RESUMEN

The incidences of thyroid cancer keep rising worldwide over the past few decades. Although most thyroid cancers are indolent and highly curable, the treatment for advanced thyroid cancer remains challengeable in clinical practice. We performed two separate cohorts to evaluate the safety and efficiency of Escin in patients with advanced thyroid cancer . In cohort 1, 120 patients were divided into four groups equally and were administrated with placebo or different dosages of Escin. The pharmacokinetics of Escin and the side effects were evaluated. In cohort 2, 120 patients were treated with Escin. Several biomarkers related to the progression of thyroid cancer were evaluated. Kaplan-Meier (KM) analyses were performed to evaluate progression-free survival (PFS) and overall survival (OS). The serum Escin concentrations were stable during the treatment. Escin (0.6 mg/kg/day for 9 days, intravenous injection) was tolerable for patients with thyroid cancer . Escin significantly reduced the serum levels of TSH, TgAb, Tg, and calcitonin and prolonged the PFS and OS for patients with advanced thyroid cancer. This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Future studies are needed to investigate the mechanism of Escin on thyroid cancer and the proper dosage of Escin clinically.

Asunto(s)

Biomarcadores de Tumor/sangre , Escina/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Anciano , Calcitonina/sangre , Escina/efectos adversos , Escina/farmacocinética , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Tiroglobulina/sangre , Neoplasias de la Tiroides/sangre , Tirotropina/sangre , Resultado del Tratamiento

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. MATERIALS AND METHODS: Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). RESULTS: After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t1/2 was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. CONCLUSIONS: The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg/kg after intravenous administration. Escin Ia is isomerized to isoescin Ia rapidly and extensively regardless of the doses.

Asunto(s)

Escina/farmacocinética , Animales , Área Bajo la Curva , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Wistar , Espectrometría de Masas en Tándem

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Adequate pharmacokinetic data of escin, a natural mixture of triterpene saponins used for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema, is of special interest in view of the growing use of escin agent in clinical medicine. However, pharmacokinetic data are inadequate to support their clinical indication. Escin Ib and isoescin Ib are the chief active ingredients in escin, pharmacokinetics study of them would be helpful for improving the practice of escin application. The goals of this study are to determine the plasma concentration of escin Ib and isoescin Ib using an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetics and bioavailability of these compounds in rats when administered as pure isomers or as sodium escinate. MATERIALS AND METHODS: Five groups of Wistar rats (n=6 per group) were treated with either an intravenous (IV) dose (2.78mg/kg) of sodium escinate (corresponding to 0.5mg/kg of escin Ib and 0.5mg/kg of isoescin Ib), an IV dose (0.5mg/kg) and an oral dose (4mg/kg) of pure escin Ib or isoescin Ib. The concentrations of escin Ib and isoescin Ib in rat plasma were determined by LC-MS/MS at various times following the administration of the drugs. The pharmacokinetic parameters were estimated by a non-compartmental analysis and then subjected to statistical analysis. RESULTS: The administration of sodium escinate, which contains the two isomers, gave rise to higher terminal phase half-life (t1/2) and mean residence time (MRT) values for both escin Ib and isoescin Ib compared to the corresponding compounds administered alone. The absorption of escin Ib and isoescin Ib was very poor, with the oral bioavailability (F) values of <2% observed for both compounds. The two compounds were found to isomerize in vivo, wherein the conversion of escin Ib to isoescin Ib was much easier than that of isoescin Ib to escin Ib. CONCLUSIONS: A comparison of the pharmacokinetics of escin Ib and isoescin Ib administered alone and together in rats suggests that the administration of herbal preparations of escin in a clinical setting may result in a longer duration of action than the administration of each isomer alone. The interconversion of escin Ib and isoescin Ib when administered alone indicates that the administration of one isomer results in exposure to the other isomer.

Asunto(s)

Escina/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Escina/sangre , Femenino , Masculino , Ratas , Ratas Wistar

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Aescin, the main active component found in extracts of horse chestnut (Aesculus hippocastanum) seed a traditional medicinal herb, is a mixture of triterpene saponins. It has been shown to be effective in inflammatory, chronic venous and edematous treatment conditions in vitro and in vivo, and is broadly used to treat chronic venous insufficiency. The purpose of this study was to find out whether aescin influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2E1 and CYP3A4) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. MATERIALS AND METHODS: A cocktail solution at a dose of 5mL/kg, which contained phenacetin (20mg/kg), tolbutamide (5mg/kg), chlorzoxazone (20mg/kg) and midazolam (10mg/kg), was given as oral administration to rats treated with a single dose or multiple doses of intravenous aescin via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effects of aescin on the mRNA expression of CYP1A2, CYP2C9, CYP2E1 and CYP3A4 in rat liver. RESULTS: Treatment with a single dose or multiple doses of aescin had inductive effects on rat CYP1A2, while CYP2C9 and CYP3A4 enzyme activities were inhibited. Moreover, aescin has no inductive or inhibitory effect on the activity of CYP2E1. The mRNA expression results were in accordance with the pharmacokinetic results. CONCLUSIONS: Aescin can either inhibit or induce activities of CYP1A2, CYP2C9 and CYP3A4. Therefore, caution is needed when aescin is co-administration with some CYP1A2, CYP2C9 or CYP3A4 substrates in clinic, which may result in treatment failure and herb-drug interactions.

Asunto(s)

Sistema Enzimático del Citocromo P-450/metabolismo , Escina/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Animales , Área Bajo la Curva , Clorzoxazona/farmacocinética , Clorzoxazona/farmacología , Sistema Enzimático del Citocromo P-450/genética , Escina/farmacocinética , Semivida , Interacciones de Hierba-Droga , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Midazolam/farmacocinética , Midazolam/farmacología , Relajantes Musculares Centrales/farmacocinética , Relajantes Musculares Centrales/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Tolbutamida/farmacocinética , Tolbutamida/farmacología

RESUMEN

AIM: Aim of the study was to assess systemic effects of a cycle of treatment with a topical formulation of l-T4 and escin (Somatoline®) in healthy women based on changes in bioavailability of FT4, FT3, rT3, and TSH. METHODS: This study enrolled 20 healthy adult women with body mass index <30, not exposed to iodine-containing products. The study called for 28 consecutive days of treatment with Somatoline® followed by a 14-day follow-up period. Blood samples for FT4, FT3 and TSH levels were drawn at baseline, 5 and 24 hours after the first application and thereafter on days 14, 28 and 42. Levels of rT3 were measured during the first 24 hours postapplication. RESULTS: Subject mean age was 40.1±8.0 years and BMI from 19.1 to 29.8. Levels of FT4 always remained within normal range and did not change in a clinically relevant way from baseline (11±1.2 pg/dL), with maximum mean change from pretreatment values of 0.4 pg/mL (P=0.87). Likewise, FT3 and TSH levels did not change significantly from baseline (3±0.4 pg/dL and 1.8 ±0.9 µU/mL, respectively). Levels of rT3 behaved in a similar way, with modest changes from baseline (P=0.29). Local tolerability was defined "excellent" for 19 out of 20 women (95%) and "moderate" in one subject who experienced the onset of folliculitis, for which causal correlation with the treatment was considered "possible". CONCLUSION: Used at the posology foreseen for the marketed formulation, Somatoline® does not affect plasma levels of FT4, FT3, rT3 and TSH, either in the short term or after 28 days.

Asunto(s)

Escina/farmacocinética , Tiroxina/farmacocinética , Administración Tópica , Adolescente , Adulto , Disponibilidad Biológica , Emulsiones , Escina/administración & dosificación , Escina/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Tiroxina/administración & dosificación , Tiroxina/metabolismo , Adulto Joven

RESUMEN

Drug delivery systems present an opportunity to potentiate the therapeutic effect of antileishmanial drugs. Colloidal carriers are rapidly cleared by the phagocytic cells of the reticuloendothelial system (RES), rendering them ideal vehicles for passive targeting of antileishmanials. This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin ß-aescin. NPs were prepared using the combined emulsification solvent evaporation/salting-out technique. Confocal microscopy was used to visualise the internalisation and intracellular trafficking of fluorescein- and nile red-labelled PLGA NPs in J774A.1 macrophages infected with GFP-transfected Leishmania donovani. The in vitro activity of aescin and aescin-loaded NPs on L. infantum was determined in the axenic model as well as in the ex vivo model. The developed PLGA NPs were monodispersed with Z(ave)<300 nm, exhibited negative zeta potentials and had relatively high drug loadings ranging from 5.80 to 8.68% w/w PLGA. The fluorescent NPs were internalised by the macrophages and trafficked towards the lysosomes after 2 h in vitro incubation. Co-localisation of the NPs and the parasite was not shown. A two-fold increase in activity was observed in the ex vivo macrophage model by encapsulating ß-aescin in PLGA NPs (IC(50), 0.48-0.76 µg/mL vs. 1.55 ± 0.32 µg/mL for the free drug).

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Escina/administración & dosificación , Escina/farmacología , Ácido Láctico/química , Leishmania infantum/efectos de los fármacos , Macrófagos/efectos de los fármacos , Nanopartículas/administración & dosificación , Ácido Poliglicólico/química , Animales , Línea Celular , Escina/farmacocinética , Macrófagos/microbiología , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/estadística & datos numéricos , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Escin Ia and isoescin Ia have been traditionally used clinically as the chief active ingredients of escin, a major triterpene saponin isolated from horse chestnut (Aesculus hippocastanum) seeds for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. AIM OF THE STUDY: To establish a sensitive LC-MS/MS method and investigate the pharmacokinetic properties of escin Ia and isoescin Ia in rats and the pharmacokinetics difference of sodium escinate with pure escin Ia and isoescin Ia. The absolute bioavailability of escin Ia and isoescin Ia and the bidirectional interconversion of them in vivo were also scarcely reported. MATERIALS AND METHODS: Wister rats were administrated an intravenous (i.v.) dose (1.7 mg/kg) of sodium escinate (corresponding to 0.5mg/kg of escin Ia and 0.5mg/kg of isoescin Ia, respectively) and an i.v. dose (0.5mg/kg) or oral dose (4mg/kg) of pure escin Ia or isoescin Ia, respectively. At different time points, the concentrations of escin Ia and isoescin Ia in rat plasma were determined by LC-MS/MS method. Main pharmacokinetic parameters including t(1/2), MRT, CL, V(d), AUC and F were estimated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany) and statistical analysis was performed using the Student's t-test with P<0.05 as the level of significance. RESULTS: After administration of sodium escinate, the t(1/2) and MRT values for both escin Ia and isoescin Ia were larger than corresponding values for the compounds given alone. Absorption of escin Ia and isoescin Ia was very low with F values both <0.25%. Escin Ia and isoescin Ia were found to form the other isomer in vivo with the conversion of escin Ia to isoescin Ia being much extensive than from isoescin Ia to escin Ia. CONCLUSION: Comparison of the pharmacokinetics of escin Ia and isoescin Ia given alone and together in rat suggest that administration of herbal preparations of escin for clinical use may provide longer duration of action than administration of single isomers. The interconversion of escin Ia and isoescin Ia when given alone indicates that administration of one isomer leads to exposure to the other.

Asunto(s)

Aesculus , Escina/farmacocinética , Extractos Vegetales/farmacocinética , Administración Oral , Aesculus/química , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Liquida , Escina/análogos & derivados , Escina/sangre , Escina/aislamiento & purificación , Femenino , Inyecciones Intravenosas , Masculino , Extractos Vegetales/sangre , Ratas , Ratas Wistar , Semillas/química , Espectrometría de Masas en Tándem

RESUMEN

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of escin Ia and escin Ib in human plasma. After a solid-phase extraction (SPE), the analytes were separated on a Zorbax Extend C(18) column by isocratic elution with a mobile phase of methanol-acetonitrile-10 mm ammonium acetate (27:27:46, v/v/v) at a flow rate of 1.0 mL/min and analyzed by mass spectrometry in the positive ion multiple reaction monitoring mode. The precursor to product ion transitions of m/z 1131.8 → 807.6 was used to quantify escin Ia and escin Ib. Good linearity was achieved over a wide range of 2.00-900 ng/mL for escin Ia and 1.50-662 ng/mL for escin Ib. The intra- and inter-day precisions (as relative standard deviation) were less than 11% for each QC level of escin Ia and escin Ib. The accuracies (as relative error) were within ±5.27% for escin Ia and within ±4.07% for escin Ib. The method was successfully employed in a pharmacokinetic study after a single intravenous infusion administration of sodium aescinate injection containing 10 mg escin to each of the 10 healthy volunteers.

Asunto(s)

Cromatografía Liquida/métodos , Escina/sangre , Espectrometría de Masas en Tándem/métodos , Escina/administración & dosificación , Escina/aislamiento & purificación , Escina/farmacocinética , Humanos , Inyecciones Intravenosas , Extracción en Fase Sólida

RESUMEN

A rapid and sensitive bioassay based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of four isomeric escin saponins (escin Ia, escin Ib, isoescin Ia and isoescin Ib) in human plasma has been developed and validated. Sample preparation of plasma after addition of telmisartan as internal standard (I.S.) involved solid-phase extraction (SPE) on C18 cartridges. Separation was based on reversed phase chromatography using gradient elution with methanol-acetonitrile (50:50, v/v) and 10 mM ammonium acetate solution (pH 6.8). MS/MS detection in the positive ion mode used multiple reaction monitoring of the transition at m/z 1113.8-->807.6. Stability issues with the four saponins required the addition of formic acid to plasma samples prior to storage at -80 degrees C and analysis within 30 days. The method was linear at concentrations up to 10 ng/mL with correlation coefficients>0.996 for all analytes. The lower limit of quantitation (LLOQ) for all four saponins was 33 pg/mL. Intra- and inter-day precisions (as relative standard deviation) were all <15% and accuracies (as relative error) in the range -5.3% to 6.1%. The method was successfully applied to a pharmacokinetic study of escins in healthy volunteers after oral administration of sodium aescinate tablets containing 60 mg escin saponins.

Asunto(s)

Cromatografía Liquida/métodos , Escina/sangre , Escina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Adulto , Escina/administración & dosificación , Escina/química , Humanos , Isomerismo , Límite de Detección , Masculino , Reproducibilidad de los Resultados , Factores de Tiempo , Adulto Joven

RESUMEN

The aim of this work was to evaluate the feasibility of assessing aescin in vitro permeation through human skin by determining the amount of aescin permeated using conventional HPLC procedures after extraction of skin permeation samples by means of solid phase extraction (SPE). Aescin in vitro skin permeation was assessed from aqueous solutions and gels using both Franz-type diffusion cells and flow-through diffusion cells. The SPE method used was highly accurate (mean accuracy 99.66%), highly reproducible (intra-day and inter-day variations lower than 2.3% and 2.2%, respectively) and aescin recovery from normal saline was greater than 99%. The use of Franz-type diffusion cells did not allow us to determine aescin flux values through excised human skin, therefore aescin skin permeation parameters could be calculated only using flow-through diffusion cells. Plotting the cumulative amount of aescin permeated as a function of time, linear relationships were obtained from both aqueous solution and gel using flow-through diffusion cells. Aescin flux values through excised human skin from aqueous gel were significantly lower than those observed from aqueous solution (p < 0.05). Calculating aescin percutaneous absorption parameters we evidenced that aescin partition coefficient was lower from the aqueous gel with respect to the aqueous solution. Therefore, the SPE method used in this study was suitable to determine aescin in vitro skin permeation parameters from aqueous solutions and gels using a conventional HPLC method for the analysis of the skin permeation samples.

Asunto(s)

Escina/farmacocinética , Absorción Cutánea/fisiología , Adulto , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Cámaras de Difusión de Cultivos , Geles , Humanos , Técnicas In Vitro , Soluciones Farmacéuticas , Flujo Sanguíneo Regional/fisiología , Reproducibilidad de los Resultados , Piel/irrigación sanguínea , Extracción en Fase Sólida

RESUMEN

OBJECTIVE: To study Biotransformation of escin Ia by the crude enzymes of human intestinal bacteria and Lactobacillus brevis, determine the structures of biotransformation products and assay the inhibitory effect of desacylescin I on the tumor cell growth. METHODS: The escin Ia was incubated with crude enzymes of human intestinal bacteria and Lactobacillus brevis in vitro, respectively. The biotransformation products were isolated and purified by the chromatographic methods and the structures were determined by the spectroscopic techniques. RESULTS: Escin Ia was converted into isoescin Ia, desacylescin I, 21beta-O-tigloylprotoaescigenin and protoaescigenin by crude enzymes of human intestinal bacteria and Lactobacillus brevis. Desacylescin I showed potentially inhibitory effects on tumor cell growth of mouse sarcoma-180, hepatic carcinoma H(22) and lung carcinoma in vivo. CONCLUSION: The results suggest that Escin Ia was a prodrug and its structure can be converted by human intestinal bacteria and Lactobacillus brevis. Desacylescin I as a biotransformation product showed potentially inhibitory effects on mouse tumor, and a potential candidate for anti tumor agents.

Asunto(s)

Antineoplásicos/farmacocinética , Bacterias/metabolismo , Escina/farmacocinética , Intestinos/microbiología , Animales , Antineoplásicos/farmacología , Biotransformación , Escina/farmacología , Femenino , Humanos , Masculino , Ratones , Sarcoma 180/tratamiento farmacológico

RESUMEN

The bioavailability of beta-aescin--the main active constituent of horse chestnut seed extract--in a nonretarded test medication in comparison with that in a retarded reference formulation was evaluated in 2 randomized crossover clinical trials involving 18 healthy volunteers each. Serum concentration/time curves derived under steady-state conditions and pharmacokinetic parameters measured during both studies showed no significant difference between absorption rates for the retarded versus nonretarded preparation. In the first study, investigators found a test-to-reference ratio of 1.06 (90% confidence interval [CI] range: 99-113) for the area under the curve (AUC; the primary outcome measure). Absorption rates were diminished during the night compared with daytime rates for both study preparations. In the second study, using AUC and maximum concentration (Cmax) as the primary characteristics, investigators analyzed bioavailability based on the mean of 2 consecutive daytime periods and obtained estimates of 1.07 for AUC (90% CI range: 0.96-1.19) and 1.05 for Cmax (90% CI range: 0.90-1.21). Bioequivalence of the test and reference drug preparations was thus established according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence. Both treatments were equally well tolerated.

Asunto(s)

Aesculus , Escina/farmacocinética , Fitoterapia , Extractos Vegetales/farmacocinética , Semillas , Adulto , Disponibilidad Biológica , Estudios Cruzados , Femenino , Humanos , Masculino , Equivalencia Terapéutica

RESUMEN

OBJECTIVE: In horse chestnut seed extracts (HCSE), the triterpene saponin mixture aescin is considered the active principle. The bioavailability and pharmacokinetics of different HCSE preparations have been studied under single and repeated applications using a radioimmunological method (RIA) developed to identify beta-aescin, one of the pharmacologically active fractions of the saponin mixture. In this paper, the available pharmacokinetic data are reviewed and the observed heterogenicity between comparable studies is discussed. DATA SOURCES: Pharmacokinetic data from 5 single- and 4 multiple-dose bioequivalence studies with HCSE-containing products, were measured by the same analytical laboratory using the same RIA. EVALUATION: In studies where procedures were identical the pharmacokinetic data of beta-aescin show high variations. Even under steady-state conditions a considerable variability for the same HCSE product is obtained. CONCLUSION: Formal reasons like study design and medications can be ruled out as a source of pharmacokinetic variation. In extracts of herbal drugs like HCS, the relative concentration of the individual saponin fractions can considerably differ from batch to batch. For immunological methods, identification of such antigens with intermolecular variability, e.g., the structural aescin analogs, is of unknown validity. Therefore the shape of the concentration-time curve would only show an approximation of the time course but not for the absolute concentrations. A specific validation procedure for the RIA must be developed, otherwise a LC-MS/MS-method of sufficient sensitivity should be elaborated.

Asunto(s)

Escina/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica , Ensayos Clínicos como Asunto/métodos , Escina/sangre , Humanos , Extractos Vegetales , Plantas Medicinales , Radioinmunoensayo , Semillas

RESUMEN

The bioavailability under steady state conditions of a standard, slow-release horse chestnut seed extract (HCSE)-containing product was compared with that of an analogous, fast-release test preparation (Noricaven novo) in a prospective, randomised, double-blind study in a double cross-over design. The serum concentration of beta-escin (CAS 6805-41-0) was measured by radioimmunoassay. In addition, the biopharmaceutical properties of the HCSEs present in the products were investigated, the amount and composition of the active ingredient, escin, being analysed with a validated HPLC method. The pharmacokinetics of this study were compared with the corresponding data of a similar investigation carried out under analogous conditions concerning study design, analytical methods and reference preparation. Comparison of the similar studies revealed differences in characteristic pharmakokinetic values of beta-escin in terms of a shift of the concentration time curves as could be demonstrated for the reference product. The total amounts of escin in the two products investigated did not differ significantly. However, quantitative and qualitative differences were detected in the constituents of the two different extract preparations. It is concluded that the high specificity of the validated beta-escin radioimmunoassay leads to analytical imprecision due to the variable constituents of the extract preparations used. It is necessary to test whether this problem can be solved using an analytical approach, which is specific for each extract.

Asunto(s)

Escina/farmacocinética , Adulto , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Escina/administración & dosificación , Femenino , Humanos , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacocinética , Estudios Prospectivos , Radioinmunoensayo , Reproducibilidad de los Resultados

RESUMEN

In a steady-state cross-over study in 18 healthy volunteers, the relative bioavailability of beta-escin (CAS 11072-93-8) after oral administration of a new immediate release enteric-coated test formulation containing aesculus extract was evaluated in comparison with a prolonged-release reference preparation. The subject received the test and the reference preparation in randomised sequence for 7 days each with no washout period in between. The daily dose was 50 mg escin b.i.d. Blood samples for pharmacokinetic profiling were taken on the 7th treatment day of each period over a full 24-h cycle of two successive dosing intervals. For the determination of beta-escin serum concentrations, a highly specific radioimmunoassay (RIA) was used. Generally, escin serum concentrations were lower during the second dosing interval (night) than during the first interval, probably indicating a drug by food interaction. (The morning dose was given after overnight fasting whereas the evening dose was given between meals). Test and reference demonstrated bioequivalence with regard to the extent of absorption; for the AUC (0-24 h p.a.), the 90% confidence interval ranged from 84% to 114% (point estimate: 98%). The differences observed for rate parameters can be disregarded due to the generally slow elimination and the wide therapeutic concentration range of escin.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacocinética , Escina/farmacocinética , Plantas Medicinales/química , Administración Oral , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Escina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacocinética , Radioinmunoensayo , Comprimidos Recubiertos

RESUMEN

With a specific radioimmunoassay the pharmacokinetics and relative bioavailability of escin was measured after administration of different formulations containing Aesculus-extract. Of special interest was the relative bioavailability of escin after administration of a newly developed film-coated tablet with sustained release in comparison to a reference formulation. In a cross-over steady-state study in 24 volunteers bioequivalence of test and reference preparation could be demonstrated. The 90% confidence interval of the AUC (O-tau) was 98.3 to 120.9%.

Asunto(s)

Escina/farmacocinética , Plantas Medicinales/química , Adulto , Disponibilidad Biológica , Estudios Cruzados , Escina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Comprimidos Recubiertos , Equivalencia Terapéutica , Extractos de Tejidos/farmacocinética

Asunto(s)

Escina/farmacocinética , Administración Oral , Adolescente , Adulto , Disponibilidad Biológica , Estudios Cruzados , Formas de Dosificación , Escina/administración & dosificación , Escina/sangre , Semivida , Humanos , Masculino , Radioinmunoensayo

RESUMEN

The relative oral bioavailability of beta-escine (CAS 11072-93-8) from a sugar-coated tablet formulation was compared to a reference preparation available in capsule form in 18 healthy, male volunteers over a 48 h period. The study design was randomized, single-blind and cross-over. Both the test and the reference preparation contained 50 mg standardized horse chestnut seed extract; beta-escine was taken as the reference substance. By means of a newly developed, validated radioimmunosorbent assay (RIA), beta-escine in plasma was determined (blind samples) after oral intake of a single dose of each drug formulation. The confidence limits calculated for the AUC, Cmax and Tmax of the test preparation exceed the upper limit of the specified equivalence range of 80%--125%, but do never fall below the lower limit. Therefore, bioin-equivalence cannot be rejected statistically. All the bioavailability data for the test preparation--measured with the newly developed RIA--exceed the corresponding values for the reference preparation. As the rate of absorption of aesculetinic triterpene glycosides is low, the higher bioavailability of the test preparation is desirable from a therapeutical point of view. Since the reference preparation is classified as being clinically effective, the test preparation must also be estimated as being clinically effective. Adverse drug effects were not observed with either the test preparation or the reference preparation.

Asunto(s)

Escina/farmacocinética , Extractos Vegetales/farmacología , Adulto , Disponibilidad Biológica , Cápsulas , Estudios Cruzados , Escina/administración & dosificación , Humanos , Masculino , Método Simple Ciego , Comprimidos

RESUMEN

An original method for the determination of cell membrane permeability has been developed. Human buccal epithelium cells were treated with Indigo Carmine and the percentage of stained cells was determined. Employing this method, the age-related differences in properties of plasma membrane in cells of human buccal epithelium were demonstrated. In the group of aged donors the average level of cell stainability was higher than in the group of younger donors. These results demonstrate a decrease in outer cell membrane integrity with age.

Asunto(s)

Envejecimiento/fisiología , Permeabilidad de la Membrana Celular/fisiología , Mucosa Bucal/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Membrana Celular/metabolismo , Epitelio/metabolismo , Escina/farmacocinética , Humanos , Persona de Mediana Edad , Mucosa Bucal/citología

Asunto(s)

Escina/farmacología , Plantas Medicinales/química , Animales , Escina/farmacocinética , Humanos