YAKUGAKU ZASSHI
 Abstracts 
Vol.122, No. 8 (2002)

--Reviews--

Fundamental and Applied Studies on Transport and Metabolism of Electrolytes and Glucose--Aim to Contact with Molecular Biology

Yasunobu SUKETA

University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Shizuoka 422-8526, Japan

The authors' research focuses on polyuria, natriuresis, glucosuria, glycemia, and renal calcification in occupational lead poisoning and endemic fluorosis. Changes in electrolyte mobilization and in glucose metabolism and transport following the administration of lead compounds or fluoride were examined to elucidate these mechanisms. The results suggest fundamental approaches to the mechanism of aging and life style diseases. Our results show that: 1) Natriuresis and polyuria in lead poisoning and fluorosis are due to a decrease in renal Na/K-ATPase activity; 2) Renal calcification in fluorosis is due to stimulation of parathyroid function and activation of the renal phosphatidylinositol cascade; 3) Glycemia in fluorosis is due to elevation of renal and hepatic glucose-6-phosphatase activities; 4) Glusosuria in fluorosis is due to decreased renal Na/K-ATPase activity (but fluoride administered directly did not damage the renal Na/glucose cotransporter (SGLT)); 5) Renal calcification in fluorosis is due to stimulation of parathyroid function; and 6) The decrease in renal Na/K-ATPase and SGLT activities with aging and hypertension is due to a decrease in phosphorylation activity by protein kinase C (PKC) etc. (decrease in PKC productivity with aging and hypertension).

Key words--fluorosis; lead poisoning; aging; lifestyle diseases; ion transport; transport and metabolism of glucose

--Reviews--

Molecular Toxicological Mechanism of the Lethal Interactions of the New Antiviral Drug, Sorivudine, with 5-Fluorouracil Prodrugs and Genetic Deficiency of Dihydropyrimidine Dehydrogenase

Tadashi WATABE,^*,a,b Kenichiro OGURA,^a and Takahito NISHIYAMA^a

Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science,^a 1432-1 Horinouchi, Hachioji City, Tokyo 192-0392, Japan and Institute of Natural Medicine, Toyama Medical and Pharmaceutical University,^b 2630 Sugitani, Toyama 930-0194, Japan

In 1993, there were 18 acute deaths in Japanese patients who had the viral disease herpes zoster and were treated with the new antiviral drug sorivudine (SRV, 1-β-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil). All the dead patients had received a 5-fluorouracil (5-FU) prodrug as anticancer chemotherapy concomitant with SRV administra-tion. Studies on toxicokinetics in rats and on hepatic dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme for 5-FU catabolism in rats and humans, strongly suggested that in the patients who received both SRV and the 5-FU prodrug, tissue levels of highly toxic 5-FU markedly increased as a result of irreversible inactivation of DPD in the presence of NADPH by 5-(2-bromovinyl)uracil (BVU), a metabolite formed from SRV by gut flora in rats and humans. Recombinant human (h) DPD was also irreversibly inactivated by [¹⁴C]BVU in the presence of NADPH. MALDI-TOF MS analysis of radioactive tryptic fragments from the radiolabeled and inactivated hDPD demonstrated that a Cys residue located at position 671 in the pyrimidine-binding domain of hDPD was modified with an allyl bromide type of reactive metabolite, dihydro-BVU. Thus artificial DPD deficiency caused by BVU from SRV led to patient deaths when coadministered with the 5-FU prodrug. Human population studies using healthy volunteers have demonstrated that there are poor and extensive 5-FU metabolizers who have very low and high DPD activities, respectively. Administration of a clinical dose of 5-FU or its prodrug to poor 5-FU metabolizers may cause death unless DPD activity is determined using their peripheral blood mononuclear cells prior to the administration of the anticancer drug.

Key words--lethal drug interaction; dihydropyrimidine dehydrogenase; 5-FU prodrug; sorivudine; MALDI-TOF MS

--Reviews--

Foundation of the Bases for Protein Research and Its Application to the Pharmaceutical Science Field

Taiji IMOTO

Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1 Higashi-ku, Fukuoka 812-8582, Japan

This paper reviews the results of basic research conducted by the author's group to determine appropriate methods to develop protein-based drugs. These include production strategies, elucidation of physiologic function, improving existing pharmaceuticals, de novo design, and protein reconstruction. The antigenicity of modified proteins and methods to induce antigenic protein tolerance are also described.

Key words--antigenicity; fluctuation; folding; lysozyme; protein; stability; tolerance

--Reviews--

Induction of Cell Differentiation and Development of New Anticancer Drugs

Noriko TAKAHASHI

Department of Health Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Cell differentiation is essential for normal growth and homeostasis, and drug-induced differentiation of tumor cells into benign or normal cells is an important approach for anticancer chemotherapy. Studies of induction mechanisms for cell differentiation and discovery of differentiation-inducing factors are thus critical components of drug development. The Screening of differentiation-inducing factors, such as purified aldehyde reductase, a xenobiotic metabolite enzyme, that induces differentiation of human acute myeloid leukemia HL60 cells into monocyte/macrophage cells is described. Mechanisms of all-trans-retinoic acid (RA)-induced differentiation are also covered. RA is a potent inducer of HL60 cell differentiation and when used as a sole agent it can induce complete remission in patients with acute promyelocytic leukemia (APL). While one mechanism of the effect of RA involves RA nuclear receptors, retinoylation (a posttranslational modification of proteins by RA) may be a new nongenomic mechanism by which RA acts on cells. An early event in RA-induced differentiation may be retinoylation of RIIα (regulatory subunits of cAMP-dependent protein kinase), in which RIIα units are retinoylated and the retinoylated RIIα is then translocated to the nucleus. Drugs can also be combined with RA in RA-differentiation therapy. Cytodifferation therapy by RA in APL patients exhibits limitations due to the resistance of relapsed patients to further RA treatment. This may occur through the induction of expression of various genes that reduce RA blood concentrations. Treatment with combinations of RA and other agents may be one way to reduce induction of those genes. Good candidates for such agents include cAMP-elevating agents, retinoids, steroids, and fatty acids that synergistically induce differentiation of HL60 cells. Two derivatives of falconensone A, falconensone A p-bromophenylhydrazone, which has a bromophenyl residue, and falconensone A dioxime, which possesses a hydroxy residue, were synthesized to incorporate features of RA and N-[4-hydroxyphenyl]retinamide. Both derivatives have exhibited more potent biological activity than the parent falconensone A in vitro and in vivo.

Key words--cell differentiation; retinoic acid; retinoylation; protein modification; anticancer drug; protein kinase A

--Reviews--

Microanalysis of Tryptophan Metabolites and Suppressor Factor of Delayed-type Hypersensitivity in Mice

Mitsuo WATANABE

Faculty of Pharmaceutical Sciences, Teikyo University, 1091 Suarashi, Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan

Binding of Gα_o N-Terminus is Responsible for the Voltage-Resistant Inhibition of α_1A (P/Q-Type, Ca_v2.1) Ca²⁺ Channels

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

G-protein-mediated inhibition of presynaptic voltage-dependent Ca²⁺ channels is comprised of voltage-dependent and -resistant components. The former is caused by a direct interaction of Ca²⁺ channel α₁ subunits with Gβγ, whereas the latter has not been well characterized. Here, we show that the N-terminus of Gα_o is critical for the interaction with the C-terminus of the P/Q-type channel subunit, and that the binding induces voltage-resistant inhibition. A P/Q-type C-terminal peptide, an antiserum raised against the Gα_o N-terminus, and a Gα_o N-terminal peptide all attenuated the voltage-resistant inhibition of P/Q-type currents. Furthermore, the N-terminus of Gα_o bound to the C-terminus of α_1A in vitro, which was prevented either by the P/Q-type channel C-terminal or Gα_o N-terminal peptide. Although the C-terminal domain of the N-type channel showed similar ability to binding with Gα_o N-terminus, the above-mentioned treatments were ineffective in the N-type channel current. These findings demonstrate that the voltage-resistant inhibition of the P/Q-type channel is caused by the interaction between the C-terminal domain of the Ca²⁺ channel α_1A subunit and the N-terminal region of Gα_o.

Key words--voltage-dependent Ca²⁺ channel; P/Q type; Gα_o; voltage-resistant inhibition; Xenopus oocyte

--Regular Articles--

Creation and Evaluation of the Respective Rank Problem Solution Worksheet for Improvement Pharmaceutical Management Quality

Naozumi NISHIZONO

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Masayo TANAKA,^*,a Takao ORII,^a Noriko KAWAI,^b and Yoshiko KONDO^c Department of Pharmacy, Kanto Medical Center NTT EC,^a 5-9-22 Higashigotanda, Shinagawa-ku, Tokyo 141-8625, Japan, OFUNA Central Hospital,^b 6-2-24 Ofuna Kamakura City, Kanagawa 247-0056, Japan and Department of Pharmaceutical Sciences, Kitasato University,^c 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan

A respective rank problem solution worksheet was developed focusing on problem solution in training in pharmaceutical management. How the training influenced the instructions given to patients was then evaluated in two pharmacists in the NTT East Kanto Medical Center and three in an Ofuna central hospital. After the five pharmacists underwent the training, the records of 10 medication instructions to patients given by each before and after the training were compared. The records were analyzed based on a point calculation table, and the number of acquisition points was computed. The acquisition points increased significantly after training for all five pharmacists, from a mean of 3.56 before training to a mean of 8.34 after training. Although the acquisition points related to patient education were high, those for intervention during therapeutic monitoring, such as for adverse drug reaction or the selection of appropriate pharmaceuticals were acceptable, increasing to a mean 8.4 items after training compared with 4.4 items before. The respective rank problem solution worksheet is therefore considered useful in improving the quality of training pharmaceutical management.

Key words--pharmaceutical management; evaluation of training; problem solution worksheet

--Reviews--

Investigation and Multivariate Statistical Analysis of the Factors Influencing Risk Management

Hiroaki IKEDA,*^,a Akihiro SAWA,^b Eiji SATO,^a Ryo MUKAI,^a Yasuhiro KIMURA,^a,c and Kenji KIHIRA^a,c

Department of Pharmaceutical Services, Hiroshima University Hospital,^a Hiroshima, Department of Pharmaceutical Services, Mazda Hospital of Mazda Co., Ltd.,^b Hiroshima and Division of Clinical Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University,^c Hiroshima, Japan

A questionnaire survey for medical practitioners was conducted to clarify their basic awareness and concepts of risk management. One hundred and sixty-three medical practitioners participated in the fourth. Chugoku Yakugaku Kenkyukai. More than 50% of the participants (n = 83, aged 39.7 ± 10.8 years) answered correctly questions about the awareness of risk management and the existence of a risk management committee in their medical institution. All of those survey participants had experienced common risk managements incidents (approximately 12 times/year) during working hours.

When multivariate statistical analysis was performed on the survey results, the factors influencing the presence of a risk management committee in a medical institution were a system for the submission of incident reports, the number of beds, and the presence of a person assigned to manage risk. The analysis showed that in a number of cases medical institutions did not have a system for incident reports and did not appoint risk management staff. Moreover, the analysis showed that factors influencing the presence of a risk management committee were staff age, experience in submitting incident reports, and participation of the top executive in the operation of the risk management committee. Participants younger than 40 years of age were dissatisfied with the reporting system of risk management committees those older. The younger group usually reported incidents to those older than 40 years of age, who only accepted the reports and did not submit them to the risk management committee.

In conclusion, our results suggest that in a risk management program it is important to establish a committee and a system for the submission of incident reports. Incident reports should not only include expressions of regret for medication errors but also propose a plan for improvement.

Key words--risk management; questionnaire survey, multivariate statistical analysis; medication error; incident reports; risk manager

--Notes--

Appropriate Administration Schedule of D-Penicillamine for Pediatric Wilson's Disease Patients Based on Urinary Copper Excretion

Noriyasu FUKUOKA,^*,a Shushi MORITA,^a Shizuka HAMATANI,^b Hitoshi OKADA,^b Mayumi KONDOH,^b Tadashi IMAI,^b Shoju OHNISHI,^b and Susumu ITOH^b

Department of Hospital Pharmacy,^a Department of Pediatrics,^b Kagawa Medical University, Kagawa, Japan

The purpose of this study was to increase the amount of copper excreted resulting from the administration of D-penicillamine(DP) in pediatric Wilson's disease(WD) patients. By measuring the urinary copper excretion after adjusting the administration schedules, the appropriate timing for DP administration was investigated. The subjects were three brothers with pediatric WD. The initial daily dose of DP was 5 mg/kg/day, and gradual1y increased to the maintenance dose of 20 mg/kg/day. Until the maintenance daily dose was reached, DP was administered 2 h after the morning and evening meal. After reaching the maintenance daily dose of DP, the appropriate timing for taking DP was investigated in both the morning and evening. Three schedules of DP administration were compared: 2 h after meals; 30 min before meals (with fasting); and 1 h before the morning and l.5 before the evening meal (direction 1). The resulting urinary copper excretion on each dosing schedule was compared. Little difference was found in urinary copper excretion on the first two schedules, i. e., 2 h after meals and 30 min before meals. When DP was administered 30 min before meals, urinary copper excretion [μg/day] was 1173 in the first brother, 918 in the second, and 875 in the third. When DP was administered according to direction 1, however, urinary copper excretion was increased significantly to 1701 in the first brother, 2701 in the second, and 3808 in the third. It is known that the efficiency of urinary copper excretion with DP administration depends on the maintenance of chelating ability after absorption from the gastrointestinal tract. Our results indicate that the excretion was lower when DP was administered 2 h after or 30 min before meals (with fasting), as recommended in the package insert. Thus to achieve better copper excretion efficiency, direction 1 is recommended for WD patients.

Key words--Wi1son's disease; D- penicillamine; urinary copper excretion; administration schedule

--Notes--

Evaluation of the Permeability of Corticosteroid in Hairless Mouse and Hairless Micropig Skin from Admixture of Commercially Available Corticosteroid Ointments and/or Creams

Michiteru OHTANI,^*,a Hajime KOTAKI,^b Satoru KARIYA,^a Katsuyoshi UCHINO,^a and Tatsuji IGA^c

Department of Hospital Pharmacy, Tokyo Postal Services Agency Hospital,^a 2-14-23, Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan, The Institute of Medical Science, The University of Tokyo,^b 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan, and Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo,^c 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

Yucatan hairless micropig (YHMP) skin has been shown to have histologi and physiologic properties similar to human skin. To assess the relationship between the permeability of corticosteroid ointments and five types of commonly used admixtures of corticosteroid through hairless mice (HM) or YHMP skin and the clinical effects in humans, we conducte by in vitro experiments using HM and YHMP skin. The permeability of corticosteroid in admixtures with urea or heparinoid ointments across HM or YHMP skin was 1.5-4-fold greater than that of corticosteroid ointments alone. HM skin was found to have faster permeability than YHMP skin, but otherwise was similar to YHMP skin. These experiments demonstrated a close relationship between the permeability of HM or YHMP skin and vasoconstrictor activity in humans. These results suggest that the in vitro permeability of corticosteroid measurements across HM skin could be a useful, rapid, and easy method for assessing the vasoconstrictor activity of topical corticosteroids and the admixtures of commercially available ointments and/or creams in humans.

Key words--Yucatan hairless micropig; hairless mice; skin permeability; corticosteroids; vasoconstrictor activity; admixture

--Articles--

A Trial Production of a Table of the Optical Crystallographic Characteristics of Crystalline Drugs Including Crystal Habits (Study of Crystalline Drugs by Means of a Polarizing Microscope. XIX¹⁾)

Atsushi WATANABE

Kenbikogaku-Kenkyusho Ltd., 7-4, Matsunouchi-cho, Ashiya City 659-0094, Japan

It was clarified in previous report that the predominant faces of crystal habits mainly coincide with the morphologic crystal face at (001), (010), or (100), and therefore the two measurable key refractive indices are closely related to the principal sections of the two axial wave surfaces and coincide with the one or two of the three principal refractive indices. The three principal refractive indices of biaxial crystalline drugs were measured and tabulated in the “General Information” section of the National Formulary compiled by the American Pharmaceutical Association. A series of studies was conducted to measure the key refractive indices of the crystalline drugs listed in the Japanese Pharmacopoeia X or XI so that the data could be used to improve the quantitative analysis of their crystal habits. The purpose of the present study was to examine data on both the key and principal refractive indices and attempt to produce a general authorized table of optic crystallographic characteristics, including crystal habits, for simpler and more reliable polarizing microscopy studies.

Key words--key principal refractive index; crystal habit predominant face; polarizing microscopy