RESUMEN
Ketanserin is an antihypertensive drug that is increasingly being used parenterally in the treatment of pre-eclampsia. Because of lack of efficacy in a substantial part of our pre-eclamptic patients, we determined the plasma concentrations of ketanserin in 51 pre-eclamptic patients. Population pharmacokinetic parameters were assessed using the iterative two-stage Bayesian population procedure. The influence of individual pharmacokinetic parameters on antihypertensive response, expressed as the attainment of a diastolic blood pressure Asunto(s)
Hipertensión/tratamiento farmacológico
, Ketanserina/farmacocinética
, Preeclampsia/tratamiento farmacológico
, Adulto
, Antihipertensivos/administración & dosificación
, Antihipertensivos/farmacocinética
, Femenino
, Humanos
, Hipertensión/fisiopatología
, Infusiones Intravenosas
, Ketanserina/administración & dosificación
, Ketanserina/sangre
, Tasa de Depuración Metabólica
, Preeclampsia/fisiopatología
, Embarazo
, Tercer Trimestre del Embarazo
, Factores de Tiempo
, Resultado del Tratamiento
RESUMEN
OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) is recognized as a likely mediator of the excessive endothelial activation and injury that is a key pathogenetic mechanism of preeclampsia. We used whole blood cell cultures from 12 patients with severe preeclampsia and from 12 healthy pregnant and nonpregnant women to determine the release of TNF-alpha by unstimulated leukocytes as a measure of their state of activation, and their response to stimulation with lipopolysaccharide (LPS) as an indicator of their state of priming. METHODS: Blood was cultivated without and with LPS, and TNF-alpha release was measured after six and 24 hours of cultivation by enzyme-linked immunoassays. Differential leukocyte counts were performed, and TNF-alpha values calculated per 10(5) monocytes. RESULTS: In unstimulated whole blood cultures, TNF-alpha release after six hours of cultivation was similar in all three groups; but after 24 hours, TNF-alpha concentrations in culture supernatants from preeclamptic patients were significantly higher than were values obtained in blood from normotensive pregnant women. In LPS-stimulated blood cultures with a maximum of TNF-alpha release at six hours cultivation time, TNF-alpha concentrations were significantly lower in preeclamptic women than they were in both control groups. We showed in an additional experiment that a strong LPS challenge following preactivation with high doses of LPS resulted in reduced release of TNF-alpha compared with release of TNF-alpha following preactivation with low doses of LPS. CONCLUSIONS: The observed high capacity for spontaneous TNF-alpha release by leukocytes in preeclampsia indicates activation of TNF-alpha producing leukocytes by the disease process. Preactivation and exhaustion of leukocytes by leakage of TNF-alpha could lead to the reduced response to TNF-alpha inducer LPS as observed in blood cultures from preeclamptic patients.
Asunto(s)
Preeclampsia/sangre , Teofilina/análogos & derivados , Factor de Necrosis Tumoral alfa/análisis , Adulto , Endotelio Vascular/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Recuento de Leucocitos , Leucocitos/metabolismo , Lipopolisacáridos , EmbarazoRESUMEN
BACKGROUND: The purpose of this case-controlled study was to investigate whether plasma concentrations of TNF-receptors I and II and tumor necrosis factor-alpha-induced cell adhesion molecule 1 VCAM-1 could serve as more sensitive markers of tumor necrosis factor-alpha release in preeclamptic women than a direct measurement of circulating tumor necrosis factor-alpha. METHODS: Plasma concentrations of soluble tumor necrosis factor receptor I and II, immunoreactive tumor necrosis factor-a and soluble cell adhesion molecule VCAM-1 were determined in 21 patients with severe proteinuric preeclampsia (23-35 weeks' gestation) and 21 gestational age-matched normotensive controls by enzyme-linked immunoassays. Concentrations of bioactive tumor necrosis factor-alpha were assessed by the WEHI 164 bioassay. Data were statistically evaluated by Wilcoxon's rank sum and sign tests, and Spearman's test was used to evaluate clinical and biochemical correlations. RESULTS: Bioactive tumor necrosis factor-alpha was detected in 19 of 21 preeclamptic and 18 of 21 normotensive women, with no difference in plasma concentrations between both groups. Immunoreactive tumor necrosis factor-alpha, soluble TNF-receptors and soluble cell adhesion molecule VCAM-1 were significantly increased in plasma of preeclamptic patients, and a statistically significant positive correlation was observed between immunoreactive tumor necrosis factor-alpha and TNFRII. In preeclamptic patients a statistically significant negative correlation was observed between TNFRII and platelet count, and between soluble cell adhesion molecule VCAM-1 and birthweight ratio. CONCLUSION: These results show that plasma concentrations of soluble tumor necrosis factor receptor II and soluble cell adhesion molecule VCAM-1 reflect the release of tumor necrosis factor-alpha and provide sensitive markers of excessive release of this cytokine in preeclampsia.