Abstract
Velnacrine maleate is a novel, orally active acetylcholinesterase inhibitor of the acridine class with a longer duration of action than physostigmine. Velnacrine has shown efficacy in the treatment of Alzheimer's disease and in improving both normal and experimentally impaired mnemonic function in animals and humans. To characterize this action further, the present study evaluated velnacrine for its ability to ameliorate the decline in short-term memory associated with aging in non-human primates at two time points after velnacrine administration: (1) 30 min and (2) 24 h. Initially, doses of 1, 2, 4, and 6 mg/kg, PO (free base corrected) were administered once to each of six aged (25–40 years), memory-impaired macaques that had been trained to perform a delayed matching-to-sample (DMTS) paradigm. The dose associated with the greatest improvement in session performance was administered three more times to the same individual. Four of the six monkeys showed improved DMTS performance during the repeated best dose phase (phase 2). Almost all of the improvement occurred during long-delay trials. Compared to placebo trials, velnacrine induced a significant improvement of long delay DMTS (58.0–66.7%, 13.4% of the placebo value). Long delay DMTS remained significantly improved during the test session conducted 24 h following velnacrine administration. Pharmacokinetic analysis following administration of 4 or 6 mg/kg velnacrine to three aged monkeys revealed peak plasma concentrations ranging from 27 to 166 ng/ml, 30–60 min after dosing. Six hours after dosing velnacrine plasma levels decreased to 5.1–11.8 ng/ml; and 24 h after dosing, velnacrine plasma levels were less than the limit of quantitation (5 ng/ml). Thus, the improved DMTS performance observed 0.5–1.5 h after velnacrine administration coincided with the peak absorption of the drug in plasma; however, the improved DMTS performance observed 24 h post-dosing was not explained by plasma levels. Possibly, the 24-h improvement was induced by some secondary process, such as long term potentiation.
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References
Bartus RT (1979) Physostigmine and recent memory: effects in young and aged nonhuman primates. Science 206:1087–1089
Bartus RT (1978) Evidence for a direct cholinergic involvement in the scolpolamine-induced amnesia in monkeys: effects of concurrent administration of physostigmine and methylphenidate with scopolamine. Pharmacol Biochem Behav 9:833–836
Berryman R, Cumming WW, Neven JA (1963) Acquisition of delayed matching in the pigeon. J Exp Anal Behav 6:101–107
Brockmeier D, Luckel G (1992) HOEREP PC Interactive pharmacokinetic program. Hoechst AG Document No. 011502, 4/13/92
Buccafusco JJ, Jackson WJ (1991) Beneficial effects of nicotine administered prior to a delayed matching-to-sample task in young and aged monkeys. Neurobiol Aging 12:233–238
Buccafusco JJ, Jackson WJ, Terry AV (1992) Effects of concomitant cholinergic and adrenergic stimulation of learning and memory performance by primates. Life Sci 51:[PL]7–12
Burgard EC, Sarvey JM (1990) Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus. Neurosci Lett 116:34–39
Chesson SM, Hsu RS, DiLeo EM, Wichman JK, Ellis DB (1989) Pharmacokinetics of velnacrine in rats and dogs. Pharmacologist 31:152
Cumming WW, Berryman R (1965) The complex discriminated operant: studies of matching-to-sample and related problems. In: Mostofsky DI (ed) Stimulus generalization. Stanford University Press Stanford, CA, pp 284–330
Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, Drachman DA, Schneider LS, Whitehouse PJ, Hoover TM, Morris JC, Kawas CH, Knopman DS, Earl NL, Kumar V, Doody RS, and the Tacrine Collaborative Study Group (1992) A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. N Engl J Med 327:1253–1259
Dawson GR, Heyes CM, Iversen SD (1992) Pharmacological mechanisms and animal models of cognition. Behav Pharmacol 3:285–297
DiLeo EM, Turk DJ (1993) Internal bioanalytical communication of Hoechst-Roussel Pharmaceuticals, Inc. 5/22/93
DiLeo EM, Broughan LR, Turk DJ, Effland RC (1993) Quantitation of velnacrine and its monohydroxy metabolites in human plasma by HPLC analysis. Hoechst-Roussel Pharmaceuticals, Inc., Bioanalytical Standard Operating Procedure SOP/CMI0002, 12/1/93
Drachman DA (1977) Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 27:783–790
Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology 87:357–363
Dunnett SB, Evenden JL, Iversen SD (1988) Delay-dependent short-term memory deficits in aged rats. Psychopharmacology 96:174–180
Dunnett SB, Rogers DC, Jones GH (1989) Effects of nucleus basalis magnocellularis lesions in rats on delayed matching and nonmatching to position tasks. Eur J Neurosci 1:395–406
Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NPV, Quirion R (1986) Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease. Neuroscience 19:1279–1291
Fibiger HC (1991) Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence. Trends Neurol Sci 14:220–223
Fielding S, Cornfeldt ML, Szewczak MR, Ellis DB, Huger FP, Davis K, Wilker JC, Shutske GM (1989) HP 029, a new drug for the treatment of Alzheimer's disease: its pharmacological profile. In: Kewitz, Thomsen and Bickel (ed) Pharmacological interventions on central cholinergic mechanisms in senile dementia (Alzheimer's disease). W. Zuckschwerdt Munich, pp 107–117
Flicker C, Bartus RT, Crook TH, Ferris SH (1984) Effects of aging and dementia upon recent visuospatial memory. Neurobiol Aging 5:275–283
Hagan JJ, Morris RGM (1988) The Cholinergic Hypothesis of Memory: a review of animal experiments. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of Psychopharmacology, Vol 20. Plenum Press, New York, pp 237–323
Hsu RS, DiLeo EM, Chesson SM, Ellis DB, Wichmann JK (1989) Determination of velnacrine in plasma and urine by high-performance liquid chromatography. J Chromatogr 494:347–353
Ito T, Miura Y, Kadokawa T (1988) Effects of physostigmine and scopolamine on long-term potentiation of hippocampal population spikes in rats. Can J Physiol Pharmacol 66:1010–1016
Jackson WJ, Buccafusco JJ (1991) Clonidine enhances delayed matching-to-sample performance by young and aged monkeys. Pharmacol Biochem Behav 39:79–84
Jackson WJ, Pegram GV (1970) Comparison of intra- vs. extra-dimensional transfer of matching by rhesus monkeys. Psychon Sci 19:162–163
Jackson WJ, Elrod K, Buccafusco JJ (1989) Delayed matching-to-sample in monkeys as a model for learning and memory deficits: Role of brain nicotinic receptors. Adv Behav Biol 36:39–52
Jacobsen E (1986) The early history of psychotherapeutic drugs. Psychopharmacology 89:138–144
Johns CA, Haroutunian V, Greenwald BS, Mohs RC, Davis BM, Kanof P, Horvath TB, Davis KL (1985) Development of cholinergic drugs for the treatment of Alzheimer's disease. Drug Dev Res 5:77–96
Kwo-On-Yuen PF, Mandel R, Chen AD, Thal LJ (1990) Tetrahydroaminoacridine improves the spatial acquisition deficit produced by nucleus basalis lesions in rats. Exp Neurol 108:221–228
Mohs RC, Davis BM, Johns CA, Mathé AA, Greenwald BS, Horvath TB, Davis KL (1985) Oral physostigmine treatment of patients with Alzheimer's disease. Am J Psychiatry 142:1
Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by anN-methyl-d-aspartate receptor antagonist, AP5. Nature 319:774–776
Murphy MF, Hardiman ST, Nash RJ, Huff FJ, Demkovich JJ, Dobson C, Knappe UE (1991) Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease. Ann NY Acad Sci 640:253–262
Murray TK, Cross AJ, Green AR (1991) Reversal by tetrahydroaminoacridine of scopolamine-induced memory and performance deficits in rats. Psychopharmacology 105:134–136
Oscar-Berman M, Bonner RT (1985) Matching-and delayed matching-to-sample performance as measures of visual processing, selective attention, and memory in aging and alcoholic individuals. Neuropsychologia 23:639–651
Perryman KM, Fitten LJ (1993) Delayed matching-to-sample performance during a double blind trial of tacrine (THA) and lecithin in patients with Alzheimer's disease. Life Sci 53:479–486
Ridley RM, Murray TK, Johnson JA, Baker HF (1986) Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs. Brain Res 376:108–116
Santucci AC, Kanof PD, Haroutunian V (1989) Effect of physostigmine on memory consolidation and retrieval processes in intact and nucleus basalis-lesioned rats. Psychopharmacology 99:70–74
Schneider LS (1993) Clinical pharmacology of aminoacridines in Alzheimer's disease. Neurology 43:S64-S79
Shutske GM, Pierrat FA, Kapples KJ, Cornfeldt ML, Szewczak MR, Huger FP, Bores GM, Haroutunian V, Davis KL (1989) 9-Amino-1,2,3,4-tetrahydroacridin-1-ols; synthesis and evaluation as potential Alzheimer's disease therapeutics. J Med Chem 32:1805–1813
Tanaka Y, Sakurai M, Hayashi S (1989) Effect of scopolamine and HP 029, a cholinesterase inhibitor, on long-term potentiation in hippocampal slices of the guinea pig. Neurosci Lett 98:179–183
Terry AV, Jackson WJ, Buccafusco JJ (1993) Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by young and aged monkeys. Cereb Cortex 3:304–312
Turcan RG, Hillbeck D, Fartley TE, Gilbert PJ, Co RAJ, Troke JA, Vose CW (1993) Disposition of [14C] velnacrine maleate in rats, dogs, and humans. Drug Metab Dispos 21:1037–1047
Wesnes KA, Simpson PM, White L, Pinker S, Jertz G, Murphy M, Siegfried K (1991) Cholinesterase inhibition in the scopolamine model of dementia. Ann NY Acad Sci 640:268–271
Whitehouse PJ, Martino AM, Marcus KA, Zweig RM, Singer HS, Price DL, Kellar KJ (1988) Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 45:722–724
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Jackson, W.J., Buccafusco, J.J., Terry, A.V. et al. Velnacrine maleate improves delayed matching performance by aged monkeys. Psychopharmacology 119, 391–398 (1995). https://doi.org/10.1007/BF02245854
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DOI: https://doi.org/10.1007/BF02245854