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YAKUGAKU ZASSHI, 123(4),217-224, 2003
Rottlerin-like phloroglucinol derivatives isolated from the pericarps of Mallotus japonicus MUELL. ARG. (Euphorbiaceae) are reviewed. Chemical structures, cytotoxicity, antitumor and antitumor-promoting effects, antiviral activity, anti-HIV-RT activity, and inhibitory activity of activated macrophages (inhibitory activities of NO, prostaglandin E2, tumor necrosis factor-α, and interleukin-6 production) of the phloroglucinol derivatives are described.
Key words--Mallotus japonicus; phloroglucinol derivatives; biological activity; Euphorbiaceae
YAKUGAKU ZASSHI, 123(4),225-248, 2003
Synthetic study of biologically important nitrogen-containing natural products and development of new methodologies and design of leading compounds for new pharmaceuticals are described. The first total synthesis of eudistomines, manzamine C, martefragin A, cerebroside B1b, and symbioramide was accomplished and the absolute configurations of the stereogenic centers were determined. A novel methodology useful for the synthesis of alkaloids that have perhydroisoquinoline ring system such as manzamine A and B, and related alkaloids, nakadomarin A and dynemicin A, is presented. Sphingolipids, 4-stereoisomers of 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, were synthesized and antimalaria activity was investigated. Inhibition of DNA primase by sphingosine and its analogues is described. A new synthetic methodology for alkylation and reduction of imines has been developed, and the first example of a reagent-controlled enantioselective Pictet-Spengler reaction is described. Also novel and convenient methods using transition metal and rare earth metals including alkene metathesis, asymmetric Diels-Alder reaction, imino ene reaction, selective allylic halogenation, enantioselective Pictet-Spengler reaction, and enantioselective physostigmine synthesis are described.
Key words--synthesis; eudistomins; manzamines; nakadomarin A; ring closing metathesis; Yb(OTf)3-TMSCl
YAKUGAKU ZASSHI, 123(4),249-254, 2003
A prior review process was introduced in the Institutional Review Board (IRB) of the University of Tokyo Hospital to facilitate the evaluation of clinical trial plans for new drugs. This study summarizes the results of prior reviews of 73 protocols that were submitted to the IRB during 1999-2000. A total of 955 items were taken up for discussion at the prior review. Among them, 325 (34.0%) were related to the profile/description of investigational drugs themselves, and 252 (26.4%) were related to the trial plan. Major requests related to investigational drugs and given to applicants after the prior review were on adverse reactions, pharmacodynamics, and pharmacokinetics. Items related to patient selection criteria and usage of concomitant drugs were major requests related to the protocol. In some cases, protocols were amended by applications in accordance with the requests. The study shows that the review of new drug clinical trial plans prior to the evaluation by the IRB and examination from a pharmaceutical viewpoint are meaningful and worthwhile.
Key words--prior review; clinical trials; pharmaceutical evaluation; clinical research center
YAKUGAKU ZASSHI, 123(4),255-260, 2003
Terguride has been widely used for the treatment of hyperprolactinemia via partial agonistic action on dopamine D2 receptors in the pituitary. The present study analyzed retrospectively the dopamine D2 receptor binding occupancy (Φ) of terguride. The average Φ value was estimated to be 14.1% after oral administration of the average/standard therapeutic dose of terguride. Taking the intrinsic activity (α) into consideration, the value of α·Φ was 2.33%. These results suggest that the antihyperprolactinemic effect of terguride was elicited despite the low receptor occupancy. Furthermore, we developed a pharmacokinetic/pharmacodynamic model for ascertaining the serum prolactin-lowering effect of terguride, considering both the reversible binding to D2 receptors and the effect on the increase rate in the prolactin level. The developed model fit well with the actual data. Although this model could be improved, it could explain the long duration of the antihyperprolactinemic activity of terguride and might be useful for designing its rational dosage regimen.
Key words--terguride; dopamine D2 receptor occupancy, pharmacokinetic/pharmacodynamic model; antihyperprolactinemic activity; rational dosage regimen
YAKUGAKU ZASSHI, 123(4),261-266, 2003
To avoid serious adverse reactions, especially anaphylactic shock, a skin test to detect allergy is recommended prior to the administration of antimicrobial drugs. Japanese pharmaceutical companies provide skin test kits appropriate for each drug, specifying how to administer and interpret the skin test in a package insert for physicians. However, procedures are not consistent between products. We therefore examined package inserts accompanying skin tests for allergies to antimicrobial drugs in use at the Hiroshima University Hospital, including five penicillin, 13 cephalosporin, and four carbapenem preparations. Preparation of test solutions followed five different protocols. Positive responses were defined by four different criteria, and three different intervals between inoculation and reading times were specified. Such differences in procedures between skin test kits appear likely to confuse physicians when using and interpreting the tests. These results suggest that standardization of skin tests would promote more rational and effective use of antimicrobial drugs.
Key words--skin test; antimicrobial drugs; physician package inserts; positive response criteria; intervals to reading