title: [Development of a therapeutic agent for Menkes disease: solubilization of a copper-disulfiram complex].
abstract: Menkes disease (MD) is a neurodegenerative disorder characterized by copper deficiency. It is caused by defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. We investigated the effects of combination therapy with copper and disulfiram, a known lipophilic chelator. We synthesized a copper-disulfiram complex (Cu-DSF) and determined its crystal structure by X-ray crystallographic analysis. Unfortunately, Cu-DSF was not orally bioavailable due to its lipophilicity. We therefore planned to use cyclodextrin as a solubilizing agent to increase the water solubility of Cu-DSF. After comparisons of the effects of cyclodextrins (α, β, γ), it was found that addition of β-cyclodextrin (β-CyD) increased the solubility of Cu-DSF. Moreover, the modified β-CyD, hydroxypropyl-β-cyclodextrin, was yet more effective as a solubilizing agent. For the development of a convenient method to determine the concentration of Cu-DSF included by β-cyclodextrins, a standard curve based on UV-visible(VIS) absorption was derived.
authors.affiliation: Faculty of Pharma Sciences, Teikyo University.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hoshi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tani
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tabata
authors.forename: Shintaro
authors.initials: S
authors.lastname: Wakamatsu
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Munakata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
authors.forename: Tetsuta
authors.initials: T
authors.lastname: Oshitari
authors.forename: Hideaki
authors.initials: H
authors.lastname: Natsugari
authors.forename: Hideyo
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003505:Cyclodextrins / Q000737:chemistry; D004221:Disulfiram / Q000737:chemistry*; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D003300:Copper; D004221:Disulfiram