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1.
Ann Hematol ; 93(12): 2051-6, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24981689

RESUMEN

Vitamin D deficiency is common in sickle cell anaemia (SCA, HbSS), although its significance and optimal means of correction are unknown. We conducted an audit to assess the clinical significance of 25-hydroxy vitamin D (25-OHD) deficiency in children with SCA and to evaluate two methods of vitamin D supplementation. We audited 25-OHD levels in 81 children with SCA and looked for statistical associations with biochemical, haematological and clinical parameters. In a separate group of regularly transfused children with SCA, we compared changes in 25-OHD blood concentrations following treatment with either high-dose intramuscular ergocalciferol (n = 15) or 4 days of high-dose oral cholecalciferol (n = 64). Ninety-one percent of children with SCA had 25-OHD levels <20 µg/L. The 25-OHD levels were negatively correlated with increasing age (P < 0.001) but showed no significant relationship to laboratory measurements, transcranial Doppler velocities or hospital attendance. Both intramuscular ergocalciferol and oral cholecalciferol supplementations resulted in increases of 25-OHD blood concentration to normal levels. The mean dose of ergocalciferol was greater than that of cholecalciferol (7,729 versus 5,234 international units (IU)/kg, P < 0.001), but the increment in 25-OHD levels was significantly greater in the oral cholecalciferol group (6.44 versus 2.82 (ng/L)/(IU/kg), P < 0.001). Both approaches resulted in vitamin D sufficiency for about 120 days. Increased 25-OHD concentration was significantly associated with increased serum calcium concentration. Vitamin D deficiency is very common in SCA and can be effectively corrected with high-dose intramuscular ergocalciferol or 4 days of high-dose oral cholecalciferol. Prospective, randomised studies are needed to assess the clinical value of vitamin D supplementation.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Calcifediol/deficiencia , Colecalciferol/uso terapéutico , Ergocalciferoles/uso terapéutico , Deficiencia de Vitamina D/complicaciones , Administración Oral , Fosfatasa Alcalina/sangre , Anemia de Células Falciformes/sangre , Velocidad del Flujo Sanguíneo , Calcifediol/sangre , Calcio/sangre , Circulación Cerebrovascular , Niño , Colecalciferol/administración & dosificación , Estudios Transversales , Ergocalciferoles/administración & dosificación , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Inyecciones Intramusculares , Masculino , Auditoría Médica , Estudios Retrospectivos , Ultrasonografía Doppler Transcraneal , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/tratamiento farmacológico
2.
Eur J Haematol ; 92(3): 249-55, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24329965

RESUMEN

The study's objective was to assess the cost-effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low- or medium-risk surgery. Seventy patients with sickle cell disease (HbSS/Sß(0) thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost-effectiveness analysis based on evidence from that trial is presented. A decision-analytic model is used to incorporate long-term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality-adjusted life years (QALYs), are reported from the 'within-trial' analysis and for the decision-analytic model. The probability of cost-effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from -£813 to £26. All scenarios suggested preoperative transfusion had a probability of cost-effectiveness >0.79 at a cost-effectiveness threshold of £20 000 per QALY.


Asunto(s)
Anemia de Células Falciformes/economía , Anemia de Células Falciformes/terapia , Transfusión Sanguínea/economía , Anciano , Algoritmos , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Femenino , Costos de la Atención en Salud , Humanos , Masculino , Persona de Mediana Edad , Años de Vida Ajustados por Calidad de Vida , Resultado del Tratamiento
3.
J Med Chem ; 52(2): 379-88, 2009 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-19143567

RESUMEN

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.


Asunto(s)
Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Bencimidazoles/química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/farmacología
4.
Nat Chem ; 1(3): 187-92, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21378847

RESUMEN

The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.


Asunto(s)
Bibliotecas de Moléculas Pequeñas/química , Sitios de Unión , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia Magnética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/metabolismo
7.
J Med Chem ; 45(9): 1806-16, 2002 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-11960492

RESUMEN

A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.


Asunto(s)
Androstanoles/química , Ciclodextrinas/síntesis química , Fármacos Neuromusculares no Despolarizantes/síntesis química , gamma-Ciclodextrinas , Animales , Cristalografía por Rayos X , Ciclodextrinas/química , Ciclodextrinas/farmacología , Diafragma/efectos de los fármacos , Diafragma/inervación , Evaluación Preclínica de Medicamentos , Cobayas , Interacciones Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Fármacos Neuromusculares no Despolarizantes/química , Rocuronio , Electricidad Estática , Relación Estructura-Actividad , Sugammadex
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