RESUMEN
In spite of the fact that dissolution time profiles of 250mg ursodeoxycholic acid (UCDA) capsules developed by Sponsor and 250mg hard capsules produced by Ursofalk®, Dr. Falk Pharma GmbH, indicated similarity (f2=60.6), a bioavailability study indicated unexpected differences in the formulations. To find an explanation of the in vivo performance of the compared formulations, the dissolution profiles were analyzed using a novel dissolution theory considering: The dissolution model was applied to the measured data using SADAPT. Despite Cmax and AUC values showing higher values after administration of the test product, a reduction of UDCA particle size for the test formulation was suggested for reformulation. The decision was based on the strongly pH-dependent UDCA solubility, formation of insoluble crystals at low pH condition and the known high pH fluctuations ranging from pH1 to 8 in empty stomach. The performed reformulation led to increased dissolution rate of the test product and to a positive bioequivalence study which compared the reformulated test generic formulation with two reference products purchased from two highly regulated markets.
Asunto(s)
Liberación de Fármacos , Ácido Ursodesoxicólico/farmacocinética , Administración Oral , Adulto , Animales , Área Bajo la Curva , Cápsulas , Estudios Cruzados , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Modelos Biológicos , Modelos Químicos , Tamaño de la Partícula , Ratas Endogámicas BB , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/químicaRESUMEN
BACKGROUND: Thrombogenicity is an important parameter of haemodialysis (HD) membrane biocompatibility. The surface of the polyacrylonitrile AN69 ST membrane is coated with a polyethylenimine. This modification allows heparin adsorption. The binding of heparin to the membrane surface occurs during priming of the extracorporeal circuit (ECC) by rinsing it with saline and heparin. Our aims were to assess and compare the thrombogenicity of the AN69 ST membrane under conditions of two extracorporeal circuit (ECC) rinse protocols-with and without unfractionated heparin (UFH). METHODS: In a prospective, crossover and randomized study, we examined 10 patients during HD after ECC preparation with either rinse protocols. Prior to HD and at 15, 60 and 240 min, we determined plasma levels of the thrombin-antithrombin complexes (TAT), platelet factor 4 (PF4), heparin concentration (antiXa) and thrombocyte count. Systemic anticoagulation was performed using UFH. RESULTS: During HD after ECC rinse without UFH, there was a significantly earlier and more marked increase in TAT compared with UFH-containing rinse (P <0.05). Using Spearman coefficient, we demonstrated a significant correlation between TAT and antiXa at 60 min (r = -0.534) and 240 min (r = -0.538). A comparison of the TAT/antiXa ratios between rinses at 60 min revealed a significantly higher increase in TAT following UFH-free rinse (P <0.05). There was no difference in PF4 between the rinses. Platelet count did not change significantly during HD using either rinse protocol. CONCLUSION: Based on plasma TAT levels, ECC priming with an UFH-containing solution reduces the thrombogenicity of the AN69 ST membrane. There is no significant difference between both types of priming concerning PF4 and thrombocyte count.
Asunto(s)
Soluciones para Hemodiálisis/química , Diálisis Renal/instrumentación , Diálisis Renal/métodos , Resinas Acrílicas/química , Adsorción , Anciano , Materiales Biocompatibles , Plaquetas/metabolismo , Estudios Cruzados , Diseño de Equipo , Femenino , Heparina/química , Humanos , Masculino , Persona de Mediana Edad , Factor Plaquetario 4/química , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Trombosis , Factores de TiempoRESUMEN
This study was designed to assess the principal markers of thrombogenicity and biocompatibility during continuous veno-venous hemodiafiltration (CVVHDF) using regional citrate anticoagulation (RCA). In a prospective study, 11 procedures with a polysulfone membrane were performed in nine critically ill patients with acute renal failure and impaired hemostasis. Blood samples were taken before and during CVVHDF at diafilter outlet--before calcium-induced reversal of the effect of citrate--at 15, 60, 360, and 1440 minutes. In four patients, 10 CVVHDF sessions were performed with systemic heparin anticoagulation (HA) using a polyacrylonitrile membrane. During RCA, blood thrombocyte count, plasma thrombin-antithrombin III complexes, beta-thromboglobulin, and von Willebrand factor levels did not differ significantly from baseline. Plasma D dimer levels rose significantly at 360 minutes; however, the difference between diafilter inlet and outlet levels was nonsignificant. There was a significant increase in plasma C5a concentrations and a decline in blood leukocyte count in the early phase of CVVHDF. Just as in RCA, no increase in plasma thrombogenicity indices was observed during HA. However, clotting times in blood entering patients' circulation were significantly prolonged. Plasma C5a concentrations increased significantly at the beginning of CVVHDF. RCA can effectively inhibit the thrombogenic effect of the extracorporeal circuit in CVVHDF. The effect of HA may be similar, however, at the expense of systemic anticoagulation and risk of bleeding. RCA, performed in a way that overcomes thrombogenicity, does not completely eliminate complement activation and/or transient leukopenia during CVVHDF.
Asunto(s)
Anticoagulantes/uso terapéutico , Citratos/uso terapéutico , Hemodiafiltración/efectos adversos , Heparina/uso terapéutico , Trombosis/etiología , Trombosis/prevención & control , Lesión Renal Aguda/sangre , Lesión Renal Aguda/terapia , Anciano , Hemodiafiltración/métodos , Humanos , Citrato de SodioRESUMEN
BACKGROUND: The aim of the study was to compare the effect of new high-flux hemodialysis membranes made from polyacrylonitrile (AN69ST) and polysulfone (Helixone) on the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) playing a key role in hemostasis. Established thrombogenicity markers were also determined. METHODS: In a clinical prospective randomized study, 10 patients were examined using either membrane at the start and at minutes 15, 60, and 240 of hemodialysis. RESULTS: Increases in the plasma TF levels reached significance at the end of hemodialysis with both membranes, with the Helixone also after 15 min. TFPI levels tended to rise significantly from minute 15 onward while not differing from baseline at the end of the procedure. Judging by the increase in thrombin-antithrombin III complexes, both membranes significantly activated coagulation at the end of hemodialysis. Platelet factor 4 levels, released during thrombocyte and endothelial stimulation, were elevated from the start of procedures. There were no significant differences between the AN69ST and the Helixone in any of the assessed markers. CONCLUSIONS: The AN69ST and Helixone membranes do not differ in their effects on TF and TFPI or even in established thrombogenicity markers.
Asunto(s)
Resinas Acrílicas , Materiales Biocompatibles , Lipoproteínas/sangre , Membranas Artificiales , Polímeros , Sulfonas , Tromboplastina/análisis , Biomarcadores/sangre , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diálisis Renal/instrumentación , Trombosis/etiologíaRESUMEN
BACKGROUND/AIM: The tissue factor (TF) plays a key role in triggering the coagulation system in vivo. Our study was designed to determine whether or not the plasma levels of TF and its pathway inhibitor (TF pathway inhibitor; TFPI) in patients with chronic renal failure (CRF) treated by peritoneal dialysis (PD) (1) are pathologically altered; (2) differ between diabetics and nondiabetics, and (3) depend on the metabolic disorders associated with CRF and/or diabetes. METHODS: Using ELISA, plasma TF and TFPI levels were measured once in 21 PD patients (10 with diabetes, 11 without diabetes) and in 21 healthy subjects. RESULTS: As compared with healthy subjects (TF 282 pg/ml; TFPI 73 ng/ml), both TF and TFPI levels were significantly higher in PD patients with diabetes (485 pg/ml, p < 0.001, and 106 ng/ml, p < 0.01, respectively) and in PD patients without diabetes (480 pg/ml, p < 0,001, and 121 ng/ml, p < 0.001, respectively). The difference between diabetics and nondiabetics was not significant. In stepwise regression analysis, the TF levels depended on serum creatinine (partial correlation 0.39, p < 0.05), glycemia (0.43, p < 0.01), and insulin (-0.43, p < 0.05), and the TFPI levels depended on creatinine (partial correlation 0.67, p < 0.001), apolipoprotein B (0.46, p < 0.01), and plasma fibrinogen (0.43, p < 0.01). CONCLUSIONS: CRF patients on PD show increased plasma TF and TFPI levels. There is no difference between diabetics and nondiabetics. The TF and TFPI levels depend significantly on the renal function, as assessed by serum creatinine, and on some metabolic disorders. Elevated TF and TFPI levels may be related to thrombosis and atherosclerosis in CRF patients on PD.
Asunto(s)
Fallo Renal Crónico/sangre , Lipoproteínas/sangre , Enfermedades Metabólicas/sangre , Tromboplastina/análisis , Adulto , Anciano , Estudios de Casos y Controles , Diabetes Mellitus/sangre , Femenino , Hemostasis , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis Peritoneal , Factores de TiempoRESUMEN
Renal anemia significantly affects the morbidity and mortality of dialysis patients. The aim of the present study was to establish whether the severity of anemia and success of its treatment differs when using high-flux (HF) or low-flux (LF) hemodialysis. Twenty-five patients on long-term hemodialysis with a mean hematocrit (Hct) of 33%, S alb of 36 g/L, and Kt/V urea of 1.5 were divided into Groups X (n = 13) and Y (n = 12) in a prospective randomized crossover study. Group X was initially treated with LF hemodialysis to be followed by HF hemodialysis for 8 weeks each time. Group Y started with 8 week HF hemodialysis and continued, after crossover, with 8 weeks of LF hemodialysis. HF and LF hemodialysis were performed with polysulfone dialyzers F 7HPS and F60S (Fresenius Medical Care, Bad Homburg, Germany). Hct values, examined at 2 week intervals, did not differ significantly between Groups X and Y during 16 weeks of the study at any measuring interval. In another analysis, all results of HF hemodialysis (first 8 weeks of Y + second 8 weeks of X) were pooled as were all data of LF hemodialysis (first 8 weeks of X + second 8 weeks of Y). No significant relationships were noted between duration of treatment with HF hemodialysis and Hct (n = 72, rS = 0.11, p = 0.36) and between duration of LF hemodialysis and Hct (n = 74, rS = 0.02, p = 0.87) in the newly formed groups. The Hct measured during HF hemodialysis and LF hemodialysis did not differ significantly. Analysis of variance did not reveal a relationship between Hct and the HF or LF membrane. As HF and LF hemodialysis differed significantly in Kt/V urea, the variables were adjusted to identical Kt/V urea using analysis of covariance. No relationship between Hct and dialysis membrane permeability was demonstrated even in this case. Use of biocompatible LF and HF membranes in standard hemodialysis modes under conditions of adequate dose of dialysis and the time period studied did not result in different effects on anemia.