The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin

Objectives Erythropoietin (EPO) was originally described as a regulator of erythropoiesis. Recently, synthesis of EPO and expression of the EPO receptor (EPO-R) have been reported for the central nervous system (CNS). The potential use of EPO to prevent or reduce CNS injury and the paucity of information regarding its entry into the human CNS led us to examine the pharmacokinetics (PK) of recombinant human EPO (r-HuEPO) in the serum and cerebrospinal fluid (CSF).Methods Four patients with Ommaya reservoirs were enrolled to facilitate serial CSF sampling. R-HuEPO was given intravenously (IV) in single doses of 40,000 IU or 1,500 IU/kg and in multiple doses of 40,000 IU daily for 3 days.Results The EPO concentrations in the CSF increased after a period of slow equilibration. Linear first-order distribution kinetics were observed for serum and CSF. The concentration of EPO in the CSF was proportional to the serum concentration of EPO and the permeability of the blood-brain barrier (BBB), as determined by the albumin quotient (Q_A=[albumin] CSF/[albumin] serum). A rise in the CSF concentration was seen as early as 3 h after IV administration. Peak levels (C_max) were reached between 9 h and 24 h. After a single dose of 1,500 IU/kg, the C_max in the CSF ranged from 11 mIU/ml to 40 mIU/ml, and the ratios of CSF/serum C_max ranged from 3.6×10^–4 to 10.2×10^–4. The terminal half-life (t_1/2) values of EPO in serum and CSF were similar. The t_1/2 of r-HuEPO in the CSF ranged from 25.6 h to 35.5 h after a single dose of 1,500 IU/l. Using these parameters a PK model was generated that predicts the concentration-time profile of EPO in the CSF.Conclusions We report that r-HuEPO can cross the human BBB and describe for the first time the PK of EPO in the CSF after IV administration. Our data suggest that the concentration-time profile of EPO in the CSF can be predicted for individual patients if the serum concentration of EPO and the Q_A are known. This information may be useful in the design of clinical trials to explore the potential therapeutic effects of EPO during CNS injury.     

Alginate/Chitosan Nanoparticles are Effective for Oral Insulin Delivery

Purpose To evaluate the pharmacological activity of insulin-loaded alginate/chitosan nanoparticles following oral dosage in diabetic rats. Methods Nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed by chitosan polyelectrolyte complexation. In vivo activity was evaluated by measuring the decrease in blood glucose concentrations in streptozotocin induced, diabetic rats after oral administration and flourescein (FITC)-labelled insulin tracked by confocal microscopy. Results Nanoparticles were negatively charged and had a mean size of 750 nm, suitable for uptake within the gastrointestinal tract due to their nanosize range and mucoadhesive properties. The insulin association efficiency was over 70% and insulin was released in a pH-dependent manner under simulated gastrointestinal conditions. Orally delivered nanoparticles lowered basal serum glucose levels by more than 40% with 50 and 100 IU/kg doses sustaining hypoglycemia for over 18 h. Pharmacological availability was 6.8 and 3.4% for the 50 and 100 IU/kg doses respectively, a significant increase over 1.6%, determined for oral insulin alone in solution and over other related studies at the same dose levels. Confocal microscopic examinations of FITC-labelled insulin nanoparticles showed clear adhesion to rat intestinal epithelium, and internalization of insulin within the intestinal mucosa. Conclusion The results indicate that the encapsulation of insulin into mucoadhesive nanoparticles was a key factor in the improvement of its oral absorption and oral bioactivity.     

Pharmacokinetic and pharmacodynamic studies following oral administration of erythropoietin mucoadhesive tablets to beagle dogs

Oral administration of mucoadhesive tablets containing erythropoietin (EPO) and an absorption enhancer Labrasol was studied in rats and dogs. Mucoadhesive tablets were prepared using Sylysia 550 holding the absorption enhancer and Carbopol 974P as a mucoadhesive agent. Mucoadhesive tablets were covered with a water-insoluble backing layer made of cellulose acetate and a pH-sensitive covering layer made of Eudragit L/Eudragit S. Tablet was administered into the rat jejunum at EPO dose of 100 IU/kg and serum samples were collected for 6 h. Serum EPO level was analysed with a standard ELISA procedure. After administration, rats showed a maximum serum EPO level of C_max 70.6 ± 8.9 mIU/ml. Oral administration of a single tablet containing 100 IU/kg EPO to beagle dogs showed a C_max of 24.6 ± 4.1. When EPO dose was increased to 500 IU/kg and the number of tablets was also increased to 5, the C_max was 54.8 ± 9.0 mIU/ml. However, when EPO, 100 IU/kg dose was divided into five tablets, the C_max was 15.5 ± 1.8 mIU/ml. In the absence of absorption enhancer, the C_max was 35.8 ± 3.8 with 500 IU/kg dose distributed among five tablets. Pharmacodynamic studies were carried out following oral administration of mucoadhesive tablets for 6 consecutive days at an EPO dose of 500 IU/kg. Whole blood samples were collected and percent circulating reticulocytes were counted using Miller technique. The increase in percent circulating reticulocytes was found to be 1.7% on day 8 following oral administration. As a control study, EPO was administered by i.v. route at a dose of 300 IU/kg for 3 consecutive days and the percent circulating reticulocytes were counted. Mucoadhesive tablets showed promising results as an oral drug delivery system for protein therapeutics.     

Nanomedicines of Hedgehog Inhibitor and PPAR-γ Agonist for Treating Liver Fibrosis

Purpose

Hedgehog (Hh) and peroxisome proliferator-activated receptor gamma (PPAR-γ) are major signaling pathways involved in the pathogenesis of liver fibrosis. Since Hh inhibitor, vismodegib (GDC) and PPAR-γ agonist, rosiglitazone (RSG) have poor water solubility, our objective was to formulate biodegradable polymeric nanoparticles encapsulating GDC and RSG for treating liver fibrosis.

Methods

Methoxy-polyethylene-glycol-b-poly(carbonate-co-lactide) [mPEG-b-p(CB-co-LA)] was synthesized and characterized using ¹H NMR. Nanoparticles were prepared using this polymer by emulsification/solvent evaporation method to encapsulate GDC and RSG either alone or in combination. Nanoparticles were characterized for particle size, drug loading, drug release, and anti-fibrotic efficacy after tail vein injection into common bile duct ligated (CBDL) fibrotic rats.

Results

mPEG-b-p(CB-co-LA) copolymer has molecular weight of 30,000 Da as determined by ¹H NMR. Nanoparticles were monodisperse with a mean particle size of 120–130 nm. Drug loading was 5% and 2% w/w for GDC and RSG, respectively. Nanoparticles carrying both GDC and RSG were formulated at half of their individual drug loading. Systemic administration of drug loaded nanoparticles protected liver injury in CBDL rats by suppressing the activation of hepatic stellate cells, and decreasing inflammatory cytokines.

Conclusion

Polymeric nanoparticles for co-delivery of Hh inhibitor and PPAR-γ agonist have the potential to treat liver fibrosis by intervening complex fibrotic cascade.     

Poly(ε-caprolactone)/eudragit nanoparticles for oral delivery of aspart-insulin in the treatment of diabetes

Nanoparticles prepared with a blend of a biodegradable polyester (poly(ε-caprolactone)) and a polycationic nonbiodegradable acrylic polymer (Eudragit® RS) have been used as a drug carrier for oral administration of a short-acting insulin analogue, aspart-insulin. Insulin-loaded nanoparticles, about 700 nm in diameter, encapsulated 97.5% of insulin and were able to release about 70% of their content in vitro in a neutral medium over 24 h. When administered orally to diabetic rats, insulin-loaded nanoparticles (50 IU/kg) decreased fasted glycemia for a prolonged period of time and improved the glycemic response to glucose in a time-dependent manner, with a maximal effect between 12 and 24 h after their administration. In parallel, plasma insulin levels increased. However, higher (100 IU/kg) and lower (25 IU/kg) doses of insulin did not exert any biological effect. It is concluded that polymeric nanoparticles composed of poly(ε-caprolactone)/Eudragit® RS are able to preserve the biological activity of the insulin analogue aspart-insulin; however, the postprandial peak suppression was prolonged more than 24 h by comparison with regular insulin working only 6–8 h. This effect may be explained by the monomeric configuration of aspart-insulin, which is probably better taken up by the intestinal mucosa than regular insulin. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:879–889, 2010     

The pharmacokinetic profile of recombinant human erythropoietin is unchanged in patients undergoing cardiac surgery

Background

In anticipation of future studies, we examined the pharmacokinetics profile of erythropoietin (EPO) in patients undergoing cardiac surgery.

Methods

Cardiac surgical patients were enrolled into one of six groups: four cardiopulmonary bypass (CPB) groups [placebo (n?=?6), 250 IU/kg EPO (n?=?3), 500 IU/kg EPO (n =?3), and 500 IU/kg EPO, two doses (n =?6)] and two off-pump coronary artery bypass (OPCAB) groups [placebo (n?=?3) and 500 IU/kg EPO (n?=?3)]. The EPO was administered prior to anesthesia and 10 min after CPB (if required). Blood samples for serum EPO were collected at baseline, 10 min after dosing, 5 min after sternotomy, during CPB or the equivalent for OPCAB (5, 15, 45, 60 min), and post-CPB (5, 15, 45, and 60 min, 6, 12 and 24 h, and daily until day 5).

Results

Endogenous EPO increased within 24 h of surgery in the placebo group and remained elevated. There was approximately a 40% decrease in serum EPO concentration at the initiation of CPB due to an increase in circulatory blood volume. There were no differences in apparent volume of distribution in the plasma (Vc) (42.2?±?9.9, 39.8?±?6.3, 42.3?±?14.0 mL/kg), clearance (CL) (4.63?±?1.14, 3.44?±?0.68, 4.27?±?0.52 mL h/kg), and t_½ (16.4?±?8.0 16.9?±?10.6, 22.4?±?9.3 h) between the CPB treatment groups. The pharmacokinetic profile of EPO in the OPCAB group was similar to that for the CPB groups: Vc = 39.3?±?7.0 mL/kg, CL = 4.98?±?0.17 mL h/kg and t_½ = 17.1?±?18.1 h.

Conclusions

CPB had no apparent effect on the pharmacokinetics of EPO.

     

伊曲康唑纳米粒的制备及其在小鼠体内的分布

用HPLC法测定了小鼠单剂量(20mg/kg)尾静脉注射伊曲康唑纳米粒及其市售注射剂后心、肝、脾、肺、肾、脑和血浆中的药物浓度.结果表明,伊曲康唑纳米粒在肺中的AUC为注射剂的32.94倍;在心、肾组织的蓄积量减少,在各组织中的半衰期延长,尤以肝、脾、肺为甚.说明伊曲康唑纳米粒的肺靶向性明显优于市售注射剂.     

Data from a microdosed recombinant human erythropoietin administration study applying the new biotinylated clone AE7A5 antibody and a further optimized sarcosyl polyacrylamide gel electrophoresis protocol

Erythropoietin (EPO) is a hormone, which stimulates the production of red blood cells. Due to its performance-enhancing effect, it is prohibited by the World Anti-Doping Agency (WADA). In order to reduce the detection window of EPO doping, athletes have been applying low doses of recombinant EPO (e.g., <10 IU/kg body weight, daily or every second day) instead of larger doses twice or more per week (e.g., 30 IU/kg). Microdoses of Retacrit (epoetin zeta), an EPO biosimilar, were administered intravenously and subcutaneously to human males and females. Urine and serum samples were collected and analysed applying the new biotinylated clone AE7A5 EPO antibody and a further optimized sarcosyl polyacrylamide gel electrophoresis (SAR-PAGE) protocol. With the improved protocol, microdosed Retacrit (7.5 IU/kg body weight [BW]) was detectable for at least 52 h after intravenous administration. Detection windows were approximately the same for serum and urine and doubled after subcutaneous administration (~104 h). Previous studies applying different electrophoretic techniques and the not further optimized SAR-PAGE protocol revealed considerably shorter detection windows for recombinant human erythropoietin (rhEPO) microdoses. Because the new biotinylated antibody performed significantly more sensitive than the nonbiotinylated version, the new protocol will improve the sensitivity and hence detectability of recombinant EPO in doping control.     

Self-dissolving microneedles for the percutaneous absorption of EPO in mice

Erythropoietin (EPO) loaded microneedles were prepared using thread-forming polymer as a base for the percutaneous administration of EPO. The used polymers were dextrin, chondroitin sulfate and albumin. Under room temperature, EPO solution was added to high concentration of polymer solution and microneedles were prepared by forming thread with polypropylene tips. The mean weight of microneedle was 0.59 +/- 0.01 mg and length and basal diameter were 3.24 +/- 0.16 and 0.55 +/- 0.03 mm, respectively. Four microneedles were percutaneously (pc) administered to mice at the EPO dose levels of 100 IU/kg. After administration, blood samples were collected for 24 h and serum EPO levels were measured. Dextrin EPO microneedles were administered both pc and subcutaneously (sc) to mice. Serum EPO levels vs. time profiles showed Cmax of 138.6 +/- 16.1 and 146.5 +/- 8.0 mIU/ml, respectively. Tmax were 7.5 h. The values of bioavailability (BA) of EPO were 82.1 and 99.4%, respectively. By decreasing the dose from 100 to 50 and 25 IU/kg, dose-dependent serum EPO levels vs. time profiles were not clearly obtained. When chondroitin sulfate and albumin were used as the microneedle base, the serum EPO levels vs. time profiles showed almost the same pattern. Cmax of chondroitin sulfate and albumin microneedles were 96.3 +/- 8.8 and 132.2 +/- 18.9 mIU/ml, respectively. AUCs were 835.1 and 1098.7 mIU h/ml. Tmax were 8 and 6.8 h. These results suggest the usefulness of microneedles for the percutaneous administration of EPO.     

Poly (lactide-co-glycolide)-Polymethacrylate Nanoparticles for Intramuscular Delivery of Plasmid Encoding Interleukin-10 to Prevent Autoimmune Diabetes in Mice

Purpose

Determine the efficiency of cationic nanoparticles prepared by blending poly (lactide-co-glycolide; PLGA) and methacrylate copolymer (Eudragit® E100) to deliver a therapeutic gene encoding mouse interleukin-10, in vitro and in vivo.

Methods

Nanoparticles prepared with PLGA and E100 were evaluated for delivery of plasmid DNA encoding mouse interleukin-10 in vitro and in vivo in mice upon intramuscular injection. Blood-glucose, serum interferon-gamma levels and histology of pancreas were studied to determine therapeutic efficacy. Histological evaluation of skeletal muscle from the injection site was performed to assess the biocompatibility of nanoparticles.

Results

PLGA/E100 nanoparticles showed endosomal escape evidenced by confocal microscopy and buffering ability. Transfecting HEK293 cells with plasmid-loaded PLGA/E100 nanoparticles resulted in significantly (p?Conclusions Nanoparticles prepared by blending PLGA with methacrylate can efficiently and safely deliver plasmid DNA encoding mouse interleukin-10 leading to prevention of autoimmune diabetes.     

A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats

Systemic administration of recombinant erythropoietin (EPO) has been demonstrated to mediate neuroprotection. This effect of EPO may in part rely on a beneficial effect on cerebrovascular dysfunction leading to ischaemic neuronal damage. We investigated the in vivo effects of subcutaneously administered recombinant EPO on impaired cerebral blood flow (CBF) autoregulation after experimental subarachnoid haemorrhage (SAH). Four groups of male Sprague-Dawley rats were studied: group A, sham operation plus vehicle; group B, sham operation plus EPO; group C, SAH plus vehicle; group D, SAH plus EPO. SAH was induced by injection of 0.07 ml of autologous blood into the cisterna magna. EPO (400 iu kg(-1) s.c.) or vehicle was given immediately after the subarachnoid injection of blood or saline. Forty-eight hours after the induction of SAH, CBF autoregulatory function was evaluated using the intracarotid (133)Xe method. CBF autoregulation was preserved in both sham-operated groups (lower limits of mean arterial blood pressure: 91+/-3 and 98+/-3 mmHg in groups A and B, respectively). In the vehicle treated SAH-group, autoregulation was abolished and the relationship between CBF and blood pressure was best described by a single linear regression line. A subcutaneous injection of EPO given immediately after the induction of SAH normalized autoregulation of CBF (lower limit in group D: 93+/-4 mmHg, NS compared with groups A and B). Early activation of endothelial EPO receptors may represent a potential therapeutic strategy in the treatment of cerebrovascular perturbations after SAH.     

Toxicity and tissue distribution of cerium oxide nanoparticles in rats by two different routes: single intravenous injection and single oral administration

Toxicity and target organ distribution of cerium oxide nanoparticles (CeNPs) were investigated via single intravenous injection and single oral administration, respectively. Rats were sacrificed at 24 h after treatment with doses of 30 and 300 mg/kg, and cerium concentrations were measured in liver, kidney, spleen, lung, blood, urine and feces. Results revealed cerium levels in blood and tissues were considerably low in oral treated groups and most cerium was detected in feces, meaning CeNPs would not be absorbed in the gastro-intestinal system. Conversely, high concentrations of cerium were detected in all tissues of rats after intravenous injection. Liver and spleen were main target organs. Cerium levels in liver were 594.9?±?95.3 μg/g tissue in 30 mg/kg treat group and 3741.7?±?932.7 μg/g tissue in 300 mg/kg treat group. Cerium levels in spleen reached almost levels of liver. Cerium was also detected, that is relatively low compared to oral administration, in feces of rats treated via intravenous injection, that supports biliary excretion of CeNPs. Urine excretion of CeNPs was not detected in oral treatment and intravenous injection. In accordance with level of cerium distribution, toxicities based on hematology, serum biochemistry and histopathology were observed in rats treated by intravenous injection while no significance was revealed in orally treated groups.     

Effect of fiber length of carbon nanotubes on the absorption of erythropoietin from rat small intestine

Erythropoietin (EPO) loaded carbon nanotubes (CNTs) with surfactant as an absorption enhancer were prepared for the oral delivery of EPO using two types of CNTs, long and short fiber length CNTs, and the effect of CNT fiber length on the absorption efficiency of EPO was studied. After Labrasol, PEG-8 caprylic/capric glycerides, as absorption enhancer was adsorbed into long fiber CNTs of which mean fiber length was 20-80 microm, as a carrier, EPO and casein as protease inhibitor and Explotab (sodium starch glycolate) as a disintegrating agent, were mixed. The resulting solid preparation was administered into the rat jejunum and serum EPO levels were measured by ELISA. The dose of EPO, CNTs, casein and Explotab were 100 IU/kg, 5mg/kg, 25mg/kg and 2.5mg/kg, respectively. Serum EPO level reached to C(max), 69.0+/-3.9 mIU/ml, at 3.5+/-0.1h and AUC was 175.7+/-13.8 mIU h/ml. These values were approximately half of that obtained with short fiber length CNTs of which C(max) was 143.1+/-15.2 mIU/ml and AUC was 256.3+/-9.7 mIU h/ml. When amphoteric surfactant, Lipomin LA, sodium beta-alkylaminopropionic acid, was used to accelerate the disaggregation of long fiber length CNTs, C(max) was 36.0+/-4.9 and AUC was 96.9+/-11.9, which showed less bioavailability (BA) of EPO. These results suggest that the short fiber length CNTs deliver more both EPO and absorption enhancer to the absorptive cells of the rat small intestine and the aggregation of CNTs is not the critical factor for the oral delivery of EPO.     

Erythropoietin-Coated ZP-Microneedle Transdermal System: Preclinical Formulation, Stability, and Delivery

Purpose

To evaluate the feasibility of coating formulated recombinant human erythropoietin alfa (EPO) on a titanium microneedle transdermal delivery system, ZP-EPO, and assess preclinical patch delivery performance.

Methods

Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. EPO liquid formulation was coated onto titanium microneedles by dip-coating and drying. Stability of coated EPO was assessed by SEC-HPLC, CZE and potency assay. Preclinical in vivo delivery and pharmacokinetic studies were conducted in rats with EPO-coated microneedle patches and compared to subcutaneous EPO injection.

Results

Studies demonstrated successful EPO formulation development and coating on microneedle arrays. ZP-EPO patch was stable at 25°C for at least 3?months with no significant change in % aggregates, isoforms, or potency. Preclinical studies in rats showed the ZP-EPO microneedle patches, coated with 750?IU to 22,000?IU, delivered with high efficiency (75?C90%) with a linear dose response. PK profile was similar to subcutaneous injection of commercial EPO.

Conclusions

Results suggest transdermal microneedle patch delivery of EPO is feasible and may offer an efficient, dose-adjustable, patient-friendly alternative to current intravenous or subcutaneous routes of administration.     

硬肝复康防治肝硬化的初步实验研究

目的 :研究复方中药硬肝复康对小鼠实验性肝纤维化的防治作用。方法 :单次或多次给予实验小鼠CCl4 油剂 ,分别造成急性肝损伤和肝纤维化 ;给小鼠静脉注射BCG和LPS造成免疫性肝损伤。检测各组实验小鼠血清ALT、AST、ALP ,并取肝纤维化小鼠肝脏做病理学检查。结果 :CCl4 急性肝损伤实验中 ,硬肝复康 (2g/(kg·d) )组小鼠ALT、ALP( (6153±3491)IU/L、(202±24)IU/L)低于对照组 ( (9275±2744)IU/L、(421±67)IU/L) (P<0 05) ;免疫性肝损伤实验中 ,硬肝复康组ALT、AST( (36 3±13 0)IU/L、(164 4±17 2)IU/L)显著低于对照组 ( (83 2±52 6)IU/L、(235 5±73 4)IU/L) (P<0 01) ;实验性肝纤维化实验中 ,硬肝复康组ALT、ALP( (1100±342)IU/L、(166±54)IU/L)显著低于对照组 ( (1638±336)IU/L、(328±128)IU/L) (P<0 01)。病理检查显示 ,硬肝复康组肝脏纤维化程度明显较轻。结论 :硬肝复康对慢性肝损伤和肝纤维化具有较好防治作用。     

N-Acetylcysteine reverses silver nanoparticle intoxication in rats

The increasing use of silver nanoparticles (AgNPs) in consumer products raises the risk of human toxicity. Currently, there are no therapeutic options or established treatment protocols in cases of AgNPs intoxication. We demonstrated previously that thiol antioxidants compounds can reverse the cytotoxicity induced by AgNPs in Huh-7 hepatocarcinoma cells. Here, we investigated the use of N-acetylcysteine (NAC) against the systemic toxic effects of AgNPs (79.3?nm) in rats. Biochemical, histopathological, hematological, and oxidative parameters showed that a single intravenous injection of AgNPs (5?mg/kg b.w.) induced deleterious effects such as hepatotoxicity, potentially as a result of AgNPs accumulation in the liver. Treatment with a single intraperitoneal injection of NAC (1?g/kg b.w.) one hour after AgNPs exposure significantly attenuated all toxic effects evaluated and altered the bioaccumulation and release patterns of AgNPs in rats. The findings show that NAC may be a promising candidate for clinical management of AgNPs intoxication.     

Comparative toxicity and distribution of InCl3 and In2O3 nanoparticles in rats

Recent studies have reported that metal oxide nanoparticles had potential adverse effects. In this research, the tissue distribution and toxic effects of administered InCl₃ (bulk) and indium (III) oxide Nanoparticles (In₂O₃-NPs < 45?nm, BET of 43.6 m²/g and average hydrodynamic diameter of 79.97?nm) were investigated. Male Wistar rats were treated with a single intraperitoneal injection of InCl₃ (bulk) and In₂O₃-NPs (2?mg/kg body weight, daily) for four consecutive weeks. Indium, copper and iron concentrations were measured by using ICP-OES. The indium levels were highest in the liver, followed in decreasing order by the levels in the spleen, kidney and intestine. The concentration of indium in In₂O₃-NPs exposed rats was more than InCl₃ group and indium exposure caused significant decrease on Hb, RBC levels, PLT count and copper and iron concentrations in organs, which is probably due to an interference that could take place by indium (III) through iron (III) uptake mechanism.     

Population pharmacokinetics of erythropoietin in critically ill subjects

The effects of various covariate factors on the pharmacokinetics of erythropoietin (EPO) in subjects who are critically ill and admitted to an intensive care unit were evaluated. Nonlinear mixed-effects modeling was used to analyze the data from 48 patients receiving subcutaneous doses of 40,000 IU/wk epoetin alfa enrolled in a randomized, double-blind, placebo-controlled, multicenter study. The pharmacokinetics of EPO follows a 1-compartment disposition model with first-order absorption and an endogenous input rate. For a patient weighing 70 kg, the typical apparent clearance (CL/F) and apparent volume of distribution (V/F) were estimated to be 1.86 L/h and 27.8 L. The interindividual variability in CL/F and V/F was estimated to be 57.2% and 83.8%. CL/F and V/F of EPO increased with body weight, as described by the following relation: CL/F = (CL/F)std*(W/W(std))0.75, and V/F = (V/F)std*(W/W(std))1.37, where W is individual weight, and W(std) is the median weight of the study population. There was a 46% drop in exposure of EPO from the first to the subsequent dosing events. The endogenous EPO production rate was found to decrease progressively with the course of the study. In addition, the modeled endogenous EPO production rate increased with body weight. The net effect of this increase on the endogenous plasma EPO levels may not be significant because EPO clearance was found to increase with body weight. All other factors investigated (eg, Sequential Organ Failure Assessment [SOFA] scores and APACHE II scores) had no significant effect on EPO pharmacokinetics. The typical population estimate of CL/F of EPO was close to previously reported values in healthy volunteers.     

Effect of sexual steroid hormones on spiramycin disposition in genital tract secretions of the ewe.

The present work investigated the influence of sexual steroid compounds (estradiol 17 beta and fluorogestone) on antibiotic passage across the uterine barrier. Five healthy and mature ewes, with controlled hormonal impregnation, were given a single iv injection of spiramycin, a macrolide antibiotic, at a dose of 64,000 IU/kg. Plasma and uterine secretions were regularly sampled before the injection and for 30 h post-injection. Blood was collected from the jugular vein and uterine secretions were obtained by uterine flushing with a sterile saline solution containing 0.2% inulin. Spiramycin was concentrated in the uterine secretions, whatever the hormonal status; the secretions-to-plasma ratio was 4.68 +/- 1.88 under estrogen priming and 2.68 +/- 0.91 under progestagen priming. The area under the concentration-time curve (AUC) and the mean residence time (MRT) were significantly higher (p less than 0.001) in uterine secretions than in plasma. The AUC in uterine secretions was significantly higher (p less than 0.05) under estrogen priming (439.07 +/- 241.25 IU.h/mL) than under progestagen priming (141.41 +/- 89.37 IU.h/mL). The spiramycin MRTs in uterine secretions were 11.92 +/- 4.08 and 12.06 +/- 3.35 h for both estrogens and progestagen treatment, respectively. These experiments demonstrate that estrogens increase uterine bioavailability, but not the residence time, of spiramycin when administered by a systemic route.     

Glycyrrhetic acid-loaded microparticles: liver-specific delivery and therapeutic potential against carbon tetrachloride-induced hepatitis

The microparticles (MPs) of an anti-hepatotoxic drug, glycyrrhetic acid (GLA), were prepared using poly(DL-lactic acid-co-glycolic acid) as a drug carrier, and their in-vitro properties, biodistribution and therapeutic effects were investigated. The MPs showed a particle diameter distribution of 1.0-1.4 microm and a drug content of approximately 10% (w/w). In the in-vitro release in a mixture of methanol and phosphate-buffered saline pH 7.4 (3:7, v/v), slow release was observed after an initial burst release of approximately 30% (w/w). After i.v. administration of MPs in normal mice, GLA was mainly distributed to the liver. After i.v. administration in normal mice, the MPs maintained a much higher liver concentration than did GLA solution, and the plasma concentration also tended to be higher for MPs than for GLA solution. As to therapeutic effect, the liver was damaged by repeated injection of carbon tetrachloride (CCl(4)) in mice every 48 h, and the drugs were administered intravenously as a single dose 3 h after the first injection of CCl(4). At 10 mg GLA eq. kg(-1), the MPs significantly suppressed the plasma level of glutamic pyruvic transaminase for at least 141 h after administration, while GLA solution did not become significantly effective within 45 h post-administration. MPs are suggested as a possible useful system to prolong the therapeutic effect of GLA.