ABSTRACT:The

ABSTRACT:The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with 125 I. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.

ABSTRACT:Human serum albumin (HSA) is used clinically as a plasma expander in patients with hypoalbuminemia and can also function as a drug carrier. However, the administered HSA is readily eliminated from the blood circulation under pathological conditions, especially the nephrotic syndrome. In this study, we present data on the pharmacokinetics of a structurally defined HSA dimer [two HSA molecules that are cross-linked by reaction with 1,6-bis(maleimido)hexane via Cys34] in nephrotic rats and its superior circulation persistence, owing to the molecular size effect. The half-time (t 1/2 ) of the HSA dimer persisted in the circulation 1.3 times longer than that of monomeric HSA in normal rats, primarily because of the suppression of the accumulation of the HSA dimer in the skin and muscle. In nephrotic rats, the t 1/2 of the HSA monomer decreased considerably, whereas the HSA dimer remained unaltered in the blood stream, similar to that for normal rats. As a result, the t 1/2 of the HSA dimer was 2-fold longer than that of the HSA monomer. This longer t 1/2 can be attributed to the fact that accumulation in the kidney and urinary excretion of the HSA dimer were significantly suppressed. The cross-linked HSA dimer shows a longer blood circulation than native HSA monomer in nephrotic rats, which can be attributed to the suppression of renal filtration and leakage into the extravascular space. This HSA dimer has the potential for use as a drug carrier, new plasma expander, and an artificial albumin-based oxygen carrier under a high glomerular permeability condition such as nephrosis.

The HSA dimer shows potential for use as a plasma-retaining agent for antidiabetic drugs due to its favourable pharmacokinetic properties.

: In this report, the authors described the unusual case of a patient in whom the plasma phenytoin concentration was unexpectedly not detected on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique, a typical immunoassay for phenytoin. The plasma concentration was measured using PETINIA and high-performance liquid chromatography in a 69-year-old male patient treated with fosphenytoin intravenously at the standard dose for 7 days. Although the plasma concentration of phenytoin was below the limit of detection (<0.5 mcg/mL) on PETINIA after the administration of fosphenytoin, the trough plasma concentration was estimated to be between 5 and 10 mg/L on high-performance liquid chromatography. When the plasma concentrations of IgM and IgG were measured using an enzyme-linked immunosorbent assay, the plasma IgG level was within the reference range, whereas the plasma IgM level was 2-3 times higher than the upper limit of the reference range. We concluded that the PETINIA method yielded a possible false-negative result regarding the phenytoin level in this patient, perhaps because of some hindrance to the measurement process by IgM. This case suggests that false-negative results should be considered when therapeutic drug monitoring reveals abnormally low values using PETINIA and that it is necessary to evaluate the plasma IgM level.