title: A dihydropyridine conjugate which generates high and sustained levels of the corresponding pyridinium salt in the brain does not exhibit neurotoxicity in cynomolgus monkeys.
abstract: Many drugs can be selectively delivered to the brain by using a dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS). The interaction of these systems with central dopaminergic function was examined in this communication. Castrate female Sprague-Dawley rats when treated with a CDS for estradiol (i.e. 3-hydroxy-17 beta-[( (1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy) estra-1,3,5(10)-triene or E2CDS) exhibit sustained and profound suppression of serum levels of leuteinizing hormone (LH). Treatment of rats with pargyline (80 mg/kg) prior to E2CDS (2 mg/kg) did not mitigate the biological effectiveness of this estrogen indicating at least indirectly that monoamine oxidate (MAO) was not involved in the CDS activation. In a more direct examination, cynomolgus monkeys treated with various repeated doses of E2CDS (cumulative doses of 0.2-40.0 mg/kg) demonstrated neither impaired motor function nor depleted striatal dopamine concentrations. The latter parameter was measured using liquid chromatographic-electrochemical analysis. These experiments support the contention that the CDS is not neurotoxic and further strengthens the strict structure-activity requirements for MPTP-induced neurotoxicity.
authors: Center for Drug Design and Delivery, College of Pharmacy, JHMHC, University of Florida, Gainesville 32610.
authors: M E
authors: ME
authors: Brewster
authors: K S
authors: KS
authors: Estes
authors: R
authors: R
authors: Perchalski
authors: N
authors: N
authors: Bodor
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000378:metabolism / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood; D008251:Macaca / Q000378:metabolism*; D008252:Macaca fascicularis / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D010293:Pargyline / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D004095:Dihydropyridines; D009498:Neurotoxins; D011726:Pyridinium Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D004958:Estradiol; D007986:Luteinizing Hormone; D010293:Pargyline; D008995:Monoamine Oxidase; D004298:Dopamine