RESUMEN
The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.
Asunto(s)
Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Trasplante de Corazón/inmunología , Ácido Micofenólico/análogos & derivados , Sirolimus/uso terapéutico , Adulto , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/prevención & control , Quimioterapia Combinada , Femenino , Rechazo de Injerto/epidemiología , Trasplante de Corazón-Pulmón/inmunología , Humanos , Hipolipemiantes/uso terapéutico , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Neoplasias/epidemiología , Selección de Paciente , Complicaciones Posoperatorias/clasificación , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years. METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years. RESULTS: The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF. CONCLUSIONS: All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.
Asunto(s)
Azatioprina/uso terapéutico , Ciclosporina/uso terapéutico , Supervivencia de Injerto/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/fisiología , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéutico , Administración Oral , Adolescente , Adulto , Suero Antilinfocítico/uso terapéutico , Población Negra , Cadáver , Niño , Estudios Cruzados , Ciclosporina/administración & dosificación , Diabetes Mellitus/etiología , Monitoreo de Drogas , Quimioterapia Combinada , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Insulina/uso terapéutico , Pruebas de Función Renal , Trasplante de Riñón/inmunología , Trasplante de Riñón/mortalidad , Necrosis Tubular Aguda/epidemiología , Necrosis Tubular Aguda/patología , Ácido Micofenólico/análogos & derivados , Complicaciones Posoperatorias/clasificación , Complicaciones Posoperatorias/epidemiología , Tasa de Supervivencia , Tacrolimus/sangre , Factores de Tiempo , Donantes de Tejidos , Estados Unidos , Población BlancaRESUMEN
BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.
Asunto(s)
Azatioprina/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Cuidados Posoperatorios , Tacrolimus/uso terapéutico , Adulto , Azatioprina/efectos adversos , Cadáver , Ciclosporina/efectos adversos , Quimioterapia Combinada , Femenino , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Tacrolimus/efectos adversosRESUMEN
The chemical synthesis of azido-substituted saturated, monoenoic and dienoic fatty acids of high specific tritium radioactivity, together with improved methods for their introduction into phosphatidylcholine, sphingomyelin and cholesteryl ester molecules are outlined. Phospholipid vesicles with these photosensitive probes were irradiated and the main crosslinking products isolated and characterized by high resolution mass spectroscopy.
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Colesterol/análogos & derivados , Ácidos Grasos/síntesis química , Liposomas , Fosfatidilcolinas/síntesis química , Esfingomielinas/síntesis química , Azidas , Colesterol/síntesis química , Espectrometría de Masas , Métodos , Relación Estructura-ActividadRESUMEN
Native human serum high density lipoprotein (HDL) (d = 1.063--1.21g x cm-3) was enriched with phosphatidylcholines labelled with 13C in the polar head group ([N-13CH3]choline) and in the fatty acyl chains ([26-13C]cholesterol) and its linoleic acid ester using the previously described exchange method (Stoffel et al. 1978). The properties of the HDL particles with the exchanged lipid classes were the same as those of the native particles (Mr, CD, fluorescence, lipid and apoprotein stoichiometry, electrophoretic mobility). The T1-times were very similar to those obtained previously with recombined apolipoprotein-[13C]lipid complexes and further support our proposals concerning lipid and apoprotein interactions in the HDL particle.
Asunto(s)
Lipoproteínas HDL , Isótopos de Carbono , Colesterol , Humanos , Marcaje Isotópico , Lipoproteínas HDL/sangre , Liposomas , Espectroscopía de Resonancia Magnética , FosfolípidosRESUMEN
The molecular interactions and spatial arrangements of phospholipids and apoproteins of human high-density lipoprotein were studied by a chemical approach. Phosphatidylcholines and sphingomyelins substituted with fatty acyl residues of high specific radioactivity and labelled with the photosensitive azido group in specific positions were prepared by chemical synthesis. They were recombined with apolipoprotein A-I of human serum high density lipoprotein. The lipoprotein complexes containing either azido lecithins or azidosphingo-myelins were purified by agarose chromatography from excess lipids. The irradiation was performed under conditions which prohibit the interference with the apoprotein structure as proven by circular dichroism, fluorescence spectroscopy, immunodiffusion test and disc electrophoresis. Non-covalently bound lipid molecules were removed by Sephadex LH 20 chromatography. Mild alkaline treatment liberated radioactive fatty acids which were not directly linked to the polypeptide chain, but rather via neighbouring phospholipid molecules. The lipoprotein appeared as a single radioactive band in dodecylsulfate polyacrylamide gel electrophoresis as seen by radioscanning, which further proved the covalent linkage of the fatty acyl residues to the polypeptide chain. In the immunodiffusion test, there is no difference between covalently crosslinked phospholipid-apoLp A-I complex and the non-photolyticall treated complex. This is the first chemical proof of the spatial relationship of the hydrophobic side chains of the lipid and polypeptide chains in a lipoprotein complex.
Asunto(s)
Apolipoproteínas , Luz/efectos adversos , Fosfatidilcolinas , Esfingomielinas , Sitios de Unión , Dicroismo Circular , Reacciones Cruzadas , Humanos , Inmunodifusión , Lipoproteínas HDL , Peso MolecularRESUMEN
Chromatographyically and immunologically homogeneous apolipoprotein A-I (apoLp A-I) from human serum has been recombined in separate experiments with three species of sphingomyelin. The differed in the degree of saturation of their fatty acyl residues, stearoyl (18:0), oleoyl (18:1) and linoleoyl (18:2). The lipoprotein complexes formed were purified by CsCl density gradient centrifugation between 1.07 - 1.09 g/cm3 and by gel filtration. Stearoylsphingomyelin does not recombine with the apoprotein A-I below its phase transition temperature (tc = 41.5 degrees C). The lipoproteins eluted with the following apparent molecular weights: 18:0-sphingomyelin apoLp A-I, 8.0 X 10(5); 18:1-sphingomyelin apoLp A-I, 4.0 X 10(5); and 18:2-sphingomyelin apoLp A-I, 4.0 X 10(5). In electron microscopy the particles appear as discs of 160 - 170 A diameter and 50 - 60 A thickness. Their tendency to form stacked aggregates of discs decreases with the degree of their unsaturation. CD measurements underline the considerable increase in alpha-helicity of the secondary structure of apo A-I after recombination with the phospholipids. This increase in order is equal for the three sphingomyelin species (alpha-helicity of apoLP A-I = 0.46, after recombination 0.89). If the three sphingomyelin species are used in equal molar amounts in the recombination experiment, no preference for any one sphingomyelin species is observed. Recombination of apoLp A-I with sphingomyelin, labelled with the isotope 13C in the choline group, C-14 of stearic or linoleic, or C-11 of oleic acid, were performed for spin lattice relaxation time (T1) experiments. Compared with sphingomyelin liposomes, the polar head groups of these lipids in the lipoprotein particles possess a considerably higher mobility, whereas the changes in T-1-times of the C-atoms in the centre of the fatty acid chains of the lipids refer to their interactions with the polypeptide side chains. A model of the lipoprotein complexes formed is proposed on the basis of the experimental data.
Asunto(s)
Apolipoproteínas , Esfingomielinas , Centrifugación por Gradiente de Densidad , Dicroismo Circular , Humanos , Lipoproteínas HDL , Lisofosfatidilcolinas , Espectroscopía de Resonancia Magnética , Microscopía Electrónica , Peso MolecularRESUMEN
The physical methods (13C-NMR-spectroscopy and fluorescence spectroscopy) hitherto used for the elucidation of lipid-lipid and lipid-protein interactions in artificial and simple natural membranes were extended to the application of fatty acids, phospholipids and sphingolipids with photochemical labels (azide group) in defined positions, which on photolysis generate nitrenes. These highly reactive groups react with neighbouring molecules, either lipids or polypeptide chains, with insertion or addition. Highly radioactive 12-azido[9,10-3H2]stearic acid, 12-azido[12-3H]oleic acid and 18-azido-[9,10,12,13-3H4]linoleic acid were added to the growth medium of eukaryotic cell lines in tissue culture (BHK 21 cells and Chang liver cells). They were incorporated into neutral, phosphoand sphingolipids in amounts comparable with the unsubstituted parent fatty acids. The distribution of the azido fatty acids in the phospholipids has been determined by enzymatic hydrolysis (phospholipase A2) on the basis of the distribution of their radioactivity. Radio gas chromatography and combined gas chromatography and mass spectroscopy revealed that the azide group of the radioactive fatty acids remained unaltered.