RESUMEN
Between May 1994 and May 2000, we autotransplanted 48 consecutive patients, 21 females and 27 males aged over 60 years (range: 60-78, median: 63). Sixteen patients had multiple myeloma (MM), 14 high-grade non-Hodgkin's lymphoma (HGNHL), six low-grade non-Hodgkin's lymphoma (LGNHL), nine acute myeloid leukemia (AML), one chronic lymphocytic leukemia (CLL), one Hodgkin's disease (HD) and one breast cancer; the performance status (WHO) was 0-1. Seventeen patients were in 1st CR (35.4%) and one in 2nd CR (2.1%), 25 in PR (52.1%), while five patients had been transplanted with progressive disease (10.4%); seven patients with MM received a double transplant. Patients received high-dose therapy including melphalan alone (13) or associated with other drugs (26), busulfan-cyclophosphamide (three), BEAM (11) and TBI (two). All patients took a median of 11 (range: 8-25) days to reach neutrophils >500/microl, 13 (range: 9-83) days to reach platelets > 20,000/microl and 17 (range: 11-83) days to reach platelets > 50,000/microl. Hematological toxicity, hospital stay and supportive care did not differ from those of a cohort of younger patients. At present, 31 patients are alive (14 in CR, five in PR, five in PD and seven in relapse) and 16 died from PD at a median follow-up of 37 months (1-67). Only one patient died from transplant-related toxicity. Quality of life, evaluated using a QLQ-C30 questionnaire in 25 patients at day +90, was good. In our experience PBPC mobilization and transplantation is feasible in patients aged > or = 60 years and the toxicity of this procedure is acceptable, with an early transplant-related mortality of 1.8%; therefore patients with hematological malignancies potentially curable with high-dose therapy (HDT) should also be candidates for HDT.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Trasplante de Células Madre Hematopoyéticas/normas , Calidad de Vida , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Femenino , Supervivencia de Injerto , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/psicología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Encuestas y Cuestionarios , Tasa de Supervivencia , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos , Trasplante Autólogo/normas , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: The Na(+)/H(+) exchanger is the main intracellular pH (pH(i)) regulator in hepatic stellate cells (HSCs) and plays a key role in regulating proliferation and gene expression. We evaluated the effect of specific inhibition of this exchanger on HSC proliferation and collagen synthesis in vivo and in vitro. METHODS: Rat HSCs were incubated in the presence of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta1, iron ascorbate (FeAsc), and ferric nitrilotriacetate solution (FeNTA) with or without the Na(+)/H(+) exchanger inhibitor 5-N-ethyl-N-isopropyl-amiloride (EIPA). pH(i) and Na(+)/H(+) exchanger activity, cell proliferation, and type I collagen accumulation were measured by using the fluorescent dye 2',7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein, by immunohistochemistry for bromodeoxyuridine, and by enzyme-linked immunosorbent assay, respectively. In vivo liver fibrosis was induced by dimethylnitrosamine administration and bile duct ligation (BDL) in rats treated or not treated with amiloride. RESULTS: PDGF, FeAsc, and FeNTA increased Na(+)/H(+) exchange activity and induced HSC proliferation. TGF-beta1 had no effect on the Na(+)/H(+) exchanger and was able, as for FeAsc and FeNTA, to induce type I collagen accumulation. EIPA inhibited all the effects determined by PDGF, FeAsc, and FeNTA and had no effect on TGF-beta1-induced collagen accumulation. In vivo, amiloride reduced HSC proliferation, activation, collagen deposition, and collagen synthesis. CONCLUSIONS: The Na(+)/H(+) exchanger can play a key role in the development of liver fibrosis and in HSC activation in vivo.
Asunto(s)
Amilorida/análogos & derivados , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Hígado/citología , Hígado/metabolismo , Ácido Nitrilotriacético/análogos & derivados , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Amilorida/farmacología , Animales , Antiarrítmicos/farmacología , Antineoplásicos/farmacología , Ácido Ascórbico/farmacología , Carcinógenos/farmacología , División Celular/efectos de los fármacos , Colágeno/metabolismo , Diuréticos/farmacología , Compuestos Férricos/farmacología , Compuestos Ferrosos/farmacología , Expresión Génica/efectos de los fármacos , Concentración de Iones de Hidrógeno , Etiquetado Corte-Fin in Situ , Hígado/patología , Masculino , Ácido Nitrilotriacético/farmacología , Procolágeno/genética , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Timidina Fosforilasa/farmacología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
1. Frequency-domain spectral analysis of stationary ECG R-R intervals was made by fast Fourier transformation (FFT) in conditions of monitored arterial blood pressure and respiratory activity in diethyl-ether-anaesthetized and pithed adult rats. This technique yields a number of parameters which allow quantitative evaluation of the non-random distribution of the mean values obtained in time-domain studies. The frequency-analysis method enables the overall heart rate variability to be broken down into its various constituents, which are differently affected by physiological loading and capable of selective reactivity to pharmacological agents. 2. The low-frequency spectral component obtained by breaking down the total spectral density power, i.e. the appropriate variability signal (band width < 0.15 Hz) and a higher-frequency band corresponding to spontaneous (0.80-1.60 Hz) or artificially imposed (0.75 Hz) respiratory activity were estimated and their integrated areas evaluated as absolute powers or normalized fractional values. 3. The power of the high-frequency spectral component increased in all animal preparations under treatment with prazosin, dl-propranolol, endothelin-1 and the angiotensin converting enzyme (ACE) inhibitors captopril, lisinopril, quinapril and ramipril. The power of the low-frequency band increased under alpha-r atriopeptin and ACE inhibitors in the pithed preparations only, and decreased in the anaesthetized animals. 4. The new power spectrum features and trends detected indicate that these time-independent, model-dependent cardiovascular and respiratory markers are subject to some form of complex peptidergic control. 5. The relative roles of the various factors operating in the genesis of these short-term changes in spectral power in the low- and high-frequency bands cannot be interpreted as indicating a reciprocal push-pull relationship between sympathetic and parasympathetic control. 6. The study findings, however, can be interpreted as providing evidence of a different and to some extent alternative form of integrative cardiovascular control persisting in the pithed rats (i.e. in the 'peripheral', CNS-destroyed preparations). 7. New areas of theoretical and applied research are being developed in the (auto)classification of (iso)receptors and drug analogues through exploration of multiple physiological and pharmacokinetic parameters in the frequency-domain. Furthermore, model-independent frequency-domain methods not requiring stationary data will afford scope for even more significant developments by separating the overlapping dynamic processes from a whole series of correlated effects.
Asunto(s)
Factor Natriurético Atrial/farmacología , Endotelina-1/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Prazosina/farmacología , Propranolol/farmacología , Animales , Electrocardiografía/métodos , Éter/farmacología , Femenino , Masculino , Ratas , Ratas WistarRESUMEN
1. In this study, electrocardiographic second lead tracings were recorded and analyzed online and offline in the conscious and spinalized Xenopus laevis under control conditions and after treatment with at least two effective doses of racemic diltiazem, nifedipine and racemic verapamil hydrochlorides. 2. Heart rates (HR) and intercycle heart rate power spectra (IHRPS) were calculated in the various experimental conditions. 3. Dose-dependent bradycardia was found in most cases, which was associated with dose-related increases in the overall dynamic range of the largest peak of HR variability (increased IHRPS), this being particularly marked at the higher nifedipine dose. The frequency position of the largest peak was unchanged in the spinalized preparation, as well as in the various treatments. 4. These findings may contribute toward a more complete pharmacodynamic definition of calcium channel blockers in their current therapeutic use.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Estado de Descerebración/fisiopatología , Electrocardiografía/efectos de los fármacos , Corazón/efectos de los fármacos , Animales , Diltiazem/farmacología , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Nifedipino/farmacología , Verapamilo/farmacología , Xenopus laevisRESUMEN
Previous studies showed that anaesthesia with the barbiturate Thiopental induces an increase in membrane fluidity and a decrease in acetylcholinesterase activity in syncytiotrophoblast plasma membranes (SPM) obtained from placentas after Cesarean section. The aim of the present work was to compare the effect of a local anaesthetic (bupivacaine hydrochloride, trade name Marcaine) on SPM in vivo and to establish whether the anaesthetic is still present in the membrane after tissue preparation. The acetylcholinesterase activity was lower in Marcaine-anaesthetized SPM (27 +/- 3 against 39 +/- 6 in the control). The Marcaine action on the SPM can be ascribed to a competitive inhibition, similar to that reported for Thiopental. Fluorescence studies of the order parameter P showed it to be higher in SPM obtained from control (0.253 +/- 0.012) than in SPM obtained from Marcaine-exposed membranes (0.240 +/- 0.015). The local anaesthetic is still present in the SPM after their preparation (20.1 ng per mg membrane protein). It appears that the local anaesthetic exhibits an effect similar to that of the general anaesthetic, apparently due to binding to the membrane.
Asunto(s)
Anestésicos Locales/farmacología , Bupivacaína/farmacología , Fluidez de la Membrana/efectos de los fármacos , Trofoblastos/efectos de los fármacos , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Anestesia General , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Cesárea , Difenilhexatrieno/farmacología , Femenino , Polarización de Fluorescencia , Humanos , Cinética , Embarazo , Trofoblastos/enzimología , Trofoblastos/ultraestructuraAsunto(s)
Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Captopril/farmacología , Dipéptidos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Estado de Descerebración , Electrocardiografía , Femenino , Técnicas In Vitro , Lisinopril , Masculino , Ramipril , RatasRESUMEN
The persistence of the cardiac beat-to-beat control is studied in the anesthetized and the pithed adult rat by means of spectral analysis. The data show that atriopeptin affects the amplitude of the heart rate low frequency fluctuations, significantly increasing the spectral patterns both in the anesthetized and the pithed rat. The atriopeptin enhancement of the low frequency range in heart rate fluctuations provides further insight into the hypothesis that beat to beat variability in hemodynamic parameters reflects a compensatory response in the short term cardiovascular control.
Asunto(s)
Anestesia , Factor Natriurético Atrial/farmacología , Estado de Descerebración/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Animales , Femenino , Masculino , RatasRESUMEN
Spectral analysis of spontaneous heart rate fluctuations, a powerful noninvasive tool for quantifying autonomic nervous system activity, was assessed in Xenopus Laevis, intact or spinalized, at different temperatures and by use of pharmacological tools. As expected, increasing the body temperature resulted in a positive chronotropic effect, both in the conscious and the spinalized preparations. Characteristic modifications of the spontaneous heart rate fluctuations were detected in both the experimental conditions. Different receptor drugs, which selectively interfere with the variously superimposed vegetative sections of the nervous control, had been proved to be effective in the new assay.
Asunto(s)
Temperatura Corporal , Estado de Descerebración/fisiopatología , Sistema de Conducción Cardíaco/fisiología , Frecuencia Cardíaca , Xenopus laevis/fisiología , Agonistas Adrenérgicos beta/farmacología , Animales , Estado de Conciencia/fisiología , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ketanserina/farmacología , Presorreceptores/efectos de los fármacos , Propanolaminas/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , XamoterolRESUMEN
Spontaneous fluctuations in heart rate were analyzed by spectral analysis in the ether anesthetized and pithed adult rat. In order to investigate the changes in the spectral pattern of the fluctuations, the selective 5HT-2 and -3 isoreceptor blockers ritanserin and BRL 43694A were used. In both the experimental conditions, ritanserin blockade led to dose-dependent increased fluctuations in HR low and high frequencies. In both the anesthetized and pithed rats, the low frequency range HR fluctuations were drastically reduced by BRL 43694A.
Asunto(s)
Anestesia , Estado de Descerebración/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Indazoles/farmacología , Piperidinas/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Depresión Química , Relación Dosis-Respuesta a Droga , Éter , Femenino , Granisetrón , Masculino , Ratas , RitanserinaRESUMEN
The endothelium-dependent acetylcholine, metacholine, carbachol, betanechol, and furtrethonium relaxation values have been measured in vitro for the rabbit aorta, in presence of a high concentration of hexamethonium. The produced EPMR values complete the values that were obtained in a previous experiment under analogous conditions for rat bladder, ileum, iris, stomach, and trachea preparations. The complete set was analyzed by new statistical techniques of data analysis and display, which are both simpler and more precise than the statistical modeling techniques used by us in the past. This has led to new results concerning the clustering of drugs and of receptors, as well as to a characterization of the endothelium receptor.