Abstract
The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5–8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%–52%. Homovanillic acid (HVA) concentrations also decreased 27%–55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%–32% from baseline). All three metabolite concentrations reached a nadir approximately 6–10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course peaking 6–10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo. As cimoxatone's preferential effects on catecholamine metabolites were similar to those previously observed with the irreversible MAO-A inhibiting antidepressant, clorgyline, our results are consistent with limited clinical trials data suggesting that cimoxatone may also prove to be an effective antidepressant.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bowers MB Jr (1970) 5-Hydroxyindoleacetic acid in the brain and cerebrospinal fluid of the rabbit following administration of drugs affecting 5-hydroxytryptamine. J Neurochem 17:827–834
Burns D, London J, Brunswick DJ, Pring M, Garfinkel D, Rabinowitz JL, Mendels J (1976) A kinetic analysis of 5-hydroxyindoleacetic acid excretion from rat brain and CSF. Biol Psychiatry 11:125–157
Dollery CT, Davies DS, Strolin Benedetti M (1982) Clinical pharmacology of MD 780515, a selective and reversible MAO-A inhibitor. In: Kamijo K, Usdin E, Nagatsu T (eds) Monoamine oxidase — Basic and clinical frontiers. Excerpta Medica, International Congress Series 564, Amsterdam, pp 221–229
Dollery CT, Brown MJ, Davies DS, Lewis PJ, Strolin Benedetti M (1983) Oral absorption and concentration-effect relationship of tyramine with and without cimoxatone, a type-A specific inhibitor of monoamine oxidase. Clin Pharmacol Ther 34:651–662
Eisler T, Teravainen H, Nelson R, Krebs H, Weise V, Lake CR, Ebert MH, Whetzel N, Murphy DL, Kopin IJ, Calne DB (1981) Deprenyl in Parkinson's disease. Neurology 31:19–23
Fowler CJ, Strolin Benedetti M (1983a) The metabolism of dopamine by both forms of monoamine oxidase in the rat brain and its inhibition by cimoxatone. J Neurochem 40:1534–1541
Fowler CJ, Strolin Benedetti M (1983b) Cimoxatone is a reversible tight-binding inhibitor of the A form of rat brain monoamine oxidase. J Neurochem 40:510–513
Fuller RW, Hemrick-Luecke SK (1981) Elevation of epinephrine concentration in rat brain by LY 51641, a selective inhibitor of type A monoamine oxidase. Res Commun Chem Pathol Pharmacol 32:207–221
Garrick NA, Murphy DL (1980) Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain. Psychopharmacology 72:27–33
Garrick NA, Murphy DL (1981) Differences in the preferential deamination of l-norepinephrine, dopamine and serotonin by MAO in rodent and primate brain. In: Usdin E, Weiner N, Youdim MB (eds) Function and regulation of monoamine enzymes: Basic and clinical aspects. MacMillan, London, pp 517–525
Garrick NA, Murphy DL (1982) Monoamine oxidase type A: Differences in selectivity towards l-norepinephrine compared to serotonin. Biochem Pharmacol 31:4061–4066
Garrick NA, Scheinin M, Chang W-H, Linnoila M, Murphy DL (1984) Differential effects of clorgyline on catecholamine and indoleamine metabolites in the cerebrospinal fluid of rhesus monkeys. Biochem Pharmacol 33:1423–1427
Garrick NA, Seppala T, Linnoila M, Murphy DL (1985) The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey. Eur J Pharmacol (in press)
Herd JA (1969) A new antidepressant — M and B 9302. A pilot study and a double-blind controlled trial. Clin Trials 6:219–225
Huppert R, Kapfhammer H, Ruther E, Hippius H, Strolin Benedetti M, Rovei V, Orluc A (1983) Cimoxatone in the treatment of depressive syndromes. Encephale (Suppl 1) 9: B21
Kan JP, Strolin Benedetti M (1980) Antagonism between long acting monoamine oxidase inhibitors (MAOI) and MD 780515, a new specific and reversible MAOI. Life Sci 26:2165–2171
Kan JP, Strolin Benedetti M (1981) Characteristics of the inhibition of rat brain monoamine oxidase in vitro by MD 780515. J Neurochem 36:1561–1571
Lemperiere T, Lepine JP, Rouillon F, Rovei V, Strolin Benedetti M, Languillat JM (1983) Preliminary results of an open study with cimoxatone in depressed patients. Encephale (Suppl 1) 9: L33
Lipper S, Murphy DL, Slater S, Buchsbaum MS (1979) Comparative behavioral effects of clorgyline and pargyline in man: A preliminary evaluation. Psychopharmacology 62:123–128
Mendis N, Pare CM, Sandler M, Glover V, Stern GM (1981) Is the failure of l-deprenyl, a selective monoamine oxidase B inhibitor, to alleviate depression related to freedom from the cheese effect? Psychopharmacology 73:87–90
Mendlewicz J, Youdim MBH (1983) l-Deprenil, a selective monoamine oxidase type B inhibitor, in the treatment of depression: A double-blind evaluation. Br J Psychiatry 142:508–511
Murphy DL, Wright C, Buchsbaum M, Nichols A, Costa JL, Wyatt RJ (1976) Platelet and plasma amine oxidase activity in 680 normals: Sex and age differences and stability over time. Biochem Med 16:254–265
Murphy DL, Brand E, Goldman T, Baker M, Wright C, van Kammen D, Gordon E (1977) Platelet and plasma amine oxidase inhibition and urinary amine excretion changes during phenelzine treatment. J Nerv Ment Dis 164:129–134
Murphy DL, Lipper S, Campbell IC, Major LF, Slater SL, Buchsbaum MS (1979a) Comparative studies of MAO-A and MAO-B inhibitors in man. In: Singer TP, Von Korff RW, Murphy DL (eds) Monoamine oxidase: Structure, function and altered functions. Academic, New York, pp 457–475
Murphy DL, Lipper S, Slater S, Shiling D (1979b) Selectivity of clorgyline and pargyline as inhibitors of monoamine oxidases A and B in vivo in man. Psychopharmacology 62:129–132
Murphy DL, Cohen RM, Garrick NA, Siever LJ, Campbell IC (1984) Utilization of substrate selective monoamine oxidase inhibitors to explore neurotransmitter hypotheses of the affective disorders. In: Post RM, Ballenger JC (eds) Neurobiology of the mood disorders. Williams and Wilkins, Baltimore, pp 710–720
Palfreyman MG, Huot S, Wagner J (1982) Value of monoamine metabolite determinations in CSF as an index of their concentrations in rat brain following various pharmacological manipulations. J Pharmacol Methods 8:183–196
Poirier F, Susini JR, Deniker P, Rovei V, Strolin Benedetti M, Languillat JM (1983) Cimoxatone in depressed patients: Clinical, pharmacokinetic and biochemical results of an open study. Encephale (Suppl 1) 9: L31
Potter WZ, Murphy DL, Wehr TA, Linnoila M, Goodwin FK (1982) Clorgyline: A new treatment for patients with refractory rapid-cycling disorder. Arch Gen Psychiatry 39:505–510
Rovei V, Chanoine F, Strolin Benedetti M, Zini R, Tillement JP (1983a) Plasma protein binding of the reversible type A MAO inhibitor cimoxatone (MD 780515). Biochem Pharmacol 32:2303–2308
Rovei V, Rigal M, Sanjuan M, Thiola A (1983b) High-performance liquid chromatographic determination of cimoxatone and its O-demethyl metabolite in plasma. J Chromatogr 277:391–395
Scheinin M, Chang W-H, Kirk K, Linnoila M (1983) Simultaneous determination of 3-methoxy- 4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid with high performance liquid chromatography using electrochemical detection. Anal Biochem 131:246–253
Stefanis CN, Alevizos BH, Papadimitriou GN (1982) Antidepressant effect of Ro 11-1163, a new MAO inhibitor. Int Pharmacopsychiatry 17:43–48
Strolin Benedetti M, Kan JP, Keane PE (1979) A new specific reversible type A monoamine oxidase inhibitor: MD 780515. In: Singer TP, Von Korff RW, Murphy DL (eds) Monoamine oxidase: Structure, function and altered functions. Academic, New York, pp 335–340
Strolin Benedetti M, Boucher T, Fowler CJ (1983) The deamination of noradrenaline and 5-hydroxytryptamine by rat brain and heart monoamine oxidase and their inhibition by cimoxatone, toloxatone and MD 770222. Naunyn Schmiedebergs Arch Pharmacol 323:315–320
Waldmeier PC, Baumann PA (1983) Effects of CGP 11305 A, a new reversible and selctive inhibitor of MAO A, on biogenic amine levels and metabolism in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 324:20–26
Wheatley D (1970) Comparative trial of a new mono-amine oxidase inhibitor in depression. Br J Psychiatry 117:573–574
Wood JH (1980) In: Wood JH (ed) Neurobiology of cerebrospinal fluid. Plenum, New York, p 53
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Garrick, N.A., Seppala, T., Linnoila, M. et al. Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone. Psychopharmacology 86, 265–269 (1985). https://doi.org/10.1007/BF00432211
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00432211