RESUMEN
A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs.
Asunto(s)
Lenalidomida/farmacocinética , Mieloma Múltiple/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Peso Corporal , Ensayos Clínicos como Asunto , Creatinina/orina , Femenino , Voluntarios Sanos , Humanos , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Modelos Teóricos , Mieloma Múltiple/orina , Síndromes Mielodisplásicos/orina , Adulto JovenRESUMEN
We compared urinary levels of cytokines in patients with and without albuminuria, proteinuria and kidney disease (glomerular filtration rate<60 mL/min per 1.73 m(2)) after HCT. Plasma and urine were collected at baseline and weekly through day 100 and monthly through year 1, for measurement of IL-6, gp130, sIL6r, IL-10, IL15, MCP-1 and urine albumin-to-creatinine ratios (ACRs). Cox-proportional hazards modeling examined associations between urinary cytokine levels and development of these renal end points. The association of ACR with the hazard of overall mortality was assessed using Cox regression. Increasing urinary IL-6 and IL-15 were associated with an increased risk of developing proteinuria. Urinary MCP-1 during the first 100 days post HCT was associated with kidney disease at 1 year. The degree of albuminuria at any time point in the first 100 days post transplant was related to the subsequent risk of death (for ACR 30-299, hazard ratio (HR)=1.91; 95% confidence interval (CI): 1.27-2.87; for ACR >300, HR=2.82; 95% CI: 1.60-4.98). After HCT, elevated urinary levels of pro-inflammatory cytokines are associated with development of albuminuria and proteinuria, suggesting early intra-renal inflammation as an important pathogenetic mechanism. Albuminuria and proteinuria within the first 100 days post HCT are associated with decreased overall survival.
Asunto(s)
Citocinas/orina , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inflamación/orina , Enfermedades Renales/orina , Proteinuria/orina , Adulto , Anciano , Albuminuria/complicaciones , Quimiocina CCL2/orina , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Inflamación/complicaciones , Interleucina-15/orina , Interleucina-6/orina , Enfermedades Renales/complicaciones , Leucemia/complicaciones , Leucemia/terapia , Leucemia/orina , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/orina , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Proteinuria/complicaciones , Resultado del Tratamiento , Adulto JovenAsunto(s)
Péptidos Catiónicos Antimicrobianos/orina , Síndromes Mielodisplásicos/orina , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Ferritinas/sangre , Hepcidinas , Humanos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/orina , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Riesgo , Adulto JovenRESUMEN
Central diabetes insipidus (DI) is a rare but recognized complication of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that is caused by leukemic infiltration to the hypothalamo-neurohypophyseal system. In rare patients in whom a wide region of the hypothalamus is involved, central DI results in hypodipsic hypernatremia and dehydration. Typical DI symptoms such as polydipsia, polyuria, and marked thirst are concealed in these cases, because the hypothalamic "thirst center" cannot send thirst stimuli to the cerebral cortex. Herein we describe a patient with MDS developing into AML, who presented with hypodipsic hypernatremia and dehydration. A diagnosis of central DI was made on the ground of a low level of serum anti-diuretic hormone (ADH) despite high serum osmolality. A magnetic resonance imaging study revealed attenuation of a physiological "bright spot" of the neurohypophysis. An induction course chemotherapy including regular-dose cytarabine and daunorubicin produced a rapid improvement of hypernatremia. The bone marrow aspirate after two courses of chemotherapy showed complete remission. At that point, ADH release and the "bright spot" were recovered. In order to correctly diagnose central DI in association with hematological malignancies, we should not overlook this atypical type of DI.
Asunto(s)
Deshidratación/etiología , Diabetes Insípida Neurogénica/etiología , Hipernatremia/etiología , Síndromes Mielodisplásicos/complicaciones , Deshidratación/sangre , Deshidratación/orina , Diabetes Insípida Neurogénica/sangre , Diabetes Insípida Neurogénica/patología , Diabetes Insípida Neurogénica/orina , Femenino , Humanos , Hipernatremia/sangre , Hipernatremia/orina , Imagen por Resonancia Magnética , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/orina , Concentración Osmolar , Neurohipófisis/diagnóstico por imagen , CintigrafíaRESUMEN
BACKGROUND: Phosphorothioate oligonucleotides, in general, possess properties that could be utilized in the development of therapeutic heavy metal chelators. METHODS: Iron excretion was measured in 16 patients participating in studies to test the safety of OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to p53 mRNA. Patients were given OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. Urine was collected during the study and analyzed for iron, copper, cadmium, and zinc. RESULTS: We found that phosphorothioate oligonucleotides have a high affinity for iron as well as several other clinically relevant toxic metals. Analysis of patient urine following administration of OL(1)p53 reveals a 7.5-fold increase in iron excretion at low doses (0.05 mg/kg/h). CONCLUSIONS: Phosphorothioate oligonucleotides may have therapeutic potential as heavy metal chelators. Low doses of phosphorothioate oligonucleotide facilitated the excretion of iron. Renal clearance of iron-phosphorothioate oligonucleotide complexes most likely involves secretion into proximal tubules.
Asunto(s)
Quelantes del Hierro , Hierro/orina , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Tionucleótidos/farmacocinética , Cadmio/orina , Quelantes , Cobre/orina , Relación Dosis-Respuesta a Droga , Recuento de Eritrocitos , Humanos , Infusiones Intravenosas , Leucemia Mieloide Aguda/orina , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/orina , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Oligodesoxirribonucleótidos Antisentido/orina , ARN Mensajero/antagonistas & inhibidores , Espectrofotometría Atómica , Tionucleótidos/uso terapéutico , Tionucleótidos/orina , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Zinc/orinaAsunto(s)
Anemia Aplásica/orina , Biopterinas/análogos & derivados , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Enfermedad de Hodgkin/orina , Síndromes Mielodisplásicos/orina , Adolescente , Adulto , Anciano , Anemia Aplásica/tratamiento farmacológico , Biopterinas/orina , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Macrófagos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Neopterin , Estimulación QuímicaRESUMEN
Urinary glycosaminoglycan excretion is increased in a variety of human diseases, including malignancy. We have measured serum and urine glycosaminoglycan levels by the carbazole method of uronic acid determination in patients with myeloid leukemia or myelodysplasia. Eleven patients were studied during active disease as well as eight in complete remission. Serum levels in patients with active disease did not differ significantly from 11 healthy volunteers with no hematological disease. In contrast, the median urine level for the patients with active disease was 7.6 mg uronate/g Creatinine (Creat) compared to 2.6 for controls (p less than 0.002). Interestingly, the eight patients in complete remission also had a significant increase in uronate excretion with a median of 7.3 (p less than 0.002). These results suggest that elevated urinary glycosaminoglycan levels in leukemia are not due to impaired ability of the liver to clear circulating glycosaminoglycans or overproduction by leukemic cells. The observed increase in glycosaminoglycan excretion may be due to altered bone marrow matrix metabolism that is often not reversed by the achievement of hematologic remission.