Teruaki Kobayashi

Active oxygen species generation and cellular damage by additives of parenteral preparations: selenium and sulfhydryl compounds.

We investigated the relationship between active oxygen species (AOS) generation and cultured vascular endothelial cellular damage caused by simultaneous exposure to selenium compounds and sulfhydryl compounds such as cysteine (Cys) or reduced glutathione (GSH). Selenium compounds, selenite, selenate or selenomethionine (SeMet), are added to total parenteral nutrition (TPN) and intravenously administered. We confirmed by luminol dependent chemiluminescence, an indicator of AOS generation, that selenite generates AOS in the presence of clinical concentrations of sulfhydryl compounds, 0.5 mM Cys or 0.5 mM GSH, and that the amount of AOS generated reaches the maximum when their mole ratio is 1:50. However, AOS generation was not observed after simultaneous administration of various concentrations of selenate or SeMet with sulfhydryl compounds. Moreover, simultaneous exposure to 10 microM selenite and sulfhydryl compounds was found to result in significant increases in the [3H]-adenine and lactate dehydrogenase (LDH) release rates from cells, a significant decrease in the amount of cellular protein, and enhancement of cellular damage as compared with after exposure to selenite alone. However, simultaneous exposure to 10 microM selenate or 10 microM SeMet together with sulfhydryl compounds did not induce cellular damage. These findings revealed that selenite generates AOS and causes cellular damage in the presence of sulfhydryl compounds. Accordingly, it seems better to choose selenate or SeMet instead of selenite when a selenium compound is to be added to TPN.

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.

Influence of Combined Use of Selenious Acid and SH Compounds in Parenteral Preparations

The influence of the combined use of selenious acid and SH compounds (glutathione (GSH) and cysteine (Cys), or ascorbic acid (Asc)) on cultured venous vascular cells was investigated experimentally. When cultured human umbilical venous vascular endothelial cells were exposed to 10 microM of selenious acid combined with 0.5 mM-GSH or 0.5 mM-Cys, the release rates of [3H]-adenine and lactate dehydrogenase (LDH) from cells into the medium increased significantly as compared with after exposure to selenious acid alone, and damage to the vascular endothelial cells was found to be intensified. Addition of 1 microM of selenious acid simultaneously with 0.5 mM-GSH or 0.5 mM-Cys showed no differences in toxicity for the vascular endothelial cells as compared with the addition of selenious acid alone. On the other hand, simultaneous exposure to 10 microM of selenious acid and 1 mM-Asc induced no significant differences in the release rates of [3H]-adenine and LDH, and no damage was observed to the vascular endothelial cells. These results suggest that simultaneous addition of selenious acid together with GSH or Cys, which have the SH-group, may cause damage to the vascular endothelial cells. Therefore careful attention is warranted in total parenteral nutrition (TPN).

Determination of Serum Mexiletine Concentrations and its Protein Binding by High-performance Liquid Chromatography.

A new method to determine serum mexiletine (MX) concentrations using high-performance liquid chromatography (HPLC) was established.This method could reduce a sample volume to 100μ1 of serum and could shorten the pretreatment time to less than 10 minutes by using Chem Elut minicolumn. The results obtained by this method (n=28) correlated well with those obtained by gas chromatography method (r=0.997).Moreover, this method had a good recovery and reproducibility, suggesting that it is an excellent method for determining serum MX concentrations.Using this HPLC method, serum protein binding of MX was studied in healthy subjects and patients with chronic renal failure (CRF). The protein binding of MX was 60.83±4.37% in healthy subjects (n=6) and 52.45±6.22% in CRF (n=9).The protein binding of MX in CRF was significantly decreased, compared with healthy subjects, indicating an apparent elevation of free drug concentrations.In general, dose adjustment of MX in CRF is considered to be unnecessary. However, free drug concentrations may participate in the appearance of effects and adverse reactions. The possibility of enhanced pharmacological effects and increased adverse reactions due to such variations of protein binding in CRF should be also considered.

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.