DY-9760e, a Novel Calmodulin Antagonist, Reduces Infarction after Permanent Focal Cerebral Ischemia in RatsSato T. · Takamori H. · Shirasaki Y.
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), a novel calmodulin antagonist, provides effective protection against Ca2+ ionophore-induced cytotoxicity and brain injury induced by transient focal ischemia. In this study, we evaluated the effect of DY-9760e on ischemic infarct volume in rats subjected to permanent focal ischemia. DY-9760e (0.5 mg/kg/h for 6 h) significantly reduced the infarct volume when administered immediately after middle cerebral artery occlusion. Furthermore, this neuroprotection was also exerted by treatment with a 3-hour delay, implying that the therapeutic time window for this compound is at least 3 h. In addition, although treatment with 0.1 mg/kg/h for 24 h was ineffective, the combination of a loading dose of 0.3 mg/kg/h for 2 h followed by 0.1 mg/kg/h for 22 h yielded a significant reduction in infarct volume. Thus, prolonged infusion preceded by a loading dose is an efficacious dosing regimen for DY-9760e, especially at a low infusion rate. These data demonstrate the substantial neuroprotective effect of DY-9760e in a permanent focal ischemia model and indicate that this neuroprotectant may be of therapeutic value for the treatment of acute stroke.
© 2004 S. Karger AG, Basel
Yasufumi Shirasaki, PhD
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd.
1-16-13, Kitakasai, Edogawa-Ku
Tokyo 134-8630 (Japan)
Tel. +81 3 3680 0151, Fax +81 3 5696 8718, E-Mail firstname.lastname@example.org
Received: July 16, 2003
Accepted: September 25, 2003
Number of Print Pages : 8
Number of Figures : 5, Number of Tables : 0, Number of References : 48
Pharmacology (International Journal of Experimental and Clinical Pharmacology)
Founded 1959 as ‘Medicina Experimentalis’, continued 1965–1967 as ‘Medicina et Pharmacologia Experimentalis’; Founder: R. Domenjoz (1959–1977); Successors: B.B. Brodie (1968–1977); K. Lederis (1973–1985); K.-F. Sewing (1978–1998); E.S. Vesell (1970–2000)
Vol. 71, No. 1, Year 2004 (Cover Date: May 2004)
Journal Editor: J. Donnerer, Graz; M.L. Billingsley, Hershey, Pa.; T. Iijima, Akita
ISSN: 0031–7012 (print), 1423–0313 (Online)
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