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YAKUGAKU ZASSHI, 124(6),293-299, 2004
The response of patients to drugs can be affected by genetic polymorphisms/defects in drug metabolizing enzymes, transporters, and receptors. Genetic polymorphisms/defects are generated by mutation of coding regions and/or noncoding regions of target genes, such as single-point mutations, deletions/insertions, variation in the number of tandem repeats, etc. If a genetic defect in a patient which affects drug response were known, it would be possible to optimize medications individually. The author developed two improved methods for detecting CYP2C19*2 and CYP2C19*3. Using the methods, the type of CYP2C19 gene was examined in 80 inpatients, and the medication status of patients with the mutation was examined focusing on dosage and side effects. The author also examined polymorphisms of the serotonin transporter/biosynthetic or metabolizing enzymes in depressive patients treated with fluvoxamine, a selective serotonin reuptake inhibitor, and the relationship between clinical efficacy and polymorphisms was investigated. As a result, patients with the S/S genotype of 5-HTTLPR were found to experience better clinical efficacy.
Key words--Genetic Polymorphism; CYP2C19; Clinical application; serotonin transporter; drug response
YAKUGAKU ZASSHI, 124(6),301-309, 2004
Renal sodium handling is an essential physiologic function in mammal for body fluid maintenance and blood pressure regulation. Recent advances in molecular biology have led to the identification of kidney-specific sodium transporters in the renal tubule, thereby supplying vast information for renal physiology as well as systemic physiology. Renal urinary concentration for body fluid maintenance is accomplished by counter current multiplication in the distal tubule. Sodium transport in the thick ascending limb of Henle (TAL) is the initial process of this system. We have demonstrated that renal urinary concentration is regulated in part by the expression of the Na+-K+-2Cl− co-transporter (BSC1) in TAL, by showing two mechanisms of BSC1 expression: pitressin vasopressin (AVP)-dependent and AVP-independent mechanisms. Two additional findings, namely, a lack of the ability to increase BSC1 expression leads to urinary concentrating defect and an enhanced BSC1 expression underlies the edema-forming condition, confirm the close association between sodium handling in TAL and body fluid accumulation. The lines of evidence from our genetic studies of the general Japanese population suggest the importance of mendelian hypertension genes in the genetic investigation of essential hypertension. Because those genes directly or indirectly regulate sodium transport by the Na-Cl co-transporter or the epithelial sodium channel in the distal convoluted tubule to the collecting duct (distal tubular segments after TAL), sodium handling in this part of the renal tubule may be, at least in part, involved in blood pressure regulation. The unveiling of such physiologic roles of sodium handling based on the sodium transporters or on the tubular segments may lead to a better understanding of systemic physiology as well as to the development of novel therapy for body fluid or blood pressure disorders.
Key words--sodium transport; counter current multiplication; urinary concentration; mendelian hypertension; essential hypertension
YAKUGAKU ZASSHI, 124(6),311-319, 2004
The aqueous medium radical reactions of a variety of imine derivatives such as oxime ether, oxime, hydrazone, nitrone, and N-sulfonylimine were investigated. Triethylborane-mediated intermolecular alkyl radical addition to glyoxylic oxime ether, oxime, and nitrone in water proceeded smoothly to give α-amino acid derivatives in good yields. Alkyl radical addition to N-sulfonylimine proceeded in aqueous media using zinc as a radical initiator. The zinc-mediated radical reaction of the hydrazone with a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities, which could be converted into enantiomerically pure α-amino acids. The indium-mediated radical reactions provide new opportunities for carbon-carbon bond formation such as alkylation reactions of imines and 1,4-addition to electron-deficient olefins. The indium-mediated tandem reactions also proceeded effectively via two carbon-carbon bond-forming processes for the preparation of various types of functionalized cyclic compounds.
Key words--radical reaction; aqueous media; oxime ether; indium; environmentally benign reactions
YAKUGAKU ZASSHI, 124(6),321-332, 2004
OBJECTIVE: To study the effectiveness for the treatment of intermittent claudication (IC) of three drugs with antiplatelet effects, cilostazol, beraprost sodium, and prostaglandin E1 (PGE1), by using a systemic review of literature and a meta-analysis.
METHODS: A search was undertaken for studies reported between 1966-2002 in the MEDLINE database, and references in published articles and reviews were obtained. Data for maximum walking distance (MWD), pain-free walking distance (PFWD), and adverse clinical events were extracted from the articles that met the inclusion criteria.
RESULTS: The pooled estimates of the weighted mean differences (WMD) of MWD and PFWD for cilostazol were 52.19 m [95% confidence interval (CI) 32.08, 72.31] and 39.75 m [95% CI 23.39, 56.10], and those for PGE1 were 100.27 m [95% CI 15.76, 184.78] and 55.73 [95% CI 21.54, 89.92], respectively. These differences were statistically significant between the test drugs and placebo. However there was no statistical significance difference between beraprost sodium and placebo, even though there was one study that showed a tendency for improvement in walking distance. The total rate of adverse clinical events in cilostazol and beraprost sodium was higher than that for placebo, while there was no statistical significant difference between PGE1 and placebo, although PGE1 had a higher tendency for adverse clinical events.
CONCLUSION: The literature evaluation results and the meta-analysis suggest that these two drugs (cilostazol and PGE1) can be considered to be effective drugs for the treatment of IC. Due to current availability of only a few clinical reports, further studies are needed to clarify the efficacy of beraprost sodium in the treatment of IC.
Key words--cilostazol; prostaglandins; intermittent claudication; meta-analysis; effectiveness; safety
YAKUGAKU ZASSHI, 124(6),333-339, 2004
Capillary electrophoresis (CE) was applied to enantiomeric separation of chiral ephedrine derivatives (d/l-ephedrine, d/l-methylephedrine, d/l-pseudoephedrine, and d/l-norephedrine) in unregulated drug products. Unregulated drugs, referred to as dietary supplements in U.S.A., have been used legally as tonic agents, but illegal substances such as ephedrine were often detected. Baseline separation of all enantiomers of ephedrine derivatives was achieved using an electrophoretic solution containing heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-CD) as a chiral selector. The optimal conditions were established to be: capillary column of fused silica (50 μm i.d. × 56 cm); running buffer of 20 mM DM-CD with 50 mM potassium dihydrogenphosphate background electrolyte, pH 2.6; capillary temperature of 20°C; applied voltage of 30 kV; on-column detection at 195 nm; and injection pressure of 50 mbar × 3 s. Under these conditions, all four pairs of enantiomers were sufficiently resolved, and eight peaks were observed with resolution factors of greater than 1.5. The calibration curves of all enantiomers showed good linearity over the concentration range of 2.5-10 μg/ml (r =0.999). The present method was used in a survey of marketed products. The resultant chiral contents were reported and the analytical data were also compared with those from HPLC. This method is useful in the simple and rapid analysis of ephedrine derivatives in marketed products.
Key words--chiral separation; ephedrine derivatives; unregulated drugs; capillary electrophoresis; heptakis(2,6-di-O-methyl)-β-cyclodextrin
YAKUGAKU ZASSHI, 124(6),341-347, 2004
Pharmacists active in health care venues need to be able to evaluate generic drugs in terms of effectiveness, safety, and economy to ensure that they are used appropriately. As part of the ongoing study of these factors, we carried out an objective evaluation of information provided for generics. A minimum of 20 commercially available products was considered for each pharmaceutical ingredient. The information subjected to evaluation consisted of the text of drug package inserts and information noted on interview forms. Using our own criteria for evaluating drug information, we attempted to quantify the amounts of information provided. Then, based on the numerical values obtained, we calculated information quantities with reference to drug prices to study the relationship between prices and available information for original drugs and their later-developed, generic equivalents. A total of 14 different pharmaceutical ingredients (327 product items) were considered, with the information quantity for generics amounting to 27.9±17.8-46.3±21.4% (Mean±S.D.) that for the original drugs. Examined on the basis of individual pharmaceutical companies, the corresponding ratio came to 15.1±7.8-62.4±6.4% (Mean±S.D.). For generics, the relationship between drug price (expressed against a value of 1.0 for original drugs) and information quantity (Quai) came to 0.79±0.46-1.90±0.79% (Mean±S.D.). These results clearly point to the importance of evaluating information quantity for generic drugs on a maker-by-maker basis.
Key words--generic drug; drug information; pharmaceutical industry; drug evaluation; necessity factor; drug price
YAKUGAKU ZASSHI, 124(6),349-354, 2004
Daphne genkwa (Thymelaeaceae) has been used as a folk medicine in China. We investigated the effects of D. genkwa and Jyu-So-To on various pharmacologic models in mice including the azoxymethane (AOM)-induced colonic aberrant crypt focus formation assay, ornithine decarboxylase (ODC) activity assay, and two types of mouse ear swelling model. Administration of 236.3 ppm of Jyu-So-To in drinking water significantly suppressed AOM-induced colonic aberrant crypt focus formation (p < 0.05), with an inhibitory ratio of 46.7%. The effects of several extracts with organic solvents of D. genkwa on murine epidermal ODC activity were examined. In particular, the inhibitory ratio of the n-hexane extract was 30.8%. In the 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear edema model in mice, the methanol extract resulted in 56.3% inhibition compared with the control. On the other hand, there are two peaks of responses at 1 h (immediate-phase reaction; IPR) and 24 h (late-phase reaction) in biphasic cutaneous reactions, which are enhanced in the dinitrofluorobenzene model (DNFB). The water extract of D. genkwa clearly inhibited the IPR ear swelling. These results suggest that D. genkwa and Jyu-So-To should be a promising source of antitumor, antiinflammatory, and antiallergy agents.
Key words--Daphne genkwa; Jyu-So-To; antiinflammation; antiallergy; aberrant crypt focus formation; ornithine decarboxylase activity
YAKUGAKU ZASSHI, 124(6),355-364, 2004
Cooperating with hospitals and clinics, the current situation of leftover medicines for outpatients was investigated. Pharmacies played a role in receiving and counting leftover medicines. Pharmacists reported the number of leftover medicines to physicians and facilitated a decrease in the dosing days of prescriptions for the purpose of reusing leftover medicines. Our study, conducted from March 2003 to July 2003 in three pharmacies, found that the saved drug cost and pharmacist technical fees was 489830 yen. There was an income decrease of 69080 yen to the pharmacies. If, as we found in our study, an average medication savings of 40000 yen per pharmacy-month represents a conservative estimate, the total national cost due to medication saving would nearly 20 billion yen per year. The rate of forgetting to take medicine rose as the dosing frequency increased. With a dose of three times a day before every meal, the forgetting probability was 100%.
Key words--leftover medicines; waste medicine; pharmacoeconomics; compliance
YAKUGAKU ZASSHI, 124(6),365-369, 2004
Stagnation of peripheral blood flow is the cause of various diseases. Changes in peripheral blood flow after oral administration of Kampo medicines in mice with betamethasone-induced oketsu syndrome and normal mice were examined using a laser Doppler blood flow meter. The Kampo medicines used were: Toki-shakuyaku-san; Kami-shoyo-san; Keishi-bukuryo-gan; Daio-botanpi-to; Tokaku-joki-to; Goshuyu-to; and Hange-koboku-to. In the oketsu mice, blood flow was improved by single-dose administration of Toki-shakuyaku-san, Kami-shoyo-san, Keishi-bukuryo-gan, Daio-botanpi-to, Tokaku-joki-to, and Goshuyu-to, but only Toki-shakuyaku-san increased blood flow significantly in normal mice. In addition, blood flow decreased after single-dose administration of Keishi-bukuryo-gan, Daio-botanpi-to, and Tokaku-joki-to in normal mice.
Key words--peripheral blood flow rate; laser Doppler flow meter; Kampo medicine; oketsu syndrome; Toki-shakuyaku-san; Keishi-bukuryo-gan