Plasma clearance and urinary excretion after intravenous injection of stable 84Sr in humans

Systemic kinetics and urinary excretion after intravenous injection of stable strontium 84Sr were evaluated in 42 investigations in human subjects. Tracer concentrations in plasma and urine were determined by thermal ionisation mass spectrometry. The initial strontium plasma clearance measured after tracer administration was found to be much faster than that predicted by the current model of the International Commission of Radiological Protection (ICRP). The biological half-life of the fast component plasma clearance (T(1/2)) was 0.25 h in comparison with 1.1 h of the ICRP value. This early clearance could be the consequence of a more rapid transfer from blood plasma to other compartments of the human body. In vitro blood tests have shown that strontium was not bound to red blood cells. Cumulative urinary excretion is considerably lower than the model prediction. The reason could be the reduced transfer rate of strontium from plasma to urine in the first 12 h after tracer administration. Plasma clearance and urinary excretion showed no dependency on the age or gender of the adult volunteers.     

Disposition of the flavonoid quercetin in rats after single intravenous and oral doses

The pharmacokinetic and mean time tissue distribution parameters, after a single 50-mg/kg dose of quercetin administered as intravenous bolus, oral solution, and oral suspension, were determined using rat as an animal model. Following intravenous administration, the elimination rate constant and the elimination half-life were found to be 0.0062 min^-1 and 111 min, respectively. Examining the mean time tissue distribution parameters reflected a strong binding affinity of the drug molecules to both plasma and tissue proteins. In addition, the low permeability rate of drug molecules in the peripheral system was demonstrated. Following the oral administration of the drug, the extent of absorption was greater from solution than from suspension. Moreover, the solution showed a shorter T_max and a higher C_max than suspension. The absolute bioavailability for the solution was 0.275 and that for suspension was 0.162. The mean residence time (MRT) and the mean absorption time (MAT) were higher for suspension, reflecting the need for dissolving the drug in order to be absorbed. The mean (in-vivo) dissolution time (MDT_in-vivo) was 34.5 min. Thus, an oral quercetin formulation that can readily form a drug solution in the gastrointestinal tract may enhance the absorption of the drug.     

Coated hydralazine hydrochloride beads for sustained release after oral administration

Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10?h in simulated intestinal fluid.     

Comparison of urinary excretion of radon from the human body before and after radon bath therapy

Theoretically, the human body absorbs radon through the lungs and the skin and excretes it through the lungs and the excretory organs during radon bath therapy. To check this theory, the radon concentrations in urine samples were compared before and after radon bath therapy. During the therapy, the geometric mean (GM) and the geometric standard deviation of the radon concentration in air and in the bath water were 979 Bq m(-3), 1.58 and 73.6 Bq dm(-3), 1.1, respectively. Since radon was detected in each urine sample (GM around 3.0 Bq dm(-3)), urinary excretion of radon was confirmed. The results of this study can neither reject nor confirm the hypothesis of radon absorption through the skin. A 15 times higher increment of inhaled radon level did not cause significant changes in radon of urine samples.     

Sensitivity analysis of the urinary excretion of plutonium

The transfer parameters of a new age-related model for plutonium metabolism, which have the largest influence on urinary excretion, are determined by applying a sensitivity analysis and assuming a direct uptake into blood. Realistic cases of contamination via ingestion and inhalation were considered as well and sensitivity coefficients for non-systemic parameters were calculated. The most important parameters in relation to the path of intake are identified and the effects of the modifying factors proposed by the ICRP in the case of alteration of respiratory tract physiology are briefly examined.     

Uncertainty analysis of the urinary excretion of plutonium

A quantitative estimate of the uncertainty of the urinary excretion of plutonium predicted by available biokinetic models is provided. Urinary excretion is primarily considered here because the monitoring of internal contamination of plutonium mainly relies on measurements of activity in urine samples. A previous paper has identified the most significant transfer rates for urinary plutonium excretion following an acute intake. That analysis is used here as a screening method to reduce the number of model parameters to be considered. A log-normal distribution was assumed for the probability distribution of the model parameters. The spread of the values, represented by the geometric standard deviation (GSD), is explicitly calculated, as few indications of the range of variation of systemic transfer rates are available. Different values for the GSD were considered. Assuming a certain GSD for all the systemic rate constants, random values of the rates were generated (by means of a Monte Carlo simulation with a Latin hypercube sampling scheme) and the resulting predictions of urine bioassay measurements were calculated. The comparison of the mean and variance of the predictions with the available data from several studies performed on different subjects provides information about the GSD of model parameters that represents the intersubject variation of transfer parameters.     

Evaluation of hepatic glucose metabolism via gluconeogenesis and glycogenolysis after oral administration of insulin nanoparticles

Nanoparticles were designed to promote insulin intestinal absorption via the oral route, to increase portal insulin levels to better mimic the physiological pathway, providing enhanced glucose control through glycogenolysis and gluconeogenesis. Nanoparticles were formulated with insulin encapsulated in the core material consisting of alginate and dextran sulfate, associated with poloxamer and subsequently coated with chitosan then albumin. A spherical and slightly rough core was observed in electron micrographs with the appearance of a concentration gradient of the polysaccharide structure toward the periphery of the nanoparticle. Atomic force microscopy showed that the fully formed nanoparticles are about 200?nm in diameter with smooth and spherical morphology. Histopathological analysis of organs and tissues of diabetic rats dosed daily for 15 days with insulin nanoparticles was used to evaluate toxicological issues. No morphological or pathological alterations were observed in rat liver, spleen, pancreas, kidney or intestinal sections. Following, the effect of nanoencapsulated insulin on inhibiting hepatic gluconeogenesis was evaluated after a single insulin administration and oral glucose tolerance test, which represents a significant metabolic challenge to the liver. Alterations in the hepatic glucose metabolism of fasted streptozotocin-diabetic rats were determined by the percent contribution of glycogenolysis and gluconeogenesis, measured by using metabolic tracers, however similar gluconeogenesis contribution to the hepatic metabolism was observed between diabetic rats receiving nanoencapsulated insulin or insulin solution. The metabolic results may be explained by the inability of a single dose in shifting the gluconeogenesis/glycogenolysis contributions, sampling time, fasting period or by influence of the kidney enzymes and impairment in insulin signaling observed in stz-diabetic rats.     

Tissue distribution and targeting evaluation of TMP after oral administration of TMP-loaded microemulsion to mice

The aim of this study was to quantify the oral delivery systems of Tetramethylpyrazine Microemulsion (TMP ME) to heart, liver, spleen, lung, kidney and brain by comparing TMP level after oral administration at a dose of 100?mg kg^?1 with those of TMP tablet suspension (TMP SWW). This study was taken in mice to develop a suitable analytical methodology in pharmacokinetics studies and to manipulate the tissue distribution and targeting evaluation. Drug concentrations in tissues were determined at different times post-mortem. An HPLC method for separation and quantification of TMP was developed and validated by studying mice tissues. Following oral administration, TMP concentrations in different tissues were constantly detected for quite a long time and finally differed significantly from each other. The AUC rank order 3 of ME group is AUC_liver?> AUC_brain?> AUC_lung?> AUC_spleen?> AUC_heart?> AUC_kidney, while the SWW group is AUC_liver?> AUC_lung?> AUC_spleen?> AUC_heart?> AUC_brain?> AUC_spleen. Especially, the AUC value in brain region (AUC_brain) of ME is 6.06-fold of SWW. The drug relative overall targeting efficiency (RTE) are calculated: heart (7.49%), liver (3.54%), spleen (12.60%), lung (6.02%), kidney (2.86%) and brain (12.51%). The results from ME directly showed obvious targeting transport to the brain. These results indicated that this new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body.     

Modelling of stable and unstable fracture of short beam shear specimens

Finite element analysis of interlaminar shear failure in unidirectional carbon fibre/epoxy is carried out. A short beam shear test with a large loading roller is modelled including the effects of large displacements and varying contact between the rollers and the specimen. The shear stress/deformation characteristics of the interfacial layers between plies are included by means of non-linear spring elements, and shown to determine whether the overall response of the specimen is stable or unstable. The span-to-thickness ratio also affects the stability of the response. The effect of specimen geometry on stability, which has also been observed experimentally, is difficult to explain by conventional analysis approaches. These results suggest that a good representation of the interface between plies is crucial for accurate modelling of overall structural response involving interlaminar shear failure.     

口服水飞蓟素固体脂质纳米粒(SM-SLN)肝靶向性的动物实验研究

采用冷却-匀质法制备了平均粒径为170nm的水飞蓟素固体脂质纳米粒（SM-SLN）。用其给小鼠灌胃后,采用高效液相法（HPLC）测定小鼠血浆和各脏器中的药物浓度,以相对摄取率（re）、靶向效率（te）和峰浓度比（Ce）三个指标定量地评价了SM-SLN的肝靶向性。结果表明,SM-SLN组中的肝脏相对于血浆和其它脏器的te值均大于1,且肝脏中的re值（7．50）、Ce,值（8．12）均为最大值,说明SM-SLN具有良好的肝靶向性。SLN可以作为治疗肝脏疾病药物的良好肝靶向载体。     

Pharmacokinetic variations of tetramethylpyrazine phosphate after oral administration in hepatic precancerous mice and its hepatoprotective effects

Context: Pharmacokinetics of drug may be altered by abnormal physiological functions in illness, which will affect its pharmacodynamic efficacy in turn.

Objective: To assess the preventive effects of tetramethylpyrazine (TMPZ) phosphate on hepatocarcinogenesis and its pharmacokinetic differentiations in model mice.

Methods: Diethylnitrosamine (DEN) was adopted to induce hepatic precancerous model in mice through intraperitoneal injection, and prevention efficacy of TMPZ at a dose of 162?mg/kg was examined by liver histological analysis and activities of serum marker enzymes. Pharmacokinetic variations of TMPZ between control and model mice were measured for single oral administration.

Results: DEN initiation led to a remarkable increase of serum marker enzymes, and abnormality such as bile canaliculi hyperplasia and presence of tumor cells were observed in liver histopathological examination in model mice, while the control ones revealed normal architecture. Oral treatment of TMPZ resulted in a marked reduction in serum marker enzymes and improvement in liver histopathology compared with model ones. In pharmacokinetic study, values of AUC and T_max of TMPZ became significantly greater with increase of doses in both control and model mice, which elucidated the absorption was enhanced and delayed; meanwhile, its elimination was not affected markedly. When the mice were treated at same dose, the adsorption of TMPZ in model mice was greatly improved than that in control ones, while T_max and MRT had no significant difference.

Conclusion: TMPZ was partly effective to protect liver from carcinogenesis initiated by DEN, and hepatic insufficiency could change its pharmacokinetics.     

Pharmacokinetics and pharmacodynamics of FSK0808 and Gran after single intravenous drip administration or single subcutaneous administration: comparative study in healthy Japanese adult male subjects

FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200?µg/m²) and single subcutaneous dose (400?µg/m²) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration – time curve by 48 hours after administration (AUC_0–48) in a single intravenous drip (IVD) study, and AUC_0–48 and maximum blood concentration (C_max) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34⁺ cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC_0–48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for C_max and AUC_0–48 were within the range of log(0.8)–log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)–log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.     

Pellets for oral administration of low-molecular-weight heparin

Background: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. Method: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and Eudragit®RS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. Results: Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 ± 1.9% to 12.8 ± 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. Conclusion: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.     

The effect of fluorination of zinc oxide nanoparticles on evaluation of their biodistribution after oral administration

Monitoring of the behavior of metal nanoparticles in the body following exposure is very important for investigation of the physiological fates and safety of these nanoparticles. In this study, we investigated the behavior and accumulation of nano-scaled ZnO (20 nm) and submicro-scaled ZnO (100 nm) particles in organic tissues after oral administration using PET imaging. Both types of ZnO nanoparticle (20 or 100 nm) were labeled with the radionuclide (18)F in high yield via 'click reaction'. (18)F labeling on the ZnO nanoparticles was maintained stably in simulated gastric fluid (pH 1.2) for 7 h. PET images indicated that (18)F and (18)F-ethoxy azide showed radioactivity in the bone and bladder 3 h after oral administration, whereas radioactivity for (18)F-labeled ZnO nanoparticles was seen only in the gastrointestinal (GI) tract. At 5 h post-administration, biodistribution studies demonstrate that (18)F accumulated in the bone (10.19 ± 1.1%ID g(-1)) and (18)F-ethoxy azide showed radioactivity in the bone (7.55 ± 0.6%ID g(-1)), liver, and brain (0.94 ± 0.3%ID g(-1)). Unlike (18)F and (18)F-ethoxy azide, (18)F-labeled ZnO nanoparticles showed radioactivity in the lung, liver and kidney including the GI tract. Submicro-scaled (18)F-labeled ZnO nanoparticles (100 nm) showed stronger radioactivity in the liver and kidney compared to nano-scaled (18)F-labeled ZnO nanoparticles (20 nm). In conclusion, PET imaging has the potential to monitor and evaluate the behavior of ZnO nanoparticles absorbed in organic tissues following oral exposures.     

Evaluation of liposomal behavior in the gastrointestinal tract after oral administration using real-time in vivo imaging

Liposomes are regarded as promising drug carriers for enhancing the pharmacological effects of poorly absorbed drugs, such as peptides, following oral administration. Liposomal surface modifications by mucoadhesive polymers could improve drug absorption through interactions with the mucus layer. The main purpose of this study was to establish a method of monitoring the behavior of liposomes within the body after oral administration, particularly in the gastrointestinal (GI) tract, using a real-time in vivo imaging system (IVIS) to elucidate the behavior of surface-modified liposomes. Indocyanine green (ICG) was used as a near-infrared dye to label chitosan (CS) or glycol CS (GCS)-modified liposomes, and to observe the dynamic behavior of the liposomes in rats by noninvasive IVIS after oral administration. First, we validated IVIS results of the rat abdomens by comparing them to quantitative measurements of ICG fluorescence intensity in tissue homogenates. Nano-sized small unilamellar vesicles were retained longer than micro-sized multilamellar vesicles in the GI tract. Furthermore, surface-modified liposomes showed longer-term retention in the GI tract than unmodified liposomes in fasted rats. Moreover, surface modification by CS or GCS effectively prevented the excretion of liposomes from the GI tract and prolonged retention in fed rats.     

Modelling of mode-I stable crack growth under hydrogen assisted stress corrosion cracking

The paper presents a new strategy based on combined analytical and finite element (FE) solution to hydrogen assisted stress corrosion crack growth. The diffusion process is solved analytically through both one-and two-dimensional modelling. These solutions are adopted with two-dimensional FE based cohesive zone model of crack extension study. The results fit well with published experimental data and show improvement over the predictions by full FE approach. The new solution approach helps to reduce time required for simulation/computation. The study has produced a relationship between concentration dependent reduction in cohesive strength and plastic strain rate.     

Enhancement of absorption of insulin-loaded polyisobutylcyanoacrylate nanospheres by sodium cholate after oral and subcutaneous administration in diabetic rats.

Polyisobutylcyanoacrylate (PIBCA) nanospheres were employed as biodegradable polymeric carriers for oral (p.o.) and subcutaneous (s.c.) delivery of insulin. The polymerization technique used was able to hold 65%-95% of insulin added 30 min after initiation of polymerization. The percentage drug loading was monomer concentration dependent. Insulin adsorption to the nanospheres was measured by radioimmunoassay. Although Pluronic F68 (0.5%) did not significantly alter the in vitro insulin degradation half-life T50%, sodium cholate (0.5%) increased the degradation T50% of insulin by 56% (from 13.6 +/- 1.6 to 22.1 +/- 2 min). This study also investigated the in vivo performance of insulin-loaded PIBCA in aqueous suspension with or without sodium cholate (0.5%) and Pluronic F68 (0.5%) surfactants after oral and subcutaneous administration to alloxan-induced diabetic rats. Insulin absorption was evaluated by its hypoglycemic effect. Insulin associated with PIBCA nanospheres retains its biological activity up to 15 h and 24 h after oral and subcutaneous administrations, respectively. Administered orally insulin-loaded (75 U/kg) nanospheres, in the presence of surfactants, significantly reduced the mean blood glucose level from 392 +/- 32 to 80 +/- 13 mg/dl within 2 h and maintained it at 100 mg/dl or less for more than 8 h. On the other hand, the subcutaneous administration of insulin-loaded (25 U/kg) nanospheres significantly decreased the blood glucose level from 406 +/- 33 to 88.5 +/- 12.8 mg/dl within 1 h, and the lowered glucose level was maintained at 100 mg/dl or less for more than 12 h; it returned to its initial value 24 h after administration. Insulin-loaded nanospheres with surfactants showed significant (P < .05) pharmacological availability (PA%) of 37.6% +/- 3.7% and 65.2% +/- 2.7% after oral and subcutaneous dosages, respectively. The existence of surfactants with PIBCA nanospheres improved the oral PA% by 49.2%. These findings suggest that the developed PIBCA, in the presence of surfactants, would be useful not only in improving insulin gastrointestinal absorption, but also in sustaining its systemic action by lowering the blood glucose to an acceptable level.     

Derivation and validation of a urinary excretion function for plutonium based on occupational exposure

Formation of a three-component urinary excretion function using the data of occupational exposure cases is described. Measurement results of plutonium inhalation from two subjects over 6000 and 2500 d are used in the derivation of this function. The three-component excretion function obtained is U(t) = 0.0008e(-0.0566(t)) + 0.00009e(-0.0042(t)) + 0.00004e(-0.00008(t)). The function is therefore proposed as a reliable basis to make an uptake assessment for operational control for mixed class of plutonium dominated by M-class chronic exposure.     

Cyclosporine A: a review of current oral and intravenous delivery systems

As early as 1978, the immunosuppressive effect of cyclosporine A (CsA), a metabolite of the fungus Tolypocladium inflatum (Borel, 1989), was reported to be effective in inhibiting organ rejection in patients receiving kidney transplants from mismatched cadaver donors (Calne et al., 1978) and in the treatment of graft-versus-host disease in patients with acute leukemia following bone marrow transplants (Powles et al., 1978). Today, CsA is still indicated to prevent rejection following solid organ transplantations, prevent and treat graft-vs-host disease following bone marrow transplants, and has also been used in the treatment of autoimmune disease such as psoriasis, rheumatoid arthritis, and nephrotic syndrome (Canadian Pharmacists Association, 2006). The effectiveness of CsA is derived from its ability to specifically and reversibly inhibit immunocompetent lymphocytes in the G₀ and G₁ phase of the cell cycle. The T-helper cells are the main target, but suppression of the T-suppressor cells also occurs. The production and release of lymphokines, including interleukin-2 are also inhibited (Novartis, 2005a). CsA can be administered intravenously as well as orally in the form of a solution or a soft gelatin capsule. The following review will focus on the evolution of the emulsion-based oral formulations from the first generation as Sandimmune® to the second generation Neoral®, both products of Novartis Pharmaceutical, as well as on the Sandimmune® commercial intravenous formulation. The potential of alternative delivery systems, including micelles, micro- and nanoparticles, and liposomes, will also be discussed.