IDR-90104

Estredox is a novel brain-targeted delivery system for estradiol (E2). The mechanism of this estradiol-chemical delivery system (E2-CDS) is based on an interconvertible dihydropiridine <--> pyridinium salt carrier (targetor) attached to E2. After administration of the E2-CDS, the targetor moiety is oxidized to a quaternary pyridinium salt (E2-Q+). Here we demonstrate that a single i.v. injection with E2-CDS (3 mg/kg) resulted in sustained presence of E2-Q+ in three various brain regions. The sustained and gradual release of estradiol from E2-Q+ is reflected by the time-course of plasma estrogen level. At the end of repeated administration of E2-CDS (daily once 0.3 mg/kg i.v. for 10 consecutive days) we found a sharp decrease in the levels of plasma estradiol followed by a gradual decrease. The levels of E2-Q+ in the investigated brain regions decreased gradually from the first post-treatment day, however, a detectable amount of E2-Q+ was still present in the hypothalamus, striatum, and cortex even on the 24th post-treatment day. Strikingly different plasma estradiol levels were found in the groups of orchidectomized rats that received daily i.v. injections of estradiol benzoate (E2-BZ). The plasma estradiol levels in these animals were much higher compared to E2-CDS-treated animals throughout the treatment period but the level sharply dropped immediately after the treatments. In contrast to the E2-CDS-treated animals there was no estradiol in any of the brain regions of E2-BZ-treated rats on the 1st and 2nd post-treatment day. All of these data are in line with the long-lasting pharmacological effects of E2-CDS-treatment on estrogen-mediated functions in castrated rats and give further experimental support for brain-targeting estrogen-treatment approach as opposed to the traditional estrogen replacement therapy.

The present study examined the dose- and time-dependent central effects of an estradiol chemical delivery system cyclodextrin complex (E(2)-CDS-CD) on the reestablishment of copulatory behavior of castrated male and ovariectomized female rats with concomitant determination of the blood luteinizing hormone (LH) and E(2) levels. In orchidectomized males, Estredox, after single doses of 0.3 and 3.0 mg/kg iv, reestablished the mounting and intromission up to 4 weeks. The LH suppressive effect lasted to Day 7 and 28, respectively. After repeated administration for 10 days at a dose of 0.01mg/kg iv, significant effect was obtained by Day 14. Ovariectomized females were treated iv daily for 5 days either with E(2)-CDS-CD, estradiol benzoate (EB) or vehicle, and the lordosis quotient was determined. At a dose of 0.03 mg/kg the duration of EB's effect was 10 days shorter and only one-third of that of E(2)-CDS-CD. The LH suppression lasted to Day 18. On the other hand, after EB treatment there was no significant decrease in LH levels. The low plasma E(2) levels indicated fast rate of peripheral elimination in both males and females. The brain-targeting E(2) indicates better efficacy and increased safety in replacement therapies because of the reduced peripheral side effects.