RESUMEN
Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a "3+3" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.
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Ciclofosfamida/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Inmunosupresores , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Lenalidomida , Leucocitos/citología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Células Mieloides/citología , Células Neoplásicas Circulantes , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Talidomida/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hematological deficiencies increase with aging leading to anemias, reduced hematopoietic stress responses and myelodysplasias. This study tested the hypothesis that side population hematopoietic stem cells (SP-HSC) would decrease with aging, correlating with IGF-1 and IL-6 levels and increases in bone marrow fat. Marrow was obtained from the femoral head and trochanteric region of the femur at surgery for total hip replacement (N=100). Whole trabecular marrow samples were ground in a sterile mortar and pestle and cellularity and fat content determined. Marrow and blood mononuclear cells were stained with Hoechst dye and the SP-HSC profiles acquired. Marrow stromal cells (MSC) were enumerated flow cytometrically employing the Stro-1 antibody, and clonally in the colony forming unit fibroblast (CFU-F) assay. Plasma levels of IGF-1 (ng/ml) and IL-6 (pg/ml) were measured by ELISA. SP-HSC in blood and bone marrow decreased with age but the quality of the surviving stem cells increased. MSC decreased non-significantly. IGF-1 levels (mean=30.7, SEM=2) decreased and IL-6 levels (mean=4.4, SEM=1) increased with age as did marrow fat (mean=1.2mmfat/g, SEM=0.04). There were no significant correlations between cytokine levels or fat and SP-HSC numbers. Stem cells appear to be progressively lost with aging and only the highest quality stem cells survive.
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Envejecimiento/fisiología , Médula Ósea/fisiología , Citocinas/fisiología , Células Madre Hematopoyéticas/fisiología , Células de Población Lateral/fisiología , Adulto , Anciano , Antígenos de Superficie/análisis , Recuento de Células Sanguíneas , Recuento de Células , Supervivencia Celular , Estudios de Cohortes , Ensayo de Unidades Formadoras de Colonias , Células Madre Hematopoyéticas/citología , Humanos , Persona de Mediana Edad , Células de Población Lateral/citología , Células del Estroma/citología , Células del Estroma/fisiología , Adulto JovenRESUMEN
BACKGROUND: Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. OBJECTIVE: To determine if the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. RESULTS: Release of TNF-alpha and IL-1beta after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release.NF-kappaB expression, a transcriptional regulator for TNF-alpha and IL-1beta genes, corresponded to this secretion pattern. TNF-alpha release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1beta required 6 hours (p = 0.0009). CONCLUSION: Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-alpha.
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Anfotericina B/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fiebre/inducido químicamente , Interleucina-1/metabolismo , Pirógenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Anfotericina B/administración & dosificación , Anfotericina B/química , Animales , Química Farmacéutica , Ácido Desoxicólico , Endotelio/efectos de los fármacos , Endotelio/metabolismo , Lípidos , Liposomas , FN-kappa B/metabolismo , Pirógenos/química , Estereoisomerismo , Suspensiones , Porcinos , Factores de TiempoRESUMEN
BACKGROUND: Cytokine-induced mobilization of hematopoietic stem/progenitor cells to the circulation facilitates efficient harvest of blood stem cells by leukapheresis. Up to 30% of autologous, and 10-20% of allogeneic blood stem-cell donors respond poorly to mobilizing cytokines and preliminary studies implicated a circulating inhibitor of mobilization. METHODS: In this study, plasma from 11 allogeneic and 23 autologous stem cell donors was assayed for inhibition of mobilization in mice. RESULTS: There were significant correlations between CD34(+) cells collected/kg human donor weight and spleen weight, CD34(+) CD45(+) cells, GMCFC and HPP-CFC per spleen in murine recipients of these plasma samples. Overall, there was a positive association between transforming growth factor beta (TGF-beta) levels and CD34(+) cells per liter of blood processed (LBP). However, when arbitrarily segregated into good versus poor mobilizers, based on less or greater than 15 million CD34(+) cells collected per LBP, the majority (64%) of normal donors were good mobilizers. The majority of the poor mobilizers (83%) were patients. For a subset of 12 individuals whose plasma strongly inhibited mobilization in the mouse, a significant positive correlation of the extent of inhibition with TGF-beta levels was found. For 11 individuals whose plasma, based on colony assays, enhanced mobilization when injected into mice, no correlation with TGF-beta levels was evident. DISCUSSION: Elevated plasma TGF-beta levels in some stem-cell donors may be associated with poor stem-cell mobilization. It remains to be determined whether elevation of TGF-beta levels is a cause of, or a compensatory response to, poor mobilization.
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Citocinas/farmacología , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Plasma/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antígenos CD34/metabolismo , Células Cultivadas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/fisiología , Ratones , Estadística como Asunto , Trasplante HomólogoRESUMEN
Patients receiving high-dose preparation for stem cell transplantation are at risk for organ dysfunction (OD). Signs of early OD include hypoxia, mental status changes, and liver dysfunction. These early signs have not been correlated with potential cytokine mediators. We compared plasma concentrations of IL-6, TNF-alpha, and IL-10 in OD patients and controls. Cytokines were measured before preparation, 5 days before OD, day of OD, and 5 days after OD. TNF-alpha and IL-10 were not measurable prior to preparation. IL-10 was more likely to be measurable in OD patients than in controls 5 days prior to onset of OD (P = 0.039), on the day of OD (P = 0.023), and 5 days later (P < 0.0001). TNF-alpha was more likely to be measurable only on the day of OD (P = 0.0035). IL-6 was significantly elevated in OD patients at all time points. Patients who had measurable IL-6 on admission were 5.1 times more likely to develop OD (95% CI = 1.4-17.9; P = 0.011). Five days prior to OD for each 100 pg/ml increase in IL-6, patients were 2.75 times more likely to develop OD (95% CI = 1.3-5.8; P = 0.0087). The early elevation of IL-6 in patients who develop OD may help identify a high risk group where preventive therapies can be evaluated.
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Lesión Renal Aguda/etiología , Trasplante de Células Madre Hematopoyéticas , Interleucina-10/sangre , Interleucina-6/sangre , Fallo Hepático/etiología , Insuficiencia Multiorgánica/etiología , Insuficiencia Respiratoria/etiología , Acondicionamiento Pretrasplante/efectos adversos , Factor de Necrosis Tumoral alfa/análisis , Lesión Renal Aguda/sangre , Adulto , Antitrombina III/análisis , Biomarcadores , Femenino , Neoplasias Hematológicas/terapia , Humanos , Fallo Hepático/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/sangre , Neoplasias/terapia , Pronóstico , Estudios Prospectivos , Proteína C/análisis , Insuficiencia Respiratoria/sangre , Trasplante Autólogo , Trasplante HomólogoRESUMEN
BACKGROUND: Allogeneic blood stem-cell donors demonstrate more vigorous mobilization of CD34(+) cells to the circulation in response to cytokine administration than do autologous donors. Transforming growth factor (TGF-beta1) has been implicated as a mobilization inhibitor. A study was designed to determine whether plasma TGF-beta1 levels are elevated in cytokine-mobilized autologous cancer donors compared with cytokine-mobilized normal donors. METHODS: Plasma collected from 29 autologous cancer donors and 33 normal allogeneic stem-cell donors following administration of mobilizing cytokines just prior to the first collection was assayed for TGF-beta1 using a sandwich-type ELISA. Plasma from three volunteers not treated with cytokine was also analyzed. Comparisons were made using the Student's t test on log-transformed data. RESULTS: Average TGF-beta1 levels in the plasma of cancer patients were significantly higher than in allogeneic stem-cell donors (4.4 ng/mL versus 7.2 ng/mL; p = 0.038). The allogeneic donors required fewer collections to harvest greater numbers of CD34(+) cells and colony-forming unit granulocyte-macrophage (CFU-GM) than autologous donors. Plasma from three untreated volunteers had mean TGF-beta1 levels of 0.36 ng/mL, with all three levels below the 25th percentile for allogeneic donors and the 5th percentile for cancer patients. DISCUSSION: Cytokine administration was associated with increased plasma TGF-beta1 levels. The levels were higher in cancer patients being mobilized for stem-cell collection than in allogeneic blood stem-cell donors. These differences could underlie the increased number of apheresis procedures required to harvest autologous graft products from cancer patients.
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Donantes de Sangre , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/efectos de los fármacos , Neoplasias/sangre , Neoplasias/terapia , Factor de Crecimiento Transformador beta/sangre , Antígenos CD34/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Ensayo de Inmunoadsorción Enzimática , Humanos , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/terapia , Neoplasias/patología , Trasplante Autólogo , Trasplante HomólogoRESUMEN
A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.
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Cromatografía Líquida de Alta Presión/métodos , Colorimetría/métodos , Hidroxiurea/sangre , Humanos , Reproducibilidad de los ResultadosRESUMEN
An HPLC assay for etoposide in human serum was developed. Serum, spiked with podophyllotoxin (internal standard), was treated with sodium dodecyl sulphate prior to solid phase extraction. Analysis was performed on a 300x3.9 mm Bondclone 10 C18 column coupled with a fluorometric detector (lambda(ex) 230 nm, lambda(em) 330 nm). The retention times for etoposide and podophyllotoxin were 14 and 28 min respectively. The range of assay was 0.5 to 20 microg/ml with a detection limit of 0.2 microg/ml. This assay is suitable for use in clinical studies with etoposide.
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Antineoplásicos Fitogénicos/sangre , Etopósido/sangre , Cromatografía Líquida de Alta Presión , Humanos , Indicadores y Reactivos , Podofilotoxina , Estándares de Referencia , Espectrometría de FluorescenciaRESUMEN
Peripheral blood progenitor cells (PBPCs) are becoming the stem cell source of choice for rescuing patients from marrow aplasia after high-dose chemotherapy. Their advantages over bone marrow include avoidance of general anesthesia and more rapid hematologic recovery after transplantation. More rapid engraftment can reduce the risks associated with transplantation and shorten the hospital stay or, under certain circumstances, eliminate it. The cost reductions associated with a shorter stay have made PBPC transplantation cost-competitive with more conventional therapy. The move to outpatient transplantation requires increased patient and family involvement with posttransplantation care, as well as increased patient education and a multidisciplinary care team for the safe transition of patients between care sites. Improvements in outpatient transplantation may incorporate a cooperative care model with the intent of reducing readmission rates and extending this modality to most patients who undergo autologous transplantation.
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Atención Ambulatoria , Neoplasias de la Mama/terapia , Trasplante de Células Madre Hematopoyéticas , Recuento de Células Sanguíneas , Quimioterapia Adyuvante , Femenino , Humanos , Grupo de Atención al Paciente , Readmisión del Paciente , Trasplante AutólogoRESUMEN
We evaluated the antiangiogenic activity of shark cartilage, tumor necrosis factor-alpha (TNF-alpha), and a combination of the two using a human umbilical vein endothelial cell proliferation assay. Proliferation of endothelium is a hallmark of angiogenesis, and inhibition of endothelial cell proliferation indicates potential antiangiogenic activity. Shark cartilage produced a concentration-dependent decline in endothelial cell 3H-thymidine incorporation. This activity was heat stable and was found in molecular weight fractions of less than 10 kd. The antiproliferative effect of shark cartilage was specific for vascular endothelium and did not affect the proliferative rate of human astrocytoma cells or human skin fibroblasts. Shark cartilage at a concentration of 500 mu g/ml and TNF-alpha at a concentration of 10 ng/ml reduced endothelial cell proliferation by 32% and 29%, respectively. Treatment of endothelial cells with the combination of shark cartilage and TNF-alpha resulted in a 44% reduction in endothelial cell proliferation. The isolation and identification of the active components of shark cartilage is continuing.
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Cartílago/química , Endotelio Vascular/efectos de los fármacos , Tiburones , Extractos de Tejidos/farmacología , Venas Umbilicales/efectos de los fármacos , Animales , Técnicas de Cultivo de Célula , División Celular/efectos de los fármacos , Endotelio Vascular/citología , Humanos , Timidina/biosíntesis , Factor de Necrosis Tumoral alfa/farmacología , Venas Umbilicales/citologíaRESUMEN
An essential component of any in vitro model for endothelial permeability is a confluent cell monolayer. The model reported here utilizes primary human umbilical vein endothelial cells (HUVEC) cultured on recently developed polyethylene terephthalate micropore membranes. Using a modification of the Wright-Giemsa stain, confluent HUVEC monolayers grown on micropore membranes were routinely assessed using light microscopy. Determination of confluence using this method was confirmed by scanning electron microscopy. Transendothelial electrical resistance of HUVEC monolayers averaged 27.9 +/- 11.4 omega.cm2, 10 to 21% higher than literature values. Studies characterizing the permeability of the endothelial cell monolayer to 3H-inulin demonstrated a linear relationship between the luminal concentration of 3H-inulin and its flux across HUVEC monolayers. The slope of the flux versus concentration plot, which represents endothelial clearance of 3H-inulin, was 2.01 +/- 0.076 x 10(-4) ml/min (r2 = .9957). The permeability coefficient for the HUVEC monolayer-micropore membrane barrier was 3.17 +/- 0.427 x 10(-6) cm/s with a calculated permeability coefficient of the HUVEC monolayer alone of 4.07 +/- 0.617 x 10(-6) cm/s. The HUVEC monolayer reduced the permeability of the micropore membrane alone to 3H-inulin (1.43 +/- 0.445 x 10(-5) cm/s) by 78%. Evans blue dye-labeled bovine serum albumin could not be detected on the abluminal side without disruption of the HUVEC monolayer. These results demonstrate a model for endothelial permeability that can be extensively assessed for monolayer integrity by direct visualization, transendothelial electrical resistance, and the permeability of indicator macromolecules.
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Endotelio Vascular/citología , Modelos Biológicos , Albúmina Sérica Bovina/farmacocinética , Venas Umbilicales/citología , Permeabilidad de la Membrana Celular , Células Cultivadas , Electrofisiología , Humanos , Membranas ArtificialesRESUMEN
OBJECTIVE: To investigate the potential interaction between cimetidine or famotidine and cyclosporine in healthy men. DESIGN: All subjects received oral cyclosporine at baseline, after the first week of 1 histamine2 (H2)-blocker, and a third time after a 1-week washout plus 1 week of the second H2-blocker. Blood samples were collected just before each dose of cyclosporine and for up to 36 hours afterward for pharmacokinetic analysis. SETTING: A college of pharmacy in a university teaching hospital. PARTICIPANTS: The study population consisted of 8 healthy men at least 19 years of age. MAIN OUTCOME MEASURES: Cyclosporine concentrations in whole blood were measured using a polyclonal fluorescence polarization immunoassay. Cyclosporine pharmacokinetic parameters during each of the 3 treatment periods were compared. RESULTS: The average times to maximum cyclosporine concentrations were similar between baseline (3.2 h), cimetidine (2.9 h), and famotidine (3.6 h) dosing periods. There were no significant differences in area under the curve, half-life, or maximum concentration during the 3 dosing periods. CONCLUSIONS: Neither cimetidine or famotidine produced a significant change in the pharmacokinetics of single-dose oral cyclosporine in healthy men.
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Cimetidina/farmacología , Ciclosporina/farmacocinética , Famotidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Hospitales Universitarios , Humanos , MasculinoRESUMEN
Genetic analysis of behavioral differences among human beings requires both careful experimental design and appropriate genetic models. Any genetic study must be (1) valid and precise measures of individual differences, (2) appropriate methods to ascertain biological relationships, (3) research subjects who have been randomly recruited, (4) appropriate sample sizes, and (5) appropriate genetic models to interpret the data. In addition, the researchers must exercise caution in interpreting biosocial effects from the observed phenotypic correlations. To date, all studies of the genetic basis of sexual orientation of men and women have failed to meet one or more or any of the above criteria.
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Homosexualidad/genética , Femenino , Identidad de Género , Homosexualidad/psicología , Humanos , Individualidad , Masculino , Modelos Genéticos , Fenotipo , Muestreo , Estudios en Gemelos como AsuntoRESUMEN
Heterorhabditis bacteriophora is an entomopathogenic nematode that has potential as a biological control agent. As a first step in the genetic analysis of this nematode, we induced and isolated a short nematode (dumpy) from the F2 progeny of an EMS mutagenized nematode. Phenotypically, the dumpy adult is 60% shorter than the wild type. There is almost no longitudinal growth after the infective juvenile stage. Dumpy is completely recessive with 100% penetrance and uniform expressivity. When F1 progeny were allowed to self, F2 progeny segregated wild: dumpy in a 15:1 ratio (chi 2 = 0.634, .5 > P > .2). This dumpy mutation (Rhdpy) complements another dumpy mutation isolated in Israel and is the second gene known for this species.
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Mutación , Rhabditoidea/genética , Animales , Cruzamientos Genéticos , Metanosulfonato de Etilo , Femenino , Prueba de Complementación Genética , Masculino , Mariposas Nocturnas/parasitología , Control Biológico de VectoresRESUMEN
The stability of ondansetron hydrochloride, dexamethasone sodium phosphate, and lorazepam in 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride (PVC) minibags and glass bottles was studied. Triplicate solutions of 8 or 32 mg of ondansetron (as the hydrochloride salt) mixed with 20 mg of dexamethasone phosphate (as the sodium salt) with or without 2 mg of lorazepam were compounded in 50-mL PVC minibags and glass bottles containing either 5% dextrose injection or 0.9% sodium chloride injection and stored at 23-25 degrees C. Duplicate measurements were performed when drugs were added and at 1, 2, 4, 8, and 24 hours after addition. Samples of the 32-mg ondansetron admixtures were collected under aseptic conditions to inspect for precipitation and to count particles with a laser particle analyzer. Samples of all admixtures were evaluated for chemical stability by stability-indicating high-performance liquid chromatography. Ondansetron hydrochloride and dexamethasone were physically compatible and chemically stable for up to 24 hours under the study conditions. The concentration of lorazepam in PVC containers dropped below 90% of the original concentration within four hours. In addition, particle counts in lorazepam-containing solutions were higher when 0.9% sodium chloride injection was the diluent than when 5% dextrose injection was the diluent. In admixtures containing all drugs, ondansetron hydrochloride and dexamethasone sodium phosphate in 5% dextrose injection or 0.9% sodium chloride injection were stable for up to 24 hours when stored in PVC bags or glass bottles.(ABSTRACT TRUNCATED AT 250 WORDS)
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Dexametasona/química , Lorazepam/química , Ondansetrón/química , Incompatibilidad de Medicamentos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Humanos , InyeccionesRESUMEN
The homeotic mutation spineless-aristapedia (ss(a)) transforms the aristae into second tarsi. Flies with a ss(a) phenotype also show extremely positive geotaxis as measured in a Hirsch-type geotaxis maze. Other antennal mutants and flies with their aristae amputated do not show such extreme positive geotaxis. Deletion analysis has comapped the geotaxis effect with ss(a) in band 89C on the third chromosome. Finally, a biometrical analysis has detected additional genes on the X chromosome that also affects geotaxis.
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Drosophila melanogaster/genética , Genes Homeobox/genética , Modelos Genéticos , Fenotipo , Propiocepción/genética , Animales , Deleción Cromosómica , Mutación/genética , Cromosoma XRESUMEN
Chromosome analysis has been widely used as a first step in elucidating the genetic architecture of several behaviors of Drosophila melanogaster. These chromosome studies have generally used incomplete designs or fairly simple statistical analyses. Here I reanalyze two data sets on geotaxis from Pyle (1978) and Ksander (1966) using a biometrical genetic design. Results from the biometrical genetic reanalysis suggest that individual differences in geotaxis might be due to genes on all three major chromosomes which show extensive epistatic interactions.
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Mapeo Cromosómico , Drosophila melanogaster/genética , Epistasis Genética , Modelos Genéticos , Orientación/fisiología , Animales , Cruzamientos Genéticos , Tamización de Portadores Genéticos , Homocigoto , Selección GenéticaRESUMEN
We investigated the correlation between trough cyclosporine concentration in plasma measured by polyclonal fluorescence polarization immunoassay (FPIA) and polyclonal radioimmunoassay (RIA) or in whole blood measured by high-performance liquid chromatography (HPLC) and the risk of renal dysfunction or acute graft-versus-host disease in 29 patients undergoing allogeneic bone marrow transplantation for leukemia. The FPIA and RIA values were highly correlated (r = 0.93) and on the average CsA concentrations measured by FPIA were 1.56 times higher than those measured by RIA. Ten patients developed renal dysfunction and 10 developed grades II-IV acute GVHD. Although univariate analysis showed that plasma CsA concentrations measured by either FPIA or RIA were significantly correlated with renal dysfunction, the association was stronger with FPIA. Plasma CsA concentrations measured by FPIA but not RIA remained a significant risk factor for renal dysfunction in a multivariate relative risk model. Amphotericin therapy was significantly associated with renal dysfunction in the univariate analysis but not in the multivariate analysis. No significant associations were found between whole blood CsA or CsA M1 concentration, patients' age, gender, or CsA dose and the risk of renal dysfunction. None of the covariates analyzed significantly correlated with the development of acute GVHD. These data suggest that plasma CsA concentrations measured by nonspecific assays may more accurately correlate with renal dysfunction than whole-blood CsA concentrations measured by HPLC in marrow transplant recipients.
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Trasplante de Médula Ósea/efectos adversos , Cromatografía Líquida de Alta Presión/métodos , Ciclosporina/farmacología , Inmunoensayo de Polarización Fluorescente/métodos , Radioinmunoensayo/métodos , Adulto , Ciclosporina/sangre , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: Because of limited intravenous access in patients who have undergone bone marrow transplant (BMT), we undertook a study to determine the safety of mixing cyclosporine in intravenous preparations commonly administered to BMT patients. DESIGN: In a pilot study, we investigated the stability of intravenous cyclosporine (Sandimmune) in four types of intravenous fluids: dextrose 5%, NaCl 0.9%, dextrose/amino acid solutions, and lipid emulsion. Because the pilot study showed highly variable cyclosporine concentrations that suggested inadequate mixing, we undertook another study to determine the effect of the mixing method on cyclosporine concentrations. OUTCOME MEASURE: Cyclosporine was considered stable in the study solutions if concentrations remained above 90 percent of the initial concentrations. RESULTS: Substantial variation in cyclosporine concentrations was observed in lipid emulsion and dextrose/amino acid solutions and gentle swirling of the solutions was insufficient to adequately disperse the drug. The variation was eliminated by vigorous shaking either before each sampling or once after the initial addition of cyclosporine. We used vigorous shaking methods to establish that cyclosporine is stable for up to 72 hours at room temperature in dextrose 5%, 10% amino acid solution with dextrose 50%, and Liposyn 10%, and up to 8 hours in NaCl 0.9%. CONCLUSIONS: These data may be used to simplify cyclosporine administration in patients who have limited intravenous access.
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Aminoácidos/química , Ciclosporina/química , Emulsiones Grasas Intravenosas/química , Glucosa/química , Aminoácidos/análisis , Trasplante de Médula Ósea , Química Farmacéutica , Ciclosporina/administración & dosificación , Ciclosporina/análisis , Estabilidad de Medicamentos , Emulsiones Grasas Intravenosas/análisis , Glucosa/análisis , Proyectos Piloto , Cloruro de Sodio/análisis , Cloruro de Sodio/química , SolucionesRESUMEN
Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).