Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The menopause results from the decreasing production of ovarian estrogens/progestins. This loss of ovarian hormones in 75-85% of women leads to a number of brain-mediated steroid-withdrawal symptoms, the most frequent being hot flushes. Thus, replacement therapy with a brain-enhanced estrogen delivery system (E2-CDS) with sustained release of estradiol (E2) in the brain may be more effective in the treatment of menopausal symptoms than currently used estrogens. The present study was designed to evaluate the effects of E2-CDS vs. E2, on the tail-skin temperature (TST) surge associated with administration of naloxone to morphine-dependent rats, an animal model for menopausal hot flush. Ovariectomized rats received a single or multiple doses of E2-CDS at 1.0 mg/kg body weight or E2 (0.5 mg pellet) weekly for 1 or 3 weeks before temperature recording. The mean maximal elevation in TST of the control animals was 6.4 +/- 0.2 degrees C. A single injection of E2-CDS attenuated the naloxone-induced rise in TST by 25%, while multiple injections resulted in significant attenuation of the rise in TST (3.4 +/- 0.6). By contrast, multiple implants of E2 pellet (3 pellets over 3 weeks) did not affect the surge of TST. Plasma E2 levels in animals treated with E2-CDS were slightly increased to 13 pg/ml for single-injected and to 44 pg/ml for multiple-injected rats. However, the E2-pellet treatment produced plasma E2 levels that were 2-fold greater than the E2 levels produced by multiple injections of E2-CDS. Plasma gonadotropins (LH and FSH) were significantly suppressed with the E2-pellet as well as the single and multiple E2-CDS treatment. Plasma prolactin levels were significantly elevated by E2 pellet and multiple injections of E2-CDS. The kinetic profiles of E2-CDS metabolites in plasma indicated an apparent t1/2 = 8 h for E2-Q+ and 3 h for E2. Collectively, these data support the view that E2-CDS may be potentially useful in the treatment of vasomotor hot flushes.
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PMID:Effects of a brain-enhanced estrogen delivery system on tail-skin temperature of the rat: implications for menopausal hot flush. 190 49

Brain-enhanced delivery and sustained release of estradiol (E2) may be potentially useful in the treatments of vasomotor hot flushes and prostatic adenocarcinoma and for fertility regulation. Therefore, we have evaluated a redox-based estradiol-chemical delivery system (E2-CDS) for the brain. The mechanism of this drug delivery is based on an interconvertible dihydropyridine in equilibrium pyridinium salt redox reaction. In this study, we investigated the dose- and time-dependent effects of E2-CDS on the tissue distribution of E2-Q+ and E2, the inactive (intermediate) and active metabolites, respectively, of the E2-CDS. Ovariectomized rats received a single iv injection of E2-CDS at 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg or the drug's vehicle, 2-hydroxypropyl-beta-cyclodextrin (HPCD), on day 0. Tissue samples including brain and peripheral tissues were then analyzed for both E2-Q+ and E2 at 1, 7, 14, 21, or 28 days following the E2-CDS administration. Initially, both E2-Q+ and E2 were detected in all tissues analyzed. The dose-distribution and time-course study demonstrates that (1) at 24 hr (1 day) after administration of E2-CDS, all tissues showed a dose-proportional increase in concentrations of E2-Q+ and E2; (2) the enzymatic oxidation of E2-CDS to E2-Q+ was dose dependent over the 100-fold dose range examined; and (3) the disappearance of E2-Q+ as well as E2 was slow in whole brain and hypothalamus, with an apparent t1/2 = 8-9 days, while both of these metabolites were rapidly cleared from plasma, liver, fat, anterior pituitary, kidney, lung, heart, and uterus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. I. Tissue distribution. 228 Oct 37