| Project/Area Number |
61870087
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Okayama University, Faculty of Pharmaceutical Sciences |
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Principal Investigator |
WATAYA Yusuke Okayama University, Faculty of Pharmaceutical Sciences, 薬学部, 助教授 (90127598)
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| Co-Investigator(Kenkyū-buntansha) |
福川 清史 東洋醸造K.K., 医薬品研究所, グループリーダー
MATSUDA Akira Hokkaido University, Facultyh of Pharmaceutical Sciences, 薬学部, 助教授 (90157313)
ISHII Akira Okayama University Medical School, 医学部, 教授 (40012752)
FUKUKAWA Kiyoshi Toyo Jozo Co.Ltd, Medical Research Laboratory
早津 彦哉 岡山大学, 薬学部, 教授 (10012593)
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| Project Period (FY) |
1986 – 1987
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| Project Status |
Completed (Fiscal Year 1987)
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| Budget Amount *help |
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 1987: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1986: ¥4,800,000 (Direct Cost: ¥4,800,000)
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| Keywords | Anti-parasitic agents / Anti-Leishmania / Nucleoside analogues / Carbocyclic inosin 3'-deoxy-3'-fluoroinosine / 3'-Deoxyinosine / Leishmania tropica, / 核酸代謝拮抗剤 / 熱帯病 / 化学療法剤 / イノシンアナログ / ヌクレオシド / 3'-デオキシイノシン |
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| Research Abstract |
A promising approach for the development of chemotherapeutic agents possessing selective toxicity is the one based on certain unique features in structure or function of the parasite that differ from those of the host cells. Leishmania are incapable of synthesizing purine de novo and are thus dependent on the host for the source of performaed purine. This qualitative difference in the enzymes of purine salvage and interconversion pathway between host and parasite suggests a rational approach towards the design of agents selectivitgy toxic in the parasite. We found that 3'- deoxyinosine. carbocyclic inosine, 7-deazainosine and 3'-deoxy-3'-fluoroinosine area potent inhibitors of promastigotes of Leishmania but significantly less toxic mammalian cells.
In the present experiments, J774.1, a mouse macrophage line, was cultured in RPMI 1640 medium containing lipopolysaccharide. The adherent cells were exposed to promastigotes of L. donovani for 1 day, and treated with the drug. The results indicate that inosine analogues are active against amastigotes of L. donovani in vitro.
The BALB/C mice infected with L. donovani were treated with inosine analogues (3'- deoxyinosine, carbocyclic inosine, 7-deazainosine and 3'-deoxy-3'-fluoroinosine) for appraising those therapeutic effect. The mice infected with L. donovani promastigotes were treated with 5 different doses of each drug administered on alternative days. Two weeks after the impression smear of the liver was prepared to determine the parasite load which was expressed as LDU by 1000 hepatic cell nuclei. In the mice infected with L. donovani, 3'-deoxyinosine 100 mg/Kg I.V showed about 78 % effect as compared with control group, and carbocyclic inosine 100 mg/Kg I. V. showed 92 % effect. 7-Deazainosine and 3'-deoxy-3'-fluoroinosine were also effective against the infected mice.
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