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1.
Ann Pharm Fr ; 80(6): 810-818, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35662588

RESUMEN

Infection which occurs in renal kidney failure patient have to be therapeutically managed immediately and the treatment must be aggressive to be quickly efficient. In Bamako (Mali). Posology adaptation cause a problem in nephrology, especially for the most common used antibiotics to care these infections. Drug dosage is not routinely performed in Bamako. The main objective of this work is to compare anthropometric, clinical and pharmacokinetic profiles and the clinical future between infected hemodialysis patients following an antibiotic therapy in Bamako and Lyon (hospital used as a reference). To reach these objectives, a preliminary punctual study of clinical pharmacokinetic of vancomycin were set up at Bamako, following the personalization therapeutics model from Lyon. Bamako patients' samples were imported to France and dosage analysis were performed at Lyon. BestDose software was used to view and compare complete pharmacokinetic profile. It includes for the first time, in routine, the 50 ml/mn of the renal function during dialyses for 58 patients: 31 for Bamako and 21 for Lyon. The residual concentration at the beginning of the dialysis session was compared. In Bamako, patients are younger, the renal failure is more severe and arteriovenous fistula are never set up, treatments are limited in dose and in duration; the residual concentration before the dialyses are too low; as a consequence, infections are rarely quickly reduced and more especially the death linked to these infections are more important (9 in Bamako versus 1 in Lyon). Urgent corrective measures have to be proposed: propose a conciliation between therapeutic requirements formulated within Lyon protocols and the financial ability of the patient, to promote arteriovenous fistula creation as soon as possible, and develop first dose strategy (unfortunately there is often only one dose): a more aggressive dose estimated from simulation profile performed in this study.


Asunto(s)
Fístula Arteriovenosa , Vancomicina , Humanos , Diálisis Renal , Malí , Antibacterianos/uso terapéutico
2.
Antimicrob Agents Chemother ; 59(9): 5181-9, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26077251

RESUMEN

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.


Asunto(s)
Antituberculosos/farmacocinética , Isoniazida/farmacocinética , Pulmón/metabolismo , Adulto , Femenino , Humanos , Masculino , Modelos Teóricos , Método de Montecarlo , Estudios Retrospectivos
3.
Eur J Drug Metab Pharmacokinet ; 39(2): 87-91, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24599705

RESUMEN

Amikacin use is difficult because of its narrow therapeutic and its pharmacokinetic variability. This variability of amikacin is not well known. To adapt amikacin the physician assumes that there is a linear and continuous relation between the volume of distribution and the body weight. The objective of our study was to evaluate the relationship between the volume of distribution (Vd) and the body weight (BW) using a non parametric statistical analysis of dependence so called Z method. Retrospective pharmacokinetic population study and statistic analysis. 872 patients receiving intravenous amikacin. The volume of distribution was modelled using the Non Parametric Adaptive Grid algorithm (NPAG) for a two-compartment model with intravenous infusion. Z coefficient was performed to evaluate the relationships between Vd and BW. For the 872 patients (mean age of 73 ± 17 years) dispatched as follow 53 % female and 47 % male, the analysis of the statistical relationships by the non parametric Z analysis showed a scattered linkage between Vd and BW. For the whole population, the relationship between Vd and BW was not linear (regression analysis). Z analysis demonstrated that only for 80 % of patients there is a relationship between Vd and BW. For these patients, regression analysis give a significant adjustment of a linear model (r = 0.47, p < 0.001). In the whole studied population there is not a continuous and linear relationship between Vd estimated by NPAG and the BW. These results underline the difficulties to adapt doses of amikacin with only BW information.


Asunto(s)
Amicacina/farmacocinética , Antibacterianos/farmacocinética , Peso Corporal , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Ann Pharm Fr ; 70(6): 348-52, 2012 Nov.
Artículo en Francés | MEDLINE | ID: mdl-23177561

RESUMEN

BACKGROUND: Visits from pharmaceutical representatives are controlled in France by regulations, but also by a Charter of good practice. The goal of this study was to measure compliance to the conditions of this charter by participating pharmaceutical companies. MATERIAL AND METHODS: An assessment grid was drafted to determine compliance to interdictions and obligations concerning the information provided during visits from pharmaceutical representatives. RESULTS: We studied 20 visits from pharmaceutical representatives. All of the documents and obligatory information were only provided in 5% of cases. During 80% of these meetings, the pharmaceutical representatives made a comparison with competitor's drugs, which was associated with negative remarks in 44% of cases. The pharmaceutical representatives promoted cases of use outside those, which had received marketing approval in 35%. Gifts or samples were offered at the end of these meetings in 20% of cases. Prohibited practices were observed in a total of 85% of cases. DISCUSSION: This study shows that meetings are respected by pharmaceutical representatives in terms of regulations related to donations. In opposite, there is a very low compliance concerning the proper use of the drug, whether to provide official documentation, to give information respectful of other pharmaceutical companies or to promote the proper use. CONCLUSION: Our results suggest that, at present hospital visits by pharmaceutical representatives do not respect the commitments made by the pharmaceutical industry, and do not make it possible to ensure that honest information is provided to favor the proper use of drugs.


Asunto(s)
Comercio/normas , Industria Farmacéutica/normas , Comercio/ética , Comercio/legislación & jurisprudencia , Comunicación , Documentación , Industria Farmacéutica/ética , Industria Farmacéutica/legislación & jurisprudencia , Competencia Económica , Francia , Humanos , Difusión de la Información , Relaciones Interprofesionales , Legislación Farmacéutica , Comercialización de los Servicios de Salud/economía , Uso Fuera de lo Indicado
5.
Ann Pharm Fr ; 70(1): 46-52, 2012 Jan.
Artículo en Francés | MEDLINE | ID: mdl-22341008

RESUMEN

INTRODUCTION: Benzodiazepines are widely used in the elderly, but may induce potentially severe iatrogenic events like falls. The analysis of their use is difficult because of the numerous molecules and dosages available. The aim of the present study is to build a tool to monitor their consumption and to evaluate the relation between this consumption and patient's falls reported in three geriatric institutions. METHODS: Conversion coefficients found in the literature allowed the expression of benzodiazepine action with a unique comparator: diazepam. Benzodiazepine consumption observed during 20 consecutive months was collected and weighted by hospital activity. A correlation between benzodiazepine consumption and the number of falls reported during the same period was researched. RESULTS: Benzodiazepine consumption expressed in milligrams of diazepam-equivalent per hospitalization day is significantly linked to the number of falls expressed during the same period (R=0.63; p<0.01). However, no statistical bound was found between monthly falls variations and monthly benzodiazepine consumption variations. These results corroborate others published studies: benzodiazepine consumptions are statistically linked to falls, but the reduction of this consumption is of poor predictive value, maybe because of the multifactorial nature of falls. DISCUSSION AND CONCLUSION: The expression of benzodiazepine consumption in diazepam-equivalent enables one to estimate the general exposition of patients and to compare the use of each molecule. The statistical link between this indicator and a major iatrogenic event like falls makes it a tool worth interest for both clinicians and pharmacists.


Asunto(s)
Accidentes por Caídas/estadística & datos numéricos , Benzodiazepinas/efectos adversos , Hipnóticos y Sedantes/efectos adversos , Anciano , Interpretación Estadística de Datos , Diazepam/efectos adversos , Utilización de Medicamentos , Francia/epidemiología , Servicios de Salud para Ancianos , Hospitales Universitarios , Humanos , Factores de Riesgo
6.
Science ; 244(4902): 343-6, 1989 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-2711183

RESUMEN

The mouse albumin gene promoter has six closely spaced binding sites for nuclear proteins that are located between the TATA motif and nucleotide position -170. In vitro transcription with liver or spleen nuclear extracts of templates containing either mutated or polymerized albumin promoter elements establishes a hierarchy of the different protein binding sites for tissue-specific albumin gene transcription. The HNF-1 and C/EBP binding sites strongly activate transcription in a tissue-specific manner. The NF-Y binding site has a lower activation potential and is less specific, being equally efficient in liver and spleen nuclear extracts. The remaining elements are relatively weak activator sites.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Regiones Promotoras Genéticas , Albúmina Sérica/genética , Animales , Secuencia de Bases , Sitios de Unión , Proteínas Potenciadoras de Unión a CCAAT , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Núcleo Celular/metabolismo , Transportadores de Ácidos Dicarboxílicos , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Hígado/ultraestructura , Ratones , Proteínas Nucleares/metabolismo , Proteínas Nucleares/farmacología , Bazo/metabolismo , Bazo/ultraestructura , Moldes Genéticos , Factores de Transcripción , Transcripción Genética/efectos de los fármacos
7.
J Dent Res ; 98(5): 572-579, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30905259

RESUMEN

SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1 -/- Six2 -/- double-mutant mice were born with severe craniofacial deformity not seen in the Six1 -/- or Six2 -/- single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1 -/- mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1 -/-Six2 +/- mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1 -/- embryos, the E10.5 Six1 -/- Six2 +/- embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 -/- and Six1 -/- Six2 +/- embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest-specific inactivation of Six1 in Six2 -/- embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1 -/- Six2 -/- embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell-autonomous role in frontonasal morphogenesis.


Asunto(s)
Anomalías Craneofaciales , Animales , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio , Ratones , Morfogénesis , Cresta Neural , Factores de Transcripción
8.
Mol Cell Biol ; 17(2): 656-66, 1997 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9001219

RESUMEN

The human aldolase A pM promoter is active in fast-twitch muscles. To understand the role of the different transcription factors which bind to this promoter and determine which ones are responsible for its restricted pattern of expression, we analyzed several transgenic lines harboring different combinations of pM regulatory elements. We show that muscle-specific expression can be achieved without any binding sites for the myogenic factors MyoD and MEF2 and that a 64-bp fragment comprising a MEF3 motif and an NFI binding site is sufficient to drive reporter gene expression in some but, interestingly, not all fast-twitch muscles. A result related to this pattern of expression is that some isoforms of NFI proteins accumulate differentially in fast- and slow-twitch muscles and in distinct fast-twitch muscles. We propose that these isoforms of NFI proteins might provide a molecular basis for skeletal muscle diversity.


Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Proteínas de Unión al ADN/metabolismo , Fructosa-Bifosfato Aldolasa/genética , Fibras Musculares de Contracción Rápida/fisiología , Factores de Transcripción/metabolismo , Activación Transcripcional/genética , Animales , Sitios de Unión , Embrión de Pollo , Proteínas de Unión al ADN/análisis , Exones , Regulación Enzimológica de la Expresión Génica/fisiología , Humanos , Factores de Transcripción MEF2 , Ratones , Ratones Transgénicos , Fibras Musculares de Contracción Rápida/química , Factores Reguladores Miogénicos , Factores de Transcripción NFI , Proteínas Nucleares , Especificidad de Órganos , Regiones Promotoras Genéticas/genética , Ratas , Proteínas Recombinantes de Fusión , Proteína 1 de Unión a la Caja Y
9.
Mol Cell Biol ; 16(1): 76-85, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8524331

RESUMEN

The human aldolase A tissue-specific M promoter (pM) has served as a model system for identifying pathways that lead to fast-muscle-specialized expression. The current study has delimited the sequences necessary and sufficient for fast-muscle-specific expression in transgenic mice to a short 209-bp fragment extending from bp -164 to +45 relative to the pM transcription start site. Genomic footprinting methods showed that in this proximal region, the same elements that bind muscle nuclear proteins in vitro are involved in DNA-protein interactions in intact muscle nuclei of transgenic mice. Furthermore, these experiments provided the first evidence that different DNA-binding activities exist between slow and fast muscles in vivo. Fast-muscle-specific interactions occur at an element named M1 and at a muscle-specific DNase I-hypersensitive site that was previously detected by in vitro methods. The formation of the muscle-specific DNase I-hypersensitive site reflects binding of proteins to a close element, named M2, which contains a binding site for nuclear factors of the NF1 family. Mutational analysis performed with transgenic mice confirmed the importance of the M1 element for high-level fast-muscle-specific pM activity and suggested that the M2/NF1 element is differently required for correct pM expression in distinct fast muscles. In addition, two other protein binding sites, the MEF3 motif and the USF site, seem to act as stage-specific activators and/or as participants in the establishment of an active chromatin configuration at pM.


Asunto(s)
ADN/genética , ADN/metabolismo , Fructosa-Bifosfato Aldolasa/genética , Fibras Musculares de Contracción Rápida/metabolismo , Proteínas Musculares/metabolismo , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , Sitios de Unión , Cartilla de ADN/genética , Expresión Génica , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Modelos Biológicos , Datos de Secuencia Molecular , Mutación , Proteínas Nucleares/metabolismo , Distribución Tisular
10.
Mol Cell Biol ; 14(10): 6797-808, 1994 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7935397

RESUMEN

The expression of the human aldolase A gene is controlled by three alternative promoters. In transgenic mice, pN and pH are active in all tissues whereas pM is activated specifically in adult muscles composed mainly of fast, glycolytic fibers. To detect potential regulatory regions involved in the fast-muscle-specific activation of pM, we analyzed DNase I hypersensitivity in a 4.3-kbp fragment from the 5' end of the human aldolase A gene. Five hypersensitive sites were located near the transcription initiation site of each promoter in those transgenic-mouse tissues in which the corresponding promoter was active. Only one muscle-specific hypersensitive site was detected, mapping near pM. To functionally delimit the elements required for muscle-specific activity of pM, we performed a deletion analysis of the aldolase A 5' region in transgenic mice. Our results show that a 280-bp fragment containing 235 bp of pM proximal upstream sequences together with the noncoding M exon is sufficient for tissue-specific expression of pM. When a putative MEF-2-binding site residing in this proximal pM region is mutated, pM is still active and no change in its tissue specificity is detected. Furthermore, we observed a modulation of pM activity by elements lying further upstream and downstream from pM. Interestingly, pM was expressed in a tissue-specific way in all transgenic mice in which the 280-bp region was present (32 lines and six founder animals). This observation led us to suggest that the proximal pM region contains elements that are able to override to some extent the effects of the surrounding chromatin.


Asunto(s)
Fructosa-Bifosfato Aldolasa/genética , Regulación de la Expresión Génica , Músculos/enzimología , Regiones Promotoras Genéticas/genética , Animales , Secuencia de Bases , Cloranfenicol O-Acetiltransferasa/biosíntesis , Cloranfenicol O-Acetiltransferasa/genética , Desoxirribonucleasa I/metabolismo , Fructosa-Bifosfato Aldolasa/biosíntesis , Humanos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Familia de Multigenes/genética , ARN Mensajero/biosíntesis , Proteínas Recombinantes de Fusión/biosíntesis , Distribución Tisular , Transcripción Genética
11.
Mol Cell Biol ; 13(1): 9-17, 1993 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8417365

RESUMEN

The human aldolase A gene is transcribed from three different promoters, pN, pM, and pH, all of which are clustered within a small 1.6-kbp DNA domain. pM, which is highly specific to adult skeletal muscle, lies in between pN and pH, which are ubiquitous but particularly active in heart and skeletal muscle. A ubiquitous enhancer, located just upstream of pH start sites, is necessary for the activity of both pH and pN in transient transfection assays. Using transgenic mice, we studied the sequence controlling the muscle-specific promoter pM and the relations between the three promoters and the ubiquitous enhancer. A 4.3-kbp fragment containing the three promoters and the ubiquitous enhancer showed an expression pattern consistent with that known in humans. In addition, while pH was active in both fast and slow skeletal muscles, pM was active only in fast muscle. pM activity was unaltered by the deletion of a 1.8-kbp region containing the ubiquitous enhancer and the pH promoter, whereas pN remained active only in fast skeletal muscle. These findings suggest that in fast skeletal muscle, a tissue-specific enhancer was acting on both pN and pM, whereas in other tissues, the ubiquitous enhancer was necessary for pN activity. Finally, a 2.6-kbp region containing the ubiquitous enhancer and only the pH promoter was sufficient to bring about high-level expression of pH in cardiac and skeletal muscle. Thus, while pH and pM function independently of each other, pN, remarkably, shares regulatory elements with each of them, depending on the tissue. Importantly, expression of the transgenes was independent of the integration site, as originally described for transgenes containing the beta-globin locus control region.


Asunto(s)
Fructosa-Bifosfato Aldolasa/genética , Músculos/fisiología , Regiones Promotoras Genéticas , Animales , Diferenciación Celular , ADN Recombinante , Elementos de Facilitación Genéticos , Regulación Enzimológica de la Expresión Génica , Globinas/genética , Humanos , Ratones , Ratones Transgénicos , Músculos/citología , ARN Mensajero/genética
12.
Respir Care Clin N Am ; 12(2): 139-48, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16828687

RESUMEN

The mucociliary elevator is a highly evolved organ that humidifies inspired gases and protects the lungs from particulate, chemical, and microbiologic matter. Studies of disorders mucus and ciliary function have improved the understanding of this forgotten organ. The clinical implications of this understanding have yet to be explored.


Asunto(s)
Filtración , Humedad , Depuración Mucociliar/fisiología , Cilios/fisiología , Trastornos de la Motilidad Ciliar/fisiopatología , Humanos , Mucosa Respiratoria/fisiología , Enfermedades Respiratorias/fisiopatología
13.
J Mol Biol ; 289(4): 893-903, 1999 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-10369770

RESUMEN

During the post-natal period, skeletal muscles undergo important modifications leading to the appearance of different types of myofibers which exhibit distinct contractile and metabolic properties. This maturation process results from the activation of the expression of different sets of contractile proteins and metabolic enzymes, which are specific to the different types of myofibers. The muscle-specific promoter of the aldolase A gene (pM) is expressed mainly in fast-twitch glycolytic fibers in adult body muscles. We investigate here how pM is regulated during the post-natal development of different types of skeletal muscles (slow or fast-twitch muscles, head or body muscles). We show that pM is expressed preferentially in prospective fast-twitch muscles soon after birth; pM is up-regulated specifically in body muscles only later in development. This activation pattern is mimicked by a transgene which comprises only the 355 most proximal sequences of pM. Within this region, we identify a DNA element which is required for the up-regulation of the transgene during post-natal development in body muscles. Comparison of nuclear M1-binding proteins from young or adult body muscles show no qualitative differences. Distinct M1-binding proteins are present in both young and adult tongue nuclear extracts, compared to that present in gastrocnemius extracts.


Asunto(s)
Fructosa-Bifosfato Aldolasa/genética , Regulación del Desarrollo de la Expresión Génica , Músculo Esquelético/fisiología , Regiones Promotoras Genéticas , Receptores Citoplasmáticos y Nucleares/metabolismo , Alitretinoína , Animales , Sitios de Unión , Células Cultivadas , Pollos , Ratones , Ratones Transgénicos , Desarrollo de Músculos , Músculo Esquelético/embriología , Músculo Esquelético/crecimiento & desarrollo , Elementos de Respuesta , Tretinoina/metabolismo , Regulación hacia Arriba
14.
J Mol Biol ; 197(3): 425-38, 1987 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-3441006

RESUMEN

We undertook cloning and sequencing of the 5' portion of the human aldolase A gene to elucidate the mechanisms that govern synthesis of its different mRNAs. The sequenced gene is the only active gene in human-rodent fibroblastic somatic hybrids, while the other aldolase A-related sequences are inactive. S1 mapping and primer extension analysis enabled us to demonstrate that three promoter regions were implicated in the initiation of different aldolase A mRNAs, differing only in their 5' non-coding extremities. A distal promoter, N (non-specific), governs the synthesis of a 5' non-coding region of 142 bases composed of two exons, N1 and N2, which are found in a variety of tissues. A median promoter, M (muscle), is only active in skeletal muscle, and initiates the transcription by a 5' non-coding exon of 45 bases. Finally, a proximal promoter, H (housekeeping), contained in a "G + C-rich island", permits transcription of three colinear mRNAs containing 172, 126 or 112 bases of 5' non-coding sequence; their expression seems ubiquitous. These three promoters are arranged in 1.5 X 10(3) base-pairs of DNA. Homologies between rat and human genomic sequences and the absence of homology between promoters or 5' non-coding exons of the same species exclude a recent duplication of the promoter regions.


Asunto(s)
Fructosa-Bifosfato Aldolasa/genética , Regiones Promotoras Genéticas , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Genes , Humanos , Células Híbridas , Datos de Secuencia Molecular , ARN Mensajero/genética , Ratas , Homología de Secuencia de Ácido Nucleico
15.
J Mol Biol ; 253(1): 17-31, 1995 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-7473711

RESUMEN

The human aldolase A gene is expressed in several tissues through the use of three alternative promoters. The activity of one of the promoters, pM, is restricted to skeletal muscle. We reported previously that a proximal 280 bp pM fragment confers tissue-specific expression to a CAT reporter gene in transgenic mice. This small regulatory region directs expression to muscle composed mainly of fast-twitch fibers. Here we show that a minimal promoter fragment from base-pairs -164 to +45 is sufficient to highly active pM during myoblast differentiation in cell culture and demonstrate that two DNA elements play a major role in this activation. These elements consist of a binding site (M1) for unknown ubiquitous proteins and an overlapping binding site for MEF2 and NF1 families of transcription factors. The NF1 factor constitute the main binding activity on the MEF2/NF1 site and, interestingly, some of the DNA-protein complexes that form with muscle nuclear extracts on the NF1 element differ from those that form with non-muscular extracts.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Fructosa-Bifosfato Aldolasa/genética , Fibras Musculares de Contracción Rápida/enzimología , Regiones Promotoras Genéticas/genética , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Diferenciación Celular , Células Cultivadas , Huella de ADN , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Hígado , Factores de Transcripción MEF2 , Ratones , Datos de Secuencia Molecular , Fibras Musculares de Contracción Rápida/citología , Mutación , Factores Reguladores Miogénicos , Neurofibromina 1 , Proteínas/metabolismo , Codorniz , Transcripción Genética
16.
Clin Pharmacokinet ; 40(12): 947-53, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11735610

RESUMEN

OBJECTIVE: Although amikacin is primarily eliminated via glomerular filtration, drug concentrations are not consistently predicted in all patients. To better describe the relationship between amikacin clearance and both age and renal function, we used a new heuristic approach involving statistical analysis of dependence. DESIGN AND SETTING: Retrospective pharmacokinetic study using data from seven centres in France. PARTICIPANTS: 634 patients with sepsis aged between 18 and 98 years of age who received intravenous amikacin. METHODS: Clearance of amikacin was modelled using the NonParametric EM algorithm for a two-compartment model (NPEM2) with intravenous infusion. RESULTS: A total of 2499 serum amikacin determinations was available for analysis. The relationship between the clearance of amikacin and age was weak. Interestingly, the Z method, which filters data based on dependence criteria, selected data that were best fitted by a polynomial function (r = 0.90; p < 0.001). This representation of the polynomial function was similar to a previously proposed theoretical model describing covariations between the clearance of amikacin and age. However, the polynomial function applied to only 33% of the patients that were selected by the Z method. The correlation between the clearance of amikacin and renal function was also relatively low (r = 0.39). The Z method exhibited a continuous and strong dependence pattern between the clearance of amikacin and age for 49% of the patients. CONCLUSIONS: The Z methodology, which filters data using dependence criteria, confirms that age, renal function and amikacin clearance are strongly related, but only in less than half of a large sample of patients with sepsis without renal pathology. These results suggest that other variables should be taken into account in order to improve the description of the behaviour of amikacin. The Z methodology improved the classical description of relationships between variables, and should be applied to better select pertinent variables in pharmacokinetic studies.


Asunto(s)
Envejecimiento/metabolismo , Amicacina/farmacocinética , Antibacterianos/farmacocinética , Riñón/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Amicacina/uso terapéutico , Antibacterianos/uso terapéutico , Francia , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Probabilidad , Estudios Retrospectivos , Sepsis/tratamiento farmacológico , Sepsis/metabolismo
17.
Clin Pharmacokinet ; 34(1): 57-77, 1998 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9474473

RESUMEN

This article examines the use of population pharmacokinetic models to store experiences about drugs in patients and to apply that experience to the care of new patients. Population models are the Bayesian prior. For truly individualised therapy, it is necessary first to select a specific target goal, such as a desired serum or peripheral compartment concentration, and then to develop the dosage regimen individualised to best hit that target in that patient. One must monitor the behaviour of the drug by measuring serum concentrations or other responses, hopefully obtained at optimally chosen times, not only to see the raw results, but to also make an individualised (Bayesian posterior) model of how the drug is behaving in that patient. Only then can one see the relationship between the dose and the absorption, distribution, effect and elimination of the drug, and the patient's clinical sensitivity to it; one must always look at the patient. Only by looking at both the patient and the model can it be judged whether the target goal was correct or needs to be changed. The adjusted dosage regimen is again developed to hit that target most precisely starting with the very next dose, not just for some future steady state. Nonparametric population models have discrete, not continuous, parameter distributions. These lead naturally into the multiple model method of dosage design, specifically to hit a desired target with the greatest possible precision for whatever past experience and present data are available on that drug--a new feature for this goal-oriented, model-based, individualised drug therapy. As clinical versions of this new approach become available from several centers, it should lead to further improvements in patient care, especially for bacterial and viral infections, cardiovascular therapy, and cancer and transplant situations.


Asunto(s)
Monitoreo de Drogas , Quimioterapia/métodos , Farmacocinética , Antiarrítmicos/administración & dosificación , Antiarrítmicos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Teorema de Bayes , Digoxina/administración & dosificación , Digoxina/uso terapéutico , Humanos , Modelos Biológicos , Estadísticas no Paramétricas , Equivalencia Terapéutica , Vancomicina/administración & dosificación , Vancomicina/uso terapéutico
18.
Curr Drug Targets Infect Disord ; 4(2): 153-62, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15180462

RESUMEN

The main constraints to the administration of aminoglycosides (AG) are risks of nephrotoxicity and ototoxicity, which can lead to renal and vestibular failure. AG accumulation in the kidney may be related to the dosing schedule. As a result, administration of larger doses on a less frequent basis may reduce the drug accumulation in the renal cortex. Many methods have been proposed to reduce AG nephrotoxicity. (1) Molecular modeling and analog synthesis could lead to intrinsically less toxic AG but this approach is time consuming and expensive. Protective approaches such as the co-administration of polyaspartic acid or defferoxamine appear to be very promising in clinical practice. (2) Population pharmacokinetic computer programs, used to control AG serum concentrations, are correct predictors of efficacy but the estimated concentrations in the second compartment are not reliable predictors of nephrotoxicity because they do not take into account non-linear processes such as the AG uptake in the renal cortex or the tubuloglomerular feedback. (3) Finally, modelling the AG nephrotoxicity with probabilistic approaches and/or with deterministic approaches seems to be very promising. These two approaches appear to be not competitive but very complementary in clinical practice. The probabilistic model can be used to predict nephrotoxicity at the beginning the treatment. The deterministic model can be used to simulate and control nephrotoxicity when it is already unfolding and the treatment must be given for a long period of time.


Asunto(s)
Aminoglicósidos/efectos adversos , Antibacterianos/efectos adversos , Enfermedades Renales/inducido químicamente , Aminoglicósidos/farmacocinética , Animales , Antibacterianos/farmacocinética , Humanos , Enfermedades Renales/patología , Modelos Biológicos , Modelos Estadísticos
19.
Bone Marrow Transplant ; 32(8): 777-84, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14520421

RESUMEN

In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42+/-10 and 90+/-7 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73+/-4 vs 95+/-8 ng/ml (P=0.284). For TBC >85 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65 ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101+/-10 ng/ml, mild: 77+/-11 ng/ml, moderate: 61+/-13 ng/ml, severe: 56+/-15 ng/ml (P <0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.


Asunto(s)
Ciclosporina/sangre , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/sangre , Enfermedad Aguda , Adolescente , Teorema de Bayes , Trasplante de Médula Ósea/efectos adversos , Niño , Preescolar , Ciclosporina/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/efectos adversos , Incidencia , Lactante , Masculino , Índice de Severidad de la Enfermedad , Hermanos , Donantes de Tejidos , Trasplante Homólogo
20.
Bone Marrow Transplant ; 28(8): 743-51, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11781625

RESUMEN

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.


Asunto(s)
Alquilantes/farmacocinética , Trasplante de Médula Ósea , Busulfano/farmacocinética , Acondicionamiento Pretrasplante/métodos , Adolescente , Alquilantes/administración & dosificación , Alquilantes/sangre , Área Bajo la Curva , Teorema de Bayes , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/estadística & datos numéricos , Busulfano/administración & dosificación , Busulfano/sangre , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Enfermedades Genéticas Congénitas/terapia , Supervivencia de Injerto , Neoplasias Hematológicas/terapia , Enfermedad Veno-Oclusiva Hepática/epidemiología , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Incidencia , Lactante , Tablas de Vida , Masculino , Melfalán/administración & dosificación , Estudios Prospectivos , Inmunodeficiencia Combinada Grave/terapia , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento
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