow-up time points.


Asunto(s)
Leucemia Linfoide/tratamiento farmacológico , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Adolescente , Antineoplásicos/administración & dosificación , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Reordenamiento Génico/genética , Genes Codificadores de los Receptores de Linfocitos T/genética , Humanos , Lactante , Recién Nacido , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/genética , Masculino , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prednisona/administración & dosificación , Pronóstico , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
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