ABSTRACT
Se realiza un estudio retrospectivo y longitudinal en el Instituto Materno Infantil y Especialidades de Santiago de Los Caballeros, República Dominicana para conocer la variación del Índice de Masa Corporal (IMC), el tiempo de permanencia en el tratamiento, el rango de edad más afectado, de acuerdo al sexo, en 45 pacientes, 23 femeninos y 22 masculinos, con obesidad y sobrepeso, durante el período junio 2003 a mayo 2006. Se excluyeron del estudio a pacientes que no clasificaron como obesidad exógena. Resultados: Al inicio del tratamiento 100% de los pacientes se encontraba en rangos de IMC total correspondientes a Obesidad intensa, y por encima del 95 Percentil de IMC de acuerdo a las gráficas convencionales. El rango de 11 a 13.11 años presentó mayor número de hombres obesos, en tanto que el sexo femenino superó al masculino en el rango 2 a 8. En la fase post tratamiento se observó una reducción del IMC en el grupo total que descendió de 100 por encima del p 95 a solo 53.5% sobre este percentil. El tiempo de Permanencia en el tratamiento fluctuó entre 2 y 24 meses, con una Moda de 3 y una DS de 4.9. El IMC del grupo se redujo en un promedio de 14.8%. La Moda se situó en 11. La DS 5.8. Se concluye que el tratamiento para la obesidad benefició a todos los pacientes, en el corto plazo y medio plazo, recomendándose implementar estrategias para una adhesión al tratamiento a largo plazo
It is a retrospective and longitudinal study, realized in the Maternal Infantile and Specialties Institute, in Santiago, Dominican Republic, for to determine the Body mass Index (IMC) variation, permanency time, age and sex, i n 45 patients, 23 girls and 22 boys, with overweight and obesity, since June 2003 until May 2006. Patients without exogenous overweight and obesity were excluded to the study. Results: Previous to the treatment 100% of the patients were corresponding with intense obesity, over 95 percentile, prevailing boys over girls in range 11 - 13.11 years, and girls over boys in range 2-8 years. Posterior to the treatment 53% of patients remained over 95 percentile, whereas the 47% place under 95 IMC percentile. The permanence time in the treatment fluctuated between 2-24 months. The modal value was 3, and the Standard Deviation (SD) 4.9. The BMI of the group was reduced in 14.8%, the modal value was 11, and SD 5.8. In conclusion: the obesity treatment beneficed all patients, in short and medial term. Recommendations is to work strategy for more adhesion at long term (AU)
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Obesity/epidemiology , Body Mass Index , Body Weight , Weight Gain , Retrospective Studies , Obesity/diagnosis , Obesity/therapy , Sex Distribution , Age DistributionABSTRACT
Nectins are recently described adhesion molecules that are widely expressed on many tissues, including the hematopoietic tissue. Nectin 1 (CD111) is expressed on a higher proportion of mobilized peripheral blood (mPB) than cord blood (CB) CD34+ cells, and of CD34+/CD38+ cells when compared with CD34+/CD38- cells. We studied functional properties of human CB and mPB CD34+ cells that express low or high levels of CD111. CD34+/CD111(dim) cells contain a higher proportion of cells in G0/G1 phase than CD34+/CD111(bright) cells. CD34+/CD111(bright) cells contain more erythroid progenitors: CFU-E, than their counterparts, which on the opposite contain more HPP-CFC. Limiting dilution analyses demonstrate a higher frequency of immature progenitors: cobblestone-area colony-forming cells, CD34+/CD111(dim) than in CD34+/CD111(bright) cells. In vitro differentiation assays demonstrate a higher frequency of B-, T- and dendritic-cell precursors, but less NK-cell precursors in CD34+/CD111(dim) cells. Evaluation of engraftment in NOD-SCID mice shows that SCID repopulating cells are more frequent among mPB CD34+/CD111(dim) cells. Liquid culture of CD34+/CD111(dim) cells with erythropoietin shows that CD111 expression increases simultaneously with CD36, following CD71 and before glycophorin A expression. In conclusion, immature human hematopoietic progenitors express low levels of CD111 on their surface. During erythroid differentiation CD34+ cells acquire higher levels of the CD111 antigen.
Subject(s)
Antigens, CD34/metabolism , Cell Adhesion Molecules/metabolism , Hematopoietic Stem Cells/metabolism , Animals , Antigens, Differentiation/metabolism , Antigens, Surface/metabolism , Bone Marrow Cells/cytology , Cell Cycle , Cell Differentiation , Coculture Techniques , Colony-Forming Units Assay , Erythropoietin/metabolism , Fetal Blood/cytology , Flow Cytometry , Glycophorins/metabolism , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Nectins , Thymus Gland/cytology , Transplantation, HeterologousABSTRACT
Thalassaemia intermedia is a moderate form of thalassaemia resulting from various genetic defects. We report an undescribed mechanism leading to this condition: a somatic deletion of the beta-globin gene in the haemopoietic lineage of a heterozygous beta-thalassaemic patient. We did molecular studies and haemoglobin analysis of the patient and his parents. We found that the deletion gives rise to a mosaic of cells with either one or no functional beta-globin gene and it extends to a region of frequent loss of heterozygosity called LOH11A, which is located close to the beta-globin locus. Thus, loss of heterozygosity can be a cause of non-malignant genetic disease.
Subject(s)
Gene Deletion , Globins/genetics , Loss of Heterozygosity/genetics , beta-Thalassemia/genetics , Anemia/genetics , Child , Codon, Nonsense/genetics , Genes, Dominant/genetics , Genetic Testing , Genotype , Growth Disorders/genetics , Hemoglobins/analysis , Hepatomegaly/genetics , Heterozygote , Humans , In Situ Hybridization, Fluorescence , Male , Pedigree , Restriction Mapping , Severity of Illness Index , Splenomegaly/genetics , beta-Thalassemia/blood , beta-Thalassemia/classification , beta-Thalassemia/complicationsABSTRACT
Studies in mice suggest that the Ikaros (Ik) gene encodes several isoforms and is a critical regulator of hematolymphoid differentiation. Little is known on the role of Ikaros in human stem cell differentiation. Herein, the biological consequences of the forced expression of Ikaros 6 (Ik6) in human placental blood CD34(+) progenitors are evaluated. Ik6 is one of the isoforms produced from the Ikaros premessenger RNA by alternative splicing and is thought to behave as a dominant negative isoform of the gene product because it lacks the DNA binding domain present in transcriptionally active isoforms. The results demonstrate that human cord blood CD34(+) cells that express high levels of Ik6 as a result of retrovirally mediated gene transfer have a reduced capacity to produce lymphoid B cells in 2 independent assays: (1) in vitro reinitiation of human hematopoiesis during coculture with the MS-5 murine stromal cell line and (2) xenotransplantation in nonobese diabetic-severe combined immunodeficient mice. These results suggest that Ikaros plays an important role in stem cell commitment in humans and that the balance between the different isoforms is a key element of this regulatory system; they support the hypothesis that posttranscriptional events can participate in the control of human hematopoietic differentiation.
Subject(s)
Antigens, CD34/blood , DNA-Binding Proteins , Fetal Blood/immunology , Hematopoietic Stem Cells/drug effects , Transcription Factors/pharmacology , Animals , B-Lymphocytes/drug effects , Cell Differentiation/drug effects , Cell Line , Cell Lineage/drug effects , Coculture Techniques , Fetal Blood/cytology , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Humans , Ikaros Transcription Factor , Mice , Mice, Inbred NOD , Mice, SCID , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Isoforms/pharmacology , Retroviridae/genetics , Stromal Cells/cytology , Transcription Factors/genetics , Transcription Factors/metabolism , Transduction, Genetic , Transplantation, HeterologousABSTRACT
La calidad de vida de los niños que padecen trastorno psicomotor puede estar directamente afectada por la presencia de diversas patologías que se suman a su enfermedad de base. Estas alteraciones pueden ser de carácter sensitivo motor, cognitivo y conductual. A nivel del tracto digestivo son frecuentes las patologías bucales de diverso orden, los trastornos deglutorios faríngeos y esofágicos, las alteraciones en el tono del cardias y del píloro, el vaciado gástrico lento, el reflujo gastroesofágico, la gastritis y el estreñimiento. Estas alteraciones, diversas en su expresión e intensidad, afectan en grado variable la conducta alimentaria y su calidad de vida total. El riesgo de padecer malnutrición es elevado en este grupo de pacientes. Por ello es importante la detección precoz de estos trastornos para aplicar a tiempo un tratamiento adecuado. La interacción de un equipo interdisciplinar y la aplicación de una terapia reeducativa es de suma trascendencia (AU)
Subject(s)
Female , Child, Preschool , Male , Child , Humans , Psychomotor Disorders/diagnosis , Psychomotor Disorders/complications , Psychomotor Disorders/therapy , Quality of Life , Digestive System Diseases/complications , Digestive System Diseases/diagnosis , Digestive System Diseases/etiology , Digestive System/pathology , Digestive System/physiopathology , Deglutition Disorders/complications , Deglutition Disorders/diagnosis , Deglutition Disorders/physiopathology , Deglutition Disorders/etiology , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/therapy , Gastritis/diagnosis , Gastritis/complications , Gastritis/physiopathology , Nutrition Disorders/complications , Nutrition Disorders/diagnosis , Nutrition Disorders/epidemiology , Malocclusion/complications , Malocclusion/epidemiology , Anodontia/complications , Anodontia/diagnosis , Anodontia/etiology , Enamel Microabrasion/methods , Enamel Microabrasion , Periapical Granuloma/complications , Periapical Granuloma/diagnosis , Periapical Granuloma/therapy , Salivation , Dietetics/education , Dietetics/methods , Metoclopramide/therapeutic use , Antacids/therapeutic use , Cathartics/therapeutic use , Psychomotor Performance , Constipation/diagnosis , Constipation/complications , Constipation/therapy , Infant Nutrition Disorders/diagnosis , Infant Nutrition Disorders/etiology , Psychomotor Disorders/epidemiology , Pathology, Oral/trends , Pathology, Oral/methods , Stomatitis/complications , Stomatitis/diagnosis , Stomatitis/pathologyABSTRACT
El riesgo de padecer malnutrición es muy alto en niños y adolescentes que padecen determinado tipo de patología neurológica (PN) por una diversidad de factores que en ellos concurren: trastornos de coordinación motora de la deglución en sus distintas fases, reflujo gastroesofágico, esofagitis, gastritis, alteración del reflejo gastrocólico, estreñimiento, anorexia, etc. Estos trastornos alteran la proporcionalidad deseable entre la cantidad de alimento aportado al paciente y las ingestas netas del mismo. Debido a ello se hace necesaria 1) la valoración periódica y sistemática del estado nutricional, adaptada a este tipo de pacientes, y a partir de los datos recabados 2) la toma de decisiones oportunas referidas a su alimentación: requerimientos, opciones para el soporte nutricional, vía de administración y 3) tratamiento de las complicaciones digestivas si las hubiere. Con ello se contribuirá a mejorar su calidad de vida y a disminuir el nivel de estrés que viven las personas encargadas de su cuidado y alimentación. Importa mucho abordar con acierto las particularidades en su comportamiento alimentario. Estas acciones, complejas en su abordaje, requieren un enfoque interdisciplinar. La intencionalidad de este trabajo es contribuir a estos objetivos (AU)
Subject(s)
Female , Child, Preschool , Infant , Male , Child , Humans , Enteral Nutrition/methods , Enteral Nutrition , Enteral Nutrition/trends , Nutrition Disorders/diagnosis , Nutrition Disorders/etiology , Nutrition Disorders/therapy , Neurologic Manifestations , Food and Nutritional Surveillance , Nutritional Requirements , Clinical Protocols , Cranial Nerves/anatomy & histology , Cranial Nerves/physiology , Food Quality , Food Preservation , Water/administration & dosage , Water/physiology , Diet , Vitamins/administration & dosage , Minerals/administration & dosage , Anthropometry/methods , Prognosis , Bone Density/physiology , Food , Pharmaceutical Preparations/adverse effects , Pharmaceutical Preparations/administration & dosageABSTRACT
Si en cualquier paciente es importante la valoración de su estado nutricional, ésta se hace imprescindible en niños y adolescentes con Trastorno Psicomotor. Se sabe que un déficit de energía, proteínas y micronutrientes, interfiere con el crecimiento, desarrollo y función neuromuscular de niños y adolescentes sanos. En los que padecen trastorno psicomotor es mayor el riesgo de presentar estos déficits, lo cual se convierte en factor de agresión añadido a su estado general que puede tener graves consecuencias. Por su importancia e interés clínico en beneficio de los pacientes con trastorno psicomotor, se presenta este planteamiento de Evaluación Nutricional, que si bien tiene como base los valores estándar para individuos sanos, de edad y sexo similares, aporta algunas especificaciones útiles para la valoración de quienes presentan trastorno psicomotor. Esta evaluación será provechosa, siempre que se realice de modo sistemático y con una periodicidad determinada (AU)
Subject(s)
Adolescent , Female , Male , Child , Humans , Psychomotor Disorders/complications , Psychomotor Disorders/diagnosis , Psychomotor Disorders/diet therapy , Psychomotor Disorders/epidemiology , Diet Surveys , Anthropometry/instrumentation , Anthropometry/methods , Nutrition Assessment , Nutrition Disorders/diet therapy , Nutrition Disorders/diagnosis , Nutrition Disorders/prevention & control , Protein-Energy Malnutrition/diagnosis , Protein-Energy Malnutrition/diet therapy , Protein-Energy Malnutrition/prevention & control , Protein Deficiency/diagnosis , Protein Deficiency/diet therapy , Protein Deficiency/prevention & control , Partial Breastfeeding , Deficiency Diseases/diagnosis , Deficiency Diseases/diet therapy , Deficiency Diseases/prevention & control , Medical History Taking/methods , Weight by Height , Weight Gain , Nutritional Status , Densitometry , Food and Nutritional Surveillance , Water Consumption (Environmental Health) , Energy Metabolism , Child Nutrition Disorders/diet therapy , Child Nutrition Disorders/diagnosis , Child Nutrition Disorders/prevention & control , Infant Nutritional Physiological Phenomena/education , Psychomotor Performance , Infant, Low Birth Weight/growth & development , Infant, Low Birth Weight/psychology , Growth Disorders/diet therapy , Growth Disorders/prevention & controlABSTRACT
The biological effects of flt3-L, and the expression of its tyrosine kinase receptor (flt3, CD135) were investigated on the immature subsets of human circulating peripheral blood progenitors obtained from cancer patients or normal volunteer donors, after mobilization with rhG-CSF or chemotherapy. flt3 was expressed at low levels, and its expression increased concomitantly with expression of CD38 within the CD34+ cell population. Despite this low-level expression, flt3-L exerted synergistic effects with a combination of c-kit ligand, IL-3, IL-6, GM-CSF and G-CSF, mainly to induce proliferation of CD34+/CD38- cells. In addition, flt3-L increased the detection of HPP-CFC, both immediately after cell selection, and after 7 and 14 d of cultures. We conclude that flt3-L is active on circulating early mobilized haemopoietic progenitors, despite the low- level expression of its receptor.
Subject(s)
Antigens, CD , Hematopoietic Stem Cells/metabolism , Membrane Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Antigens, CD34 , Antigens, Differentiation , Cell Division/physiology , Cell Survival , Flow Cytometry , Hematopoiesis , Hematopoietic Stem Cells/cytology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Membrane Glycoproteins , NAD+ Nucleosidase , Tumor Cells, CulturedABSTRACT
The subset of blood cells that expresses both CD34 and Thy1 (CD90) cell surface molecules is enriched in hematopoietic stem cell activity and can be obtained from the peripheral blood of cancer patients after mobilization by chemotherapy and granulocyte colony-stimulating factor (G-CSF). Because transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of hematopoietic progenitor proliferation and differentiation, in this study we analyzed the impact of neutralizing TGF-beta1 activity during culture and retroviral transduction of CD34+Thy1+ cells. When purified CD34+Thy1+ cells were cultured in the presence of a neutralizing antibody against TGF-beta1, the percentage of cycling cells, proliferation, and absolute number of clonogenic progenitors were increased in comparison to the cultures performed without the addition of antibody. Antibody-mediated neutralization of TGF-beta1 during retroviral transduction performed by coculture of CD34+Thy1+ cells with a MFG-S-nlsLacZ retroviral vector-producing cell line did not affect the percentage of transduced progenitors as assessed by direct X-Gal staining of colonies in clonogenic assays. However, due to the better expansion of CD34+Thy1+ cells in the presence of anti-TGF-beta1, the absolute number of transduced progenitors recovered at the end of the culture was increased.
Subject(s)
Antigens, CD34/physiology , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/physiology , Thy-1 Antigens/physiology , Transforming Growth Factor beta/immunology , Antibodies/pharmacology , Antibodies/physiology , Cell Count/drug effects , Cell Division/immunology , Genetic Vectors/blood , Hematopoietic Stem Cells/drug effects , Humans , Retroviridae/genetics , Transduction, GeneticABSTRACT
Relative transduction efficiency with retroviral vector-producing clones was assayed by cocultivating TF-1, a human CD34+ hematopoietic cell line and YR-2, a sheep B-lymphoid cell line, with LacZ containing vector-producing cells, and then by scoring the percentage of X-Gal+ cells. At the same time, viral titer was estimated by titration assay with murine fibroblasts. Results clearly demonstrated a lack of correlation between viral titer and efficiency of transduction into hematopoietic cells, which depends neither on the type of packaging cell line, PG-13 and GP-envAM12 in this study, nor on the type of LacZ containing retroviral vector. These results strongly favor consideration of interactions between producers and target cells of the study for the screening of producing cell lines.
Subject(s)
Bone Marrow Cells , Retroviridae/genetics , Transduction, Genetic , Cell Line , Gene Transfer Techniques , Humans , Lac Operon , Retroviridae/isolation & purificationABSTRACT
We report the possibility to transfer marker genes coding for beta-galactosidase activity using retroviral vectors into human peripheral blood CD34+ cells, peripheral blood T-lymphocytes and into the growth factor-dependent human hematopoietic cell line TF-1. Using the MFG-nisLacZ and the FLac vector and various packaging cell lines, we demonstrated retroviral transfer and high expression of a bacterial beta-galactosidase activity induced by the nisLacZ gene or the Sh-ble/LacZ gene. Kinetics of expression of the transgenes were analyzed both in primary cells and cell lines. Absence of cytotoxicity related to the expression of the bacterial beta-galactosidase was assessed in both cell types. These results open interesting prospectives for the use of the beta-galactosidase activity to mark and follow the fate of genetically modified cells isolated from patients prior to reimplantation.
Subject(s)
Gene Transfer Techniques , Genetic Therapy/methods , Hematopoietic Stem Cells/cytology , Retroviridae , T-Lymphocytes , beta-Galactosidase/genetics , Antigens, CD , Antigens, CD34 , Cell Division , Cells, Cultured , Coculture Techniques , Gene Expression , Genes, Bacterial , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/pathology , Humans , Neoplasms/blood , Neoplasms/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , beta-Galactosidase/biosynthesisABSTRACT
T lymphocytes are a promising cell vehicle for gene therapy purposes. By cocultivating retroviral vector producing cells and target cells, highly efficient gene transfer was achieved with activated human T lymphocytes derived from peripheral blood with vectors carrying different forms of the bacterial beta-galactosidase gene including the regular LacZ gene, the Sh-ble::LacZ gene and the nlsLacZ gene. Infection kinetics of T cells activated by a combination of monoclonal antibodies directed against CD2 and CD28 indicated that the highest efficiencies of transduction were obtained when the cocultivation began 4 days after stimulation. In fact, with the FLac vector, a new retroviral vector which expresses the Sh-ble::LacZ gene, we observed up to 78% transduction efficiency assessed by X-gal staining performed 2 days after the end of the cocultivation. Expression of the transduced genes was observed throughout the period of culture. Neither the cocultivation step nor the expression of the transduced Sh-ble::LacZ gene altered cell culture proliferation or the expression of selected cell surface antigens. In addition, we showed that CD4+ and CD8+ T cells were equally transduced.
Subject(s)
Genetic Therapy/methods , Genetic Vectors , T-Lymphocyte Subsets , Transfection , Antibodies, Monoclonal/immunology , CD2 Antigens/immunology , CD28 Antigens/immunology , Cells, Cultured , DNA, Recombinant/genetics , Gene Expression , Genes, Reporter , Genetic Vectors/genetics , Humans , Immunophenotyping , T-Lymphocyte Subsets/metabolismABSTRACT
Few data are available concerning behavior of reimplanted human hematopoietic cells after autologous stem cell transplantation. This paper reports the possibility to transfer gene markers coding for beta-galactosidase (beta-Gal) activity by retroviral vectors into a human leukemic growth factor-dependent cell line, TF-1, and into human hematopoietic progenitors isolated from peripheral blood or bone marrow. Using various combinations of retroviral vectors and packaging cell lines, we demonstrated high expression of a bacterial beta-Gal activity induced by the LacZ gene, the nlsLacZ gene, or the Sh-ble/LacZ gene, in human hematopoietic cells. The expression of the nlsLacZ construct was stable until the end of the culture in infected CD34+ cell-enriched cell populations, and a slow decrease of transgene expression was observed in a transduced TF-1 cell population during a 1-year long-term culture. Data obtained with the nlsLacZ gene demonstrate that both retroviral transfer and corresponding gene expression were not found to modify the pattern of cell proliferation and differentiation. These results open interesting prospectives for the use of the nlsLacZ gene to mark and follow the fate of progenitor cells isolated from patients with cancers prior to reimplantation.
Subject(s)
Genes, Reporter , Genetic Therapy/methods , Genetic Vectors/genetics , Hematopoietic Stem Cells , Recombinant Fusion Proteins/biosynthesis , Retroviridae/genetics , Transfection , beta-Galactosidase/biosynthesis , Animals , Antigens, CD/analysis , Antigens, CD34 , Cell Line , Forecasting , Hematopoietic Cell Growth Factors/pharmacology , Hematopoietic Stem Cells/metabolism , Humans , Leukemia/pathology , Rats , Time Factors , Tumor Cells, Cultured/drug effects , beta-Galactosidase/geneticsABSTRACT
Methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) plasma concentration-time curves (AUC) have been analyzed in 24 patients after different routes of MTX administration. After an i.v. bolus (50 mg/m2), the AUC for 7-OH-MTX is correlated with that for MTX and inversely correlated with the MTX plasma clearance. When MTX is administered with plasma steady level standardization, using the test-dose protocol, at a level of 10(-5) M over 36 hr (10(-5), 36 hr), 7-OH-MTX-AUC is still correlated with the i.v. bolus pharmacokinetic parameters. The dose prediction using the classical test-dose protocol provides a less efficient MTX dose adjustment at 5 X 10(-4) M over 8 hr (5.10(-4), 8 hr) and the hydroxylation process is no more correlated with the i.v. parameters. On the opposite, upon 6 successive infusions with 10(-5), 36 hr or 5.10(-4), 8 hr protocols, the plasma concentrations of 7-OH-MTX are not significantly modified. This suggests that the hydroxylation process is not inducible.
Subject(s)
Methotrexate/analogs & derivatives , Methotrexate/administration & dosage , Adolescent , Adult , Aged , Child , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Humans , Hydroxylation , Infusions, Intravenous , Injections, Intravenous , Methotrexate/blood , Methotrexate/pharmacokinetics , Middle Aged , Osteosarcoma/drug therapy , Osteosarcoma/metabolismABSTRACT
It has been suggested that the intra-erythrocyte levels of methotrexate (MTX) and its polyglutamized derivatives could offer a method for evaluating intracellular MTX accumulation and its metabolism in children with acute lymphoblastic leukemia. We were interested in measuring the intra-erythrocyte levels of MTX in patients with solid tumors receiving high-dose MTX treatment. After a first incorporation stage occurring during infusion, MTX concentrations subsequently increased 9-12 days after the treatment as polyglutamized derivatives. Thirty days after the infusion, MTX and its polyglutamates were still measurable in erythrocytes. The percentage of polyglutamization varied on an individual basis, but two groups of patients could be separated according to their ability to form polyglutamates. We also noted the presence of 7-hydroxy-methotrexate (7-OH-MTX) appearing 48 hours after the beginning of the infusion which was still present in 17/20 samples 30 days after the treatment.
Subject(s)
Erythrocytes/metabolism , Methotrexate/pharmacokinetics , Adult , Aged , Chromatography, High Pressure Liquid , Female , Folic Acid Antagonists/metabolism , Humans , Male , Methotrexate/analogs & derivatives , Methotrexate/blood , Methotrexate/metabolism , Methotrexate/therapeutic use , Middle Aged , Neoplasms/analysis , Neoplasms/drug therapy , Neoplasms/metabolism , Polyglutamic Acid/analogs & derivatives , Polyglutamic Acid/metabolism , Time FactorsABSTRACT
High-dose methotrexate (HD-MTX) infusions associated with vindesine (VDS) have been used in the treatment of head and neck cancer. In a previous study, VDS was shown to increase the apparent plasma clearance of MTX. We have studied the MTX hydroxylation process in the presence of VDS. Different routes of administration have been tested (IV pushes and 24-h or 36-h infusions). A radioimmunoassay has been developed to measure 7-OH-MTX. The defined protocols enabled us to show that VDS influences not only the pharmacokinetic behavior of methotrexate but also its hydroxylation, which is decreased in presence of VDS.
Subject(s)
Head and Neck Neoplasms/drug therapy , Methotrexate/administration & dosage , Vindesine/administration & dosage , Adult , Aged , Drug Interactions , Female , Humans , Hydroxylation , Male , Metabolic Clearance Rate , Methotrexate/metabolism , Middle AgedABSTRACT
Methotrexate (MTX) and vindesine (VDS) have both been found effective in the treatment of acute leukemia. With regard to their pharmacological effects at the cellular level they can reportedly interact. Administration of MTX at high dose levels has been suggested as both a curative and preventive treatment of blastic meningitis. The purpose of this work was to determine whether an injection of VDS leads to any change in MTX clearance and uptake in the cerebrospinal fluid (CSF). The plasma pharmacokinetic and CSF influx of MTX and VDS were assayed after high dose systemic MTX with an intravenous bolus of VDS administered in the treatment of acute lymphoblastic leukemia. The MTX concentration was determined by enzymatic assay and VDS by radio immunoassay. No interrelation between these drugs was found. MTX levels in the CSF were sufficient for therapeutic effectiveness but were not affected by intravenous VDS. Detectable amounts of VDS were observed in the CSF but were not altered by MTX.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphoid/drug therapy , Adult , Dose-Response Relationship, Drug , Humans , Infusions, Parenteral , Kinetics , Lymphoma, Non-Hodgkin/drug therapy , Methotrexate/administration & dosage , Methotrexate/metabolism , Middle Aged , Vindesine/administration & dosage , Vindesine/metabolismABSTRACT
A preliminary methotrexate (MTX) kinetic evaluation following administration of an IV bolus (test-dose) allowed individualization of high-dose infusions (HD-MTX). This approach combined with therapeutic drug monitoring was found to have good performance over a large scale of predicted steady-state levels (Css) (10(-5) to 10(-4) M over 24 to 36 h) corresponding to 17 to 650 mg/h deliveries (root mean squared error : rmse (precision) = 1.54 X 10(-5) M (21.4%) and mean error : me (bias) = 0.043 X 10(-5) M (NS)). However a significative (p less than 0.05) but rather low over-estimation of dosage (me = 7.38 X 10(-5) M (14.8%)) associated to a decrease in the prediction precision (rmse = 13.3 X 10(-5) M (26.6%)) occurred in 5 X 10(-4) M predicted Css over 8 h (970 to 1970 mg/h deliveries). However in a number of cases (6 out of 29) important deviations from predicted Css occurred, implying the need to stop the infusion before 8 h. These results indicated that MTX pharmacokinetics was linear from low test-dose bolus injections to high-dose infusions. This allowed dosage predictions based upon preliminary estimation of MTX clearance and associated to therapeutic drug monitoring during and following infusion.
Subject(s)
Methotrexate/metabolism , Head and Neck Neoplasms/drug therapy , Humans , Kinetics , Mathematics , Methotrexate/administration & dosage , Osteosarcoma/drug therapy , Sarcoma/drug therapy , Time FactorsABSTRACT
Population pharmacokinetics of methotrexate (MTX) was evaluated from intravenous test-dose (TD) data (n = 20 corresponding to 174 measured samples). Bayesian prediction of MTX clearance from TD experiments combining population data with measured levels (at times 0.5 and 6 h) was found to be feasible in routine situations with good performance (root mean squared error : rmse (precision) = 1.14 1.h-1 (11.2%) and mean error : me (bias) = 0.06 1.h-1 (NS) relatively to weighted least-square estimates, n = 50). The precision of Bayesian prediction was comparable to that of the model independent which is used in routine practice and involves 9 measured levels over 30 h, (rmse = 1.35 1.h-1 (10.9%), n = 50). However, the routine method presented a significative bias (me = -0.81 1.h-1, n = 50).
Subject(s)
Methotrexate/metabolism , Models, Biological , Humans , Kinetics , Mathematics , Metabolic Clearance Rate , Methotrexate/administration & dosage , Neoplasms/drug therapy , Time FactorsABSTRACT
Determination of methotrexate (MTX) kinetics after an IV bolus (50 mg/m2) allows prediction of the steady-state plasma level of this drug during a constant infusion. This prediction allows high-dose MTX (HD-MTX) therapy without major toxicity. Patients with head and neck carcinoma received HD-MTX and vindesine (VDS) infusions concomitantly. The therapeutic survey of these patients showed that the predicted plasma level of MTX was not achieved in the presence of VDS. Moreover, the computed dose of MTX had to be increased by a larger amount if the MTX plasma clearance after the identification IV push was low (less than 9 l/h). In the presence of VDS, the creatinine clearance is lower than when MTX is infused alone, and MTX renal elimination is identical (MTX or MTX + VDS infusions). Thus it seems that the decrease of the MTX plasma level during MTX-VDS infusion could be due to an increase of cellular incorporation.
