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YAKUGAKU ZASSHI, 122(2),127-155, 2002
Our studies on creation of functional organic compounds and their applications, have focused on three areas, namely, (A) organic chemical studies on VD (vitamin D) analogues, (B) studies on solitary wasp venoms, and (C) studies on functional building blocks for organic synthesis. In the first area, several novel and important vitamin D analogues were synthesized and biologically evaluated, and their high VDR (vitamin D receptor) binding affinities were discussed on the basis of conformational analysis and docking study by Molecular Mechanics Calculation to the LBD (ligand binding domain) of VDR: These compounds include 24,24-difluoro-1α,25-dihydroxy-VD3 (2) (an anti-metabolism agent, the first VD analogue having higher potency than the natural hormone (1)), 2α-methyl-1α,25-dihydroxy-VD3 (42b) (the first A-ring-modified VD analogue exhibiting stronger VDR affinity than 1) and its 20-epimer (43b) (a VD analogue having a highest HL-60 cell differentiation inducing activity with a relatively low calcemic effect), and 2α-(ω-hydroxypropyl)-1α,25-dihydroxy-VD3 (exceptionally high calcemic effect). In the second area, we isolated and determined the structure of pompilidotoxins (76, 77), novel peptide neurotoxins in solitary wasp venoms. In the third area, we created furan-fused 3-sulfolene, 4H, 6H-thieno[3,4-c]-furan 5,5-dioxide and pyrrole-fused 3-sulfolene (96), 3,5-dihydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide (125), and studied their inter- and intramolecular Diels-Alder reactions.
Key words--structure-activity relationship; structural determination; vitamin D analogues; peptide neurotoxins in solitary wasp venoms; heteroaromatic-fused sulfolenes; Diels-Alder reaction
YAKUGAKU ZASSHI, 122(2),157-162, 2002
In an attempt to achieve chronopharmacotherapy for asthma, press-coated tablets (250 mg), which contained aminophylline in the core tablet in the form of low-substituted hydroxypropylcellulose (L-HPC) and coated with crystalline cellulose (PH-102) and polyethylene glycol (PEG) at various molecular weights and mixing ratios in the amounts of PH-102 and PEG as the outer shell (press-coating material), were prepared (chronopharmaceutics). Their applicability as timed-release (delayed-release) tablets with a lag time of disintegration and a subsequent rapid drug release phase was investigated. Various types of press-coated tablets were prepared using a tableting machine, and their aminophylline dissolution profiles were evaluated by the JP paddle method. Tablets with the timed-release characteristic could be prepared, and the lag time of disintegration was prolonged as the molecular weight and the amount of PEG, for example PEG 500000, in the outer shell were increased. The lag time of disintegration could be controlled by the above-mentioned method, however, the pH of the medium had no effect on disintegration of the tablet and dissolution behavior of theophylline. The press-coated tablet (core tablet: aminophylline 50 mg, L-HPC and PEG 6000; outer shell: PH-102 : PEG=8 : 2 200 mg) with the timed-release characteristic was administered orally to rabbits for an in vivo test. Theophylline was first detected in plasma more than 2 h after administration; thus, this tablet showed a timed-release characteristic in the gastrointestinal tract. The time (tmax) required to reach the maximum plasma theophylline concentration (Cmax) observed after administration of the press-coated tablet was significantly (p < 0.05) delayed compared with that observed after administration of aminophylline solution in the control experiment. However, there was no difference in Cmax and area under the plasma theophylline concentration-time curve (AUC0→24) between the press-coated tablet and aminophylline solution. These results suggest that the press-coated aminophylline tablet (with the timed-release characteristic) offers a promising forms of theophylline chronotherapy for asthma.
Key words--timed-release preparation; press-coated aminophylline tablet; delayed-release profile; chronopharmacotherapy; chronopharmaceutics
YAKUGAKU ZASSHI, 122(2),163-168, 2002
KKAy mouse, a genetic animal model of diabetes mellitus, is characterized by not only hyperglycemia, but also polydipsia and polyuria like human diabetes mellitus. In this study, we investigated the effects of Byakko-ka-ninjin-to (BKN), Bofu-tsusho-san (BOF) and Gorei-san (GRE) on blood glucose level, water intake and urine volume in KKAy mice. All these Kampo medicines were administered to the mice as the food admixture containing 1.5% or 4.5% of weight of food for 4 weeks. BKN at 1.5% and 4.5% decreased water intake without affecting blood glucose level. BOF at 1.5% showed the same effects as BKN did, but it decreased both water intake and blood glucose level at 4.5%. Furthermore, BOF at 4.5% obviously, but BKN at 4.5% slightly, decreased urine volume. However, GRE at 4.5% did not show any effects on blood glucose level, water intake and urine volume. From these results, BKN is confirmed to be effective against the polydipsia accompanied by diabetes mellitus, while BOF is suggested to be effective against not only polydipsia, but also polyuria and hyperglycemia in diabetes mellitus.
Key words--Kampo medicine; hyperglycemia; polydipsia; polyuria; KKAy mouse
YAKUGAKU ZASSHI, 122(2),169-175, 2002
We evaluated risk factors for elevation of liver function test values after administration of fenofibrate to 45 hyperlipidemic patients. The effects of 23 factors of physical examinations, clinical laboratory test values, and the background of the patients on the elevation of liver function test values were analyzed by the logistic regression method. The increase of the values of liver function tests was found to be correlated with BMI, serum levels of triglycerides, and ALP before therapy, especially sex, serum γ-GTP level before therapy and reduced serum triglyceride levels. These results suggest that caution must be exercised to avoid liver dysfunction in patients treated with fenofibrate.
Key words--fenofibrate; liver function tests; hyperlipidemia; risk factor
YAKUGAKU ZASSHI, 122(2),177-184, 2002
Cycloaddition of 1-methyl-2(1H)-quinolones with electron-withdrawing groups such as methoxycarbonyl, cyano, and acetyl groups, at the 3 or 4-position with 2,3-dimethoxy- and 2-(trimethylsilyloxy)-1,3-butadienes afforded stereoselectively phenanthridone derivatives under atmospheric and high pressures. Furthermore, regioselectivities of the cycloaddition of 3- or 4-substituted 2(1H)-quinolones with 2-(trimethylsilyloxy)-1,3-butadiene were examined using MO calculation.
Key words--4-cyano-2(1H)-quinolone; 2,3-dimethoxy-1,3-butadiene; cycloaddition; regioselectivity; stereoselectivity
YAKUGAKU ZASSHI, 122(2),185-192, 2002
For pharmacists to enhance skill of pharmaceutical cares, it is necessary to learn many instructive clinical cases, which include drug-related incidences and checks of medication errors by pharmacists. However, these cases tend to be kept in each facility and there is no access to the cases for outside pharmacists. Therefore, we aimed to develop an internet-based educational system to gather such cases, append educational commentaries by university staffs, and share them between pharmacists. An exclusive site was set up on the world wide web (WWW) homepage of the Section of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University (http://seizai.phar.kyushu-u.ac.jp) on November 2000. Browsing was limited to registered pharmacists. Any pharmacist can be freely registered. Cases were collected via WWW-forms in the site. After educational commentaries and elucidation were appended, the cases were distributed to the registered pharmacists by e-mails and WWW pages. Many applications for membership have been sent from around Japan to have more than 50 members per month, and many cases have been contributed. These cases were distributed weekly by e-mail magazines. The developed system enabled us to share many educational cases of drug-related problems all over the country. This system could contribute to pharmacists to enhance their skills of pharmaceutical cares.
Key words--internet; medication errors; pharmacists; pharmaceutical education; world wide web; incidence reports
YAKUGAKU ZASSHI, 122(2),193-201, 2002
For the purpose of prevention of hospital-acquired infection caused by antibiotic-resistant bacteria, we examined a method to establish an appropriate time period for the administration of antibiotics to compromised hosts. Using these antibiotics we monitored patients who received instruction about the drug regimen in the Blood and Respiratory Diseases Department ward. We monitored a) third-generation cephalospolins, b) Imipenem/Cilastatin, and c) antibiotics used against methicillin-resistant Staphylococcus aureus. When the antibiotics were administered over 14 days, pharmacists notified physicians of the current duration of administration using a confirmation form, and confirmed their future administration schedule. We examined the antibiotic usage regimen of all the patients in this ward before and after the confirmation form was adopted. Patients given the same antibiotics within 14 days significantly increased in percentage from 82% to 91% after the confirmation form was adopted (p< 0.05). The median duration of antibiotic administration decreased from 7 days to 5 days. The case with antibiotic administration for the longest duration was a patient with leukemia who received vancomycin for 116 days after adoption of the confirmation form. This patient died 4 days after his antibiotic was changed. Only 16% of the patients administered antibiotics in this ward were monitored for the duration of antibiotic administration after adoption of the confirmation form. When the pharmacists positively provided physicians with information on some patients concerning the prolongation of antibiotic administration, the number of patients administered antibiotics for less than 14 days significantly increased throughout this ward without interfering with the treatment of patients who required long-term administration of antibiotics.
Key words--reasonable period of antibiotic administration; prevention of antibiotic-resistant bacteria; hospital pharmacist; prevention of hospital-acquired infection; compromised host; confirmation form