Kiyoshi Okuyama

Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists

BackgroundThe aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT3 receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT3 receptor occupancies, based on receptor occupancy theory.MethodsWe analyzed interindividual differences of 5-HT3 receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT3 receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron.ResultsThe interindividual difference between maximum and minimum 5-HT3 receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%.ConclusionInterindividual differences in the clinical effects of 5-HT3 receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.

Falsely Abnormally Elevated Blood Trough Concentration of Tacrolimus Measured by Antibody-Conjugated Magnetic Immunoassay in a Renal Transplant Recipient: A Case Report

This report presents a falsely abnormally elevated blood trough concentration (C(t)) of tacrolimus measured by antibody-conjugated magnetic immunoassay (ACMIA) methods in a renal transplant recipient. Because the C(t) of tacrolimus was 78.5 ng/mL at day 2 after a 52-year-old man underwent renal transplantation, we stopped the tacrolimus extended-release formulation. However, because the abnormally elevated blood C(t) continued in the range of 41.1-59.1 ng/mL, we then measured the tacrolimus concentration in a stored blood sample before renal transplantation, it was 43 ng/mL. Consequently, the day-7 blood sample was measured with both ACMIA and enzyme-linked immunoassay, showing C(t) values of 42.8 ng/mL and 0.89 ng/mL, respectively. Because the abnormally elevated C(t) was falsely measured by the ACMIA method, we restarted tacrolimus However, the calcineurin inhibitor was subsequently converted to cyclosporine at day 21 after renal transplantation. Although cyclosporine was also measured by ACMIA, there was not an abnormally elevated C(t). Subsequently, the tacrolimus concentration ratio in plasma and whole blood (P/B-tacrolimus concentration ratio) was measured by ACMIA in a posttacrolimus blood sample. The P/B-tacrolimus concentration ratio was 100%. In contrast, the P/B-tacrolimus concentration ratio was <30% in 2 control patients administered tacrolimus. It has been reported recently that there were cases showing falsely slightly elevated C(t) of tacrolimus within the therapeutic range of concentrations. Therefore, we must be careful not to reduce the tacrolimus dose falsely. We consider confirmatory methods for a falsely abnormally elevated C(t) of tacrolimus measured by ACMIA to (1) measure P/B-tacrolimus concentration ratio, (2) compare ACMIA with another measurement, and (3) evaluate a blood sample stored before tacrolimus administration.

Change in environmental bacterial flora in a new hospital building

Microbial surveillance of environmental bacteria was performed in order to study the microbial changes in a newly established hospital building. Airborne bacteria and surface-associated bacteria on floors and sinks were systematically collected between 2002 and 2005. The number of isolates obtained from frequently used floors was significantly higher than that obtained from those floors used less often. A significant increase in Staphylococcus aureus, the appearance of Pseudomonas aeruginosa, and changes among species of Gram-negative bacilli were observed 8-11 months after the new building had been opened. Furthermore, pulsed-field gel electrophoresis (PFGE) typing of meticillin-resistant S. aureus (MRSA) and P. aeruginosa showed that strains of the same PFGE groups were isolated from different sinks, floors and the adjoining old buildings. The number of MRSA isolates obtained from the new building increased as time passed. The sinks from which P. aeruginosa strains of the same PFGE type were isolated are connected by the same drainage pipe. Human movement has considerable effects on bacterial flora and their subsequent spread.

Factorial Analysis on Individual Variability of Tacrolimus Extended-Release Formulation Pharmacokinetics in the Early Period after RenalTransplantation-Factors for AUTL/AUC Decrease

Background: We have often observed that the blood trough concentration (Ct) of the once-daily, prolonged-release formulation of tacrolimus (Graceptor®; GRC) becomes unstable, and it is difficult to adjust it in the early period after transplantation. Consequently, we compared the relationships between pharmacokinetic parameters and influencing factors in a group of GRC-treated patients compared with those in a group of Prograf® (PRG)-treated patients. Methods: The study included 8 patients who were newly treated with GRC and 44 patients who were newly treated with PRG. We performed 24-hour therapeutic drug monitoring to compare the relationships between pharmacokinetic parameters, including the area under the curve (AUC), the ratio of the area under the trough level (AUTL)/AUC to indicate the relationships among AUCs, peak concentration (Cp), and Ct. The Cp/Ct values, and dose/body weight (UC/ [D/BW]) values reflected bioavailability and the influencing factors; number of days after transplantation and Dose/BW in the GRC-treated and PRG-treated patients. Results: The Cp/Ct values were higher and the AUTL/AUC and AUC corrected by dose/body weight (AUC/[D/BW]) values were lower with a low number of days after transplantation (particularly within 20 days) and a large dose than a high number of days after transplantation and a small dose in the GRC-treated patients. No such associations were observed in the PRG-treated patients. Conclusion: Care is required when using GRC as there is a tendency for Cp to increase owing to rapid absorption within 20 days after transplantation. Blood levels may be unstable and side effects may be more prevalent in some patients. Moreover, the utilization rate is low and the dose is high in such patients; therefore, unstable gastrointestinal function caused by a variety of factors may play a role in the early period after transplantation.

Synergistic Effects of Calcineurin Inhibitors and Steroids on Steroid Sensitivity of Peripheral Blood Mononuclear Cells.

The steroid receptor (SR) complex contains FKBP51 and FKBP52, which bind to tacrolimus (TAC) and cyclophilin 40, which, in turn, bind to cyclosporine (CYA); these influence the intranuclear mobility of steroid-SR complexes. Pharmacodynamic interactions are thought to exist between steroids and calcineurin inhibitors (CNIs) on the SR complex. We examined the effect of CNIs on steroid sensitivity. Methylprednisolone (MPSL) sensitivity was estimated as the concentration inhibiting mitosis in 50% (IC50) of peripheral blood mononuclear cells and as the area under the MPSL concentration-proliferation suppressive rate curves (CPS-AUC) in 30 healthy subjects. MPSL sensitivity was compared between the additive group (AG) as the MPSL sensitivity that was a result of addition of the proliferation suppressive rate of CNIs to that of MPSL and the mixed culture group (MCG) as MPSL sensitivity of mixed culture with both MPSL and CNIs in identical patients. IC50 values of MPSL and cortisol sensitivity were examined before and 2 months after CNI administration in 23 renal transplant recipients. IC50 and CPS-AUC values of MPSL were lower in the MCG than in the AG with administration of TAC and CYA. The CPS-AUC ratio of MCG and AG was lower in the TAC group. IC50 values of MPSL and cortisol tended to be lower after administration of TAC and CYA, and a significant difference was observed in the IC50 of cortisol after TAC administration. Steroid sensitivity increased with both TAC and CYA. Furthermore, TAC had a greater effect on increasing sensitivity. Thus, concomitant administration of CNIs and steroids can increase steroid sensitivity.