Yuji Yoshiyama

Influence of circadian-stage-dependent dosing schedule on nephrotoxicity and pharmacokinetics of isepamicin in rats.

Nephrotoxicity was more marked in rats receiving isepamicin at midlight than at middark. And, the once-daily administration at middark induced a lesser degree of nephrotoxicity than the twice-daily injection, which indicates that the once-daily treatment therapy may have potential value in the clinical use of aminoglycosides. Images

Nephrotoxicity of low doses of tobramycin in rats: effect of the time of administration.

The circadian and the circannual variations of the nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats. Animals were maintained on a light-dark period of 14/10 hrs (light on: 06h00 to 20h00). They were injected once daily for 4 and 10 days with saline or tobramycin at a dose of 40 mg/kg/day i.p. at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, tobramycin injected at 14h00 during 10 days induced a significant increase of [3H]-thymidine incorporation into DNA of renal cortex as compared to other groups (p < 0.01): toxicity was highest at 14h00 and lowest at 02h00. No temporal change was observed in the renal cortical accumulation of tobramycin, and in serum creatinine after the 4 or 10 days of treatment. In experiments done in April, July and October 1991 and in January 1992, no circannual variation was found in tobramycin cortical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulation in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the susceptibility of renal cells to tobramycin.

Circadian rhythm of embryotoxicity induced by sodium valproate in mice

The influence of dosing time on embryotoxicity of valproate was investigated in ICR (Institute of Cancer Research, USA) mice under light-dark (12:12) cycle. A significant circadian rhythm was shown for embryotoxicity, with the highest value at 17:00 and the lowest at 01:00. No significant difference between injection at 17:00 and 01:00 was demonstrated for valproate concentrations in the embryo. The rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity to the drug. Embryotoxicity and valproate concentrations were significantly higher on gestational day 13 than day 7. The timing of drug administration (i.e., gestational stage and circadian phase) appears to be essential in the study of embryotoxicity of valproate in mice.

Time-Dependent Interaction between Differentiated Embryo Chondrocyte-2 and CCAAT/Enhancer-Binding Protein α Underlies the Circadian Expression of CYP2D6 in Serum-Shocked HepG2 Cells

Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.

Influence of a circadian-stage-dependent dosing schedule on the pharmacokinetics of isepamicin in humans

These experiments were conducted in order to determine the influence of the time of day of drug administration on the pharmacokinetics of isepamicin. Six healthy volunteers were given 400 mg isepamicin IM, on 2 separate occasions, either in the morning (8 AM) or in the evening (8 PM). Within-subject differences in the pharmacokinetic parameters between the morning and evening dosing regimens were evaluated. The plasma concentrations of isepamicin were not significantly different between the morning and evening trials, but significant time-dependent changes were found with a lower elimination rate constant and a longer elimination half-life in patients administered isepamicin at night. Our finding suggests that isepamicin may have the same clinical effects irrespective of whether dosing takes place in the morning or in the evening, but its clearance tends to be depressed when taken in the evening. Therefore, morning therapy is desirable because of possible interference from aminoglycoside toxicity.

Pharmacokinetic Study of Mannitol in Subjects with Increased ICP

Six human subjects received mannitol as an intravenous dip (DIV) infusion. In each subject, the concentration of mannitol and serum osmolality were rapidly elevated during mannitol administration and reached the maximum at the end of mannitol administration. Then, it exponentially decreased. There was a strong positive correlation between mannitol concentration and extrinsic serum osmolality. The integrated values of mannitol concentration difference between the central (Cc) and the peripheral compartment (Pc) correlated with the changes of ICP reduction during mannitol administration. The results indicate that the changes of ICP reduction depend on the mannitol concentration difference between Cc and Pc.

Assessment of Quality of Life for Cancer Patients in Field of Palliative Care-Evaluation of the Use of Japanese Version of EQ-5D Health Related Quality of Life Questionnaire

Palliative care for cancer patients should consider individual preferences with the focus on health-related quality of life (HRQOL). In this regard, the recent participation of clinical pharmacists as important members of the palliative treatment team has achieved efficient management of medicines and effective symptom control.Assessment of HRQOL is necessary for improving medical services provided to patients by the palliative care team (PCT). EuroQol 5-Dimension (EQ-5D) is a questionnaire for this purpose which is being widely used by clinical researchers in a variety of clinical areas, e.g. diabetes mellitus, cerebrovascular diseases and rheumatic disease, and the objective of this study was to examine the possibility of the PCT using EQ-5D. Validity was assessed by reliability analysis of EQ-5D scale scores, correlation measures of pain at rest and with movement in a range of from 0 to 10, adverse effects of opioid analgesics (nausea, constipation and drowsiness) in a range from 0 to 3, total dosing days of opioid analgesics and lifespan with utility-based scores.Thirteen cancer patients in whose medication the PCT had intervened were enrolled. The Cronbach alpha score was calculated as 0.7801. Correlations were found between utility-based scores and pain at rest (r=-0.553, P 0.05).These findings suggest that EQ-5D may be adopted by the PCT in Japan for measuring utility-based HRQOL for cancer patients, though further investigation will be necessary.

Pharmacokinetics and Pharmacodynamics of Serum Glycerol in Patients with Brain Edema: Comparison of Oral and Intraveneous Administration

To clarify the pharmacokinetics and effect of ICP reduction of glycerol administered orally, the serum concentration of glycerol was measured by the enzymatic method and ICP was measured by the subdural balloon method in severe head injured patients with brain edema and increased ICP. Sequential change of serum glycerol concentration and its relationship to the reduction of ICP were analyzed. The results showed that the pharmacokinetics of glycerol through oral administration were similar to that of intravenous glycerol administration and the changes of ICP were also similar to that of intravenous glycerol administration. We determined that glycerol can be administered either per oral or per venous to obtain the same results for treatment of brain edema with raised ICP.

A Study of the Concentration of Mannitol for the Treatment of Raised ICP

Mannitol is a well known hypertonic agent for the control of raised intracranial pressure (ICP). However, the most effective method of administration of mannitol has not yet been established. In this paper, the authors made 10%, 20%, and 30% of mannitol and set volume and rate of administration of mannitol, in an attempt to clarify the most effective method of mannitol administration to obtain the lowest and the longest reduction of raised ICP.

Awareness of pharmacy students about the practical training at hospital pharmacies.

A questionnaire was used to ascertain the awareness of pharmacy students (below: p.students) about the practices and business in their field at hospitals.The subjects of this survey were 513 p.students who had participated in practical training at the Pharmacy Department of Kitasato University Hospital during the last 5 years.1.Most of the students participated in practical training at hospital pharmacies were hoping to become hospital pharmacists, and their experience through the practical training was a basis for their choice of occupation.2.Their comprehensions of pharmacist and job content at hospital pharmacies were low. 3.Through their experience at hospital pharmacies, most students realized the heavy responsibility of pharmacists and the necessity of applied pharmaceutical knowledge. 4.It is necessary to add practical training at hospital to the curriculam at pharmacy school for students hoping to work at hospital pharmacies.5.Cooperation of the specialists in this field is expected to reduce the heavy duty of the pharmacists at the hospital.