Determination of a novel calmodulin antagonist, 3-{2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl}-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, DY-9760e, in human plasma using solid-phase extraction and high-performance liquid chromatography with fluorescence detection

Tachibana, Shuko; Fukano, Aiko; Sudo, Kenichi; Tanaka, Makoto

doi:10.1016/s0378-4347(99)00329-1

Cited by 5 publications

(6 citation statements)

References 6 publications

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“…To quantitatively analyze the DY distribution inside brain, the high-performance liquid chromatography–fluorescence detection (HPLC–FLD) method reported previously was used to determine the DY concentration . The results were illustrated in Figure B,C.…”

Section: Resultsmentioning

confidence: 99%

Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

Wang

Gao

Lü

et al. 2016

ACS Appl. Mater. Interfaces

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Clinical treatment for vascular dementia still remains a challenge mainly due to the blood-brain barrier (BBB). Here, a micelle based on polysialic acid (PSA), which is a hydrophilic and endogenous carbohydrate polymer, was designed to deliver calmodulin antagonist for therapy of vascular dementia. PSA was first chemically conjugated with octadecylamine (ODA), and the obtained PSA-ODA copolymer could self-assemble into micelle in aqueous solution with a 120.0 μg/mL critical micelle concentration. The calmodulin antagonist loaded PSA-ODA micelle, featuring sustained drug release behavior over a period of 72 h with a 3.6% (w/w) drug content and a 107.0 ± 4.0 nm size was then fabricated. The PSA-ODA micelle could cross the BBB mainly via active endocytosis by brain endothelial cells followed by transcytosis. In a water maze test for spatial learning, calmodulin antagonist loaded PSA-ODA micelle significantly reduced the escape latencies of right unilateral common carotid arteries occlusion (rUCCAO) mice with dosage significantly reduced versus free drug. The decrease of hippocampal phospho-CaMKII (Thr286/287) and phospho-synapsin I (Ser603) was partially restored in rUCCAO mice following calmodulin antagonist loaded PSA-ODA micelle treatment. Consistent with the restored CaMKII phosphorylation, the elevation of BrdU/NeuN double-positive cells in the same context was also observed. Overall, the PSA-ODA micelle developed from the endogenous material might promote the development of therapeutic approaches for improving the efficacy of brain-targeted drug delivery and have great potential for vascular dementia treatment.

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Section: Resultsmentioning

confidence: 99%

Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

Wang

Gao

Lü

et al. 2016

ACS Appl. Mater. Interfaces

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“…Estimated plasma levels were calculated from pharmacokinetic data. Plasma concentrations of DY-9760e were measured according to the procedure of Tachibana et al [48] at 6 h of infusion at 0.5 mg/kg/h ($) and 24 h of infusion at 0.1 mg/kg/h (P), respectively. Estimated levels were consistent with the actual values.…”

Section: Discussionmentioning

confidence: 99%

DY-9760e, a Novel Calmodulin Antagonist, Reduces Infarction after Permanent Focal Cerebral Ischemia in Rats

Sato¹,

Takamori²,

Shirasaki³

2004

Pharmacology

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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.

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“…Following dosing, the animals were housed in metabolic cages to collect urine and feces. In rats, 14…”

Section: Excretion Of Radioactivity In Rats and Monkeysmentioning

confidence: 99%

“…While under ether anesthesia, three male rats were instrumented with polyethylene cannulae (SP-10; Natsume, Tokyo, Japan), which were inserted into their bile ducts to allow for bile collection, and were placed in a Bollman cage. After the animals had recovered from anesthesia, 14 C-DY-9760e (4.03 MBq/kg) was intravenously injected as a bolus and the bile, urine, and feces were collected. In a separate enterohepatic circulation study, the bile (10 ml) obtained from these rats was injected at a dose of 110 µg of DY-9760/kg (443 kBq) into the duodenum of the recipient rats with cannulae.…”

Section: Bile Excretionmentioning

confidence: 99%

“…The concentrations of DY-9760 and DY-9836 in the plasma were determined according to the HPLC method previously reported by Tachibana et al [14]. The brain concentrations were determined using the same methodology as used for the plasma; 2 ml aliquot of brain homogenate solution was centrifuged and the supernatant was evaporated to dryness, and then, reconstituted in 2 mL of 50 mmol/L phosphate buffer (pH 5).…”

Section: Measurement Of Drug Concentration In the Plasma And Brainmentioning

confidence: 99%

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Pharmacokinetics and Disposition of DY-9760e, a Novel Calmodulin Antagonist, in Rats and Monkeys

Tachibana¹,

Fujimaki²,

Tachibana³

et al. 2011

Arzneimittelforschung

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DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, CAS 162496-41-5) is a novel calmodulin antagonist that is being evaluated for the treatment of ischemia. The objective of this study was to characterize the pharmacokinetics and disposition of DY-9760e in rats and monkeys. After a 6 h continuous infusion at 1 mg/kg/h to male rats, the plasma concentration of unchanged DY-9760, as the anhydrous free base of DY-9760e, declined with a terminal half-life of 3.0 h. In monkeys, the plasma concentration of DY-9760 following a 4 h continuous infusion at 1 mg/kg/h declined with a terminal half-life of 3.8 h. Total clearance was 18.3 ml/min/kg in rats and 16.7 ml/min/kg in monkeys. The pharmacokinetics of DY-9760e was linear within a dose range from 1 mg/kg to 16 mg/kg in monkeys. After intravenous bolus administration of 14C-DY-9760e to rats, the radioactivity was widely distributed throughout the body except for the brain and testis. In the brain, which is the target organ of this compound, the concentrations of unchanged DY-9760 in rats were much lower than the corresponding plasma concentrations. These results indicated that the permeability of DY-9760 into the brain was restricted. In contrast, the brain concentrations of the N-dealkylated metabolite DY-9836 were approximately 2- to 3-fold higher than those observed in the plasma. The administered radioactivity was excreted mostly in the feces (95.2% in rats, 83.6% in monkeys), and the biliary excretion of the radioactivity in bile duct-cannulated rats was 86.2% within 48 h, part of which (11.1%) was re-absorbed. The urinary excretion of unchanged DY-9760 was less than 0.5% in both species. The metabolic profile characterized by thin-layer chromatography demonstrated that most of the radioactivity in the urine and bile referred to many polar metabolites. These results indicate that DY-9760e is eliminated mainly through hepatic metabolic clearance in both rats and monkeys.

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Cited by 5 publications

References 6 publications

Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

DY-9760e, a Novel Calmodulin Antagonist, Reduces Infarction after Permanent Focal Cerebral Ischemia in Rats

Pharmacokinetics and Disposition of DY-9760e, a Novel Calmodulin Antagonist, in Rats and Monkeys

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