YAKUGAKU ZASSHI
 Abstracts 
Vol.124, No. 2 (2004)

--Reviews--

Asymmetric Reactions Based on Activation and Structure Control of Molecule
-Asymmetric Reaction of Lithiated Nucleophiles-

Kiyoshi TOMIOKA

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

The methodology we developed relies on an external chiral coordinating reagent that forms a deaggregated chelate complex with organolithium reagents. Under the positive control of a chiral dimethyl ether of stilbenediol 4, an asymmetric conjugate addition reaction of organolithium reagents with unsaturated imines and esters proceeded successfully to yield the corresponding addition products with reasonably high stereoselectivity. The sense of stereochemistry is predictable based on a coordination model. The methodology has been extended to a catalytic asymmetric 1,2-addition reaction of organolithium reagents with imines. An enantiotopic group differentiating the opening of cyclohexene oxide with organolithium was also mediated by a chiral ligand. The asymmetric Horner-Wadsworth-Emmons reaction of phosphonates and Peterson reaction of α-silylester with 4-substituted cyclohexanone were another successful extension of the methodology. A three-component reagent of lithium ester enolate, lithium amide, and chiral diether reacts with imines to afford β-lactam with reasonably high enantioselectivity. Tridentate aminoether ligands were also shown to affect the catalytic asymmetric addition of lithium ester enoaltes to imines, giving β-lactams with high enantioselectivity. Asymmetric conjugate addition of lithium amide to enoates was mediated by a chiral diether ligand to give the β-aminoester with high yield and enatioselectivity. The methodology has been successfully applied to an asymmetric synthesis of biologically potent compounds. Dihydrexidine, a promising anti-Parkinsonism candidate, and salsolidine, a representative isoquinoline alkaloid, have been synthesized using asymmetric addition reactions of organolithium reagents as the key steps.

Key words--chelation; organolithium; lithium enolate; ligand; coordination; addition reaction

--Reviews--

Preparation of a Gel-Forming Ointment Base Applicable to the Recovery Stage of Bedsore and Clinical Evaluation of a Treatment Method with Different Ointment Bases Suitable to each Stage of Bedsore

Masato SHIGEYAMA

Department of Pharmacy, Takayama Red Cross Hospital, 3-11 Tenman-cho, Takayama City 506-8550, Japan

An ointment base for better treatment of bedsores was developed to improve the release rate of minocycline hydrochloride (MH) and the water absorption capacity using various types of hydrophobic to hydrophilic ointment bases. The effect of purified lanolin (PL) on the release behavior of MH from a hydrophilic ointment (HO) base was the primary focus. It was found that the drug release rate from the ointment base was modified according to the method of preparation of the ointment base and the type of cyclodextrins admixed. The physicochemical properties, such as viscosity, elution volume, and water absorption, of the ointment base were also modified by those factors. To develop an ointment formulation suitable for the recovery stages of bedsores, including the proliferation period of granulation and the formative period of epidermis, the physicochemical properties of Macrogol ointment containing various hydrophilic polymers, which have gel-forming ability, were tested. A novel ointment base suitable for the treatment in the recovery stage of bedsores was developed using hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC). Considerably sustained release of MH (T₅₀ of 170 at a min) was attained with a macrogol ointment mixed with HM-HPMC and Carbopol formulation ratio of 3 : 7. We clinically evaluated the effectiveness of bedsore treatment by applying different ointment bases to patients with different stages of bedsores.

Key words--gel-forming ointment; bedsore; carbopol; hydrophobically modified hydroxypropyl methylcellulose; controlled release

--Reviews--

Metabolic Aspects of Endotoxin as a Model of Septic Shock-Approached from Oxidative Stress-

Shuhei SAKAGUCHI

First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca²⁺, Zn²⁺, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca²⁺ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms.

--Regular Articles--

Items of Concern Associated with Source Document Verification of Clinical Trials for New Drugs

Risa TAKAYANAGI,^*,a Kaori WATANABE,^b Ayako NAKAHARA,^b Hitoshi NAKAMURA,^a Yasuhiko YAMADA,^a Hiroshi SUZUKI,^aYoshihiro ARAKAWA,^b Masao OMATA,^b and Tatsuji IGA^a

Departments of Pharmacy,^a and Clinical Research Center,^b The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

In the present study, we analyzed concerns of the sponsors of clinical trials regarding source document verification (SDV) procedures performed at the University of Tokyo Hospital during April 1999 and March 2001, with special focus on the differences in description between the source document and case report form (CRF). Of 132 SDV procedures (78 protocols, 496 cases), the sponsors had problematic concerns with 348 cases (70.2%) totalling 693 items, which consisted of description inconsistencies between the source documents and the CRF (41.4%), lack of description in the CRF (39.8%), and lack of description in the source documents (8.8%). The most frequently found inconsistencies between the source documents and CRF were concerning items regarding observations, laboratory examinations, and compliance, which were associated with misdescription of clinical data and/or items for evaluation in the CRF. It was also revealed that the frequent lack of description in the CRF was associated with patient history and/or complications, adverse events, and concomitant drugs and/or therapy. In contrast, the frequent lack of description in the source documents was associated with items concerning patient background, observations, and informed consent. Further, we found that submission of a report of deviation from the protocols was required for 4.0% of the claims. These results suggest the necessity of better data management during the practice of clinical trials for the purpose of maintaining the quality of clinical trials.

--Notes--

Survey of Mixing Commercially Available Corticosteroid Ointments with Other Ointments and the Anti-inflammatory Activity of the Admixtures

Junko KIZU,^a Wataru ICHIHARA,^a Eriko TOMONAGA,^a Junko ABE,^aTomoko WATANABE,^b Tadao INOUE,^b and Seiji HORI^c

Department of Practical Pharmacy, Kyoritsu University of Pharmacy,^a 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Department of Pharmacy, St. Luke's International Hospital,^b 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Department of Pharmacology (I), Jikei University School of Medicine,^c 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan

We surveyed the prescriptions from the Department of Dermatology in a city hospital to determine the status of the use of admixtures of corticosteroid ointments with other ointments. Thirty percent of the prescriptions of topical ointment therapy for outpatients of the Department were for admixture ointments. They were prescribed for patients aged 2 months to over 90 years. The mixing ratios of corticosteroid ointments with other ointments were 1 : 1 to 5 : 3. One-to-one dilution was most frequently used. Corticosteroid ointments classified into strongest, very strong, strong and medium groups were used for admixtures. We studied the effect of admixture ointments on carrageenan-induced edema in rat hind paws to assess the anti-inflammatory activity of these admixtures. Dermovate^TM, its 1 : 3-diluted preparation with white petrolatum and 1 : 1-diluted preparation of Lidomex^TM with white petrolatum exerted significant anti-inflammatory activity (p < 0.05, compared with white petrolatum). These results suggest that the admixtures of different corticosteroid ointments have different anti-inflammatory activities. When admixture preparations are used, the properties of the corticosteroid and other ointments should be taken into account individually.