title: Effective plasma concentration of a novel Na+/Ca2+ channel blocker NS-7 for its cerebroprotective actions in rats with a transient middle cerebral artery occlusion.
abstract: The effect of a novel Na+/Ca2+ channel blocker NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride] on the cerebral infarction, edema, and mortality was examined in rats with a transient middle cerebral artery occlusion (MCAO), and the effective plasma concentration of this compound for producing the cerebroprotective action was subsequently determined. MCA was occluded by inserting a thread through internal carotid artery for 2 h, and then recirculated for 6 h. NS-7 (0.125-1 mg/kg), when injected i.v. immediately after recirculation, significantly reduced the infarct volume as well as the cerebral edema. Delayed treatment with NS-7 at 1 h after recirculation produced an equivalent inhibition of the infarction, and was still effective, although to a lesser extent, when injected at 2 h but not 3 h after recirculation. Glycerol (4 g/kg) suppressed the cerebral edema but did not reduce the size of cerebral infarction in the cerebral cortex or striatum. Therefore, it is likely that the suppression of brain edema does not always lead to the reduction of the infarct size. NS-7 treated in combination with glycerol further decreased the water content in the occluded brain. Moreover, NS-7 significantly lowered the mortality observed up to 10 days after a transient MCAO. From these data, it is suggested that the presence of NS-7 in plasma during 1 to 3 h after recirculation is important for producing the neuroprotective action. To determine the pharmacologically effective plasma concentration of NS-7, the effect of continuous infusion of this compound on the cerebral infarction was examined. Infusion of NS-7 at 0.3 mg/kg over 2 h, starting immediately after recirculation, significantly reduced the infarct size. Its plasma concentration during 1 to 3 h was 14.5 to 28.5 ng/ml (36.9-72.3 nM). From these finding it is suggested that NS-7 has a potent anti-infarct action in addition to antiedema action in the rat transient MCAO model. Moreover, its effective plasma concentration was assumed to be 36.9 to 72.3 nM.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Nishiohji Hachijo Minami-ku, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Tamura
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: T
authors.initials: T
authors.lastname: Seto
authors.forename: K
authors.initials: K
authors.lastname: Nonaka
authors.forename: H
authors.initials: H
authors.lastname: Mukai
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D002343:Carotid Artery, Internal / Q000502:physiology; D004594:Electrophysiology; D005990:Glycerol / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008026:Ligation; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D018696:Neuroprotective Agents / Q000097:blood / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers
chemical_list: C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D005990:Glycerol