European Journal of Clinical Pharmacology

, Volume 18, Issue 6, pp 483–487 | Cite as

Biochemical effects of zimelidine in man

  • L. Bertilsson
  • J. R. Tuck
  • B. Siwers
Original

Summary

The novel drug zimelidine 50–300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7±10.2 and 82.8±9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r=0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect on 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was also an effect on the dopaminergic system, probably secondary to the action on serotonergic neurons.

Key words

zimelidine norzimelidine depression serotonin noradrenaline dopamine neuronal uptake inhibition 5-HIAA cerebrospinal fluid 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Åberg A, Holmberg G (1979) Preliminary clinical test of zimelidine (H 102/09), a new 5-HT uptake inhibitor. Acta Psychiatr Scand 59: 45–58PubMedGoogle Scholar
  2. Åsberg M, Ringberger VA, Sjöqvist F, Thorén P, Träskman L, Tuck RJ (1977) Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine. Clin Pharmacol Ther 21: 201–207PubMedGoogle Scholar
  3. Bertilsson L (1973) Quantitative determination of 4-hydroxy-3-methoxyphenyl glycol and its conjugates in cerebrospinal fluid by mass fragmentography. J Chromatogr 87: 147–153PubMedGoogle Scholar
  4. Bertilsson L, Palmér L (1973) Determination of isomeric acid dopamine metabolites by mass fragmentography. Life Sci 13: 859–866PubMedGoogle Scholar
  5. Bertilsson L, Atkinson AJ Jr, Althaus JR, Härfast Å, Lindgren JE, Holmstedt B (1972) Quantitative determination of 5-hydroxyindole-3-acetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Anal Chem 44: 1434–1438PubMedGoogle Scholar
  6. Bertilsson L, Åsberg M, Thorén P (1974) Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenalin in depression. Eur J Clin Pharmacol 7: 365–368PubMedGoogle Scholar
  7. Carlsson A, Corrodi H, Fuxe K, Hökfelt T (1969a) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethylmeta-tyramine. Eur J Pharmacol 5: 357–366PubMedGoogle Scholar
  8. Carlsson A, Corrodi H, Fuxe K, Hökfelt T (1969b) Effect of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4-alpha-dimethyl-metatyramine. Eur J Pharmacol 5: 367–373PubMedGoogle Scholar
  9. Hamberger B, Tuck JR (1973) Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma. Eur J Clin Pharmacol 5: 229–235Google Scholar
  10. Mellström B, Tybring G (1977) Ion-pair liquid chromatography of steady-state plasma levels of chlorimipramine and demethylchlorimipramine. J Chromatogr 143: 597–605PubMedGoogle Scholar
  11. Neckers LM, Biggio G, Moja E, Meek JL (1977) Modulation of brain tryptophan hydroxylase activity by brain tryptophan content. J Pharmacol Exp Ther 201: 110–116PubMedGoogle Scholar
  12. Persson S-Å (1979) Effect of chlorimipramine on the synthesis and metabolism of dopamine in the rat striatum. Psychopharmacology 66: 13–17PubMedGoogle Scholar
  13. Ross SB, Ögren SO, Renyi AL (1976) (Z)-Dimethyl-amino-1-(4-bromophenyl)-1-(3-pyridyl) propene (H 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake. Acta Pharmacol Toxicol (Kbh) 39: 152–166Google Scholar
  14. Ross SB, Renyi AL (1977) Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)-and (E)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl) allylamines and their secondary analogues. Neuropharmacology 16: 57–63PubMedGoogle Scholar
  15. Siwers B, Ringberger VA, Tuck JR, Sjöqvist F (1977) Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients. Clin Pharmacol Ther 21: 194–200PubMedGoogle Scholar
  16. Träskman L, Åsberg M, Bertilsson L, Cronholm B, Mellström B, Neckers LM, Sjöqvist F, Thorén P, Tybring G (1979) Plasma levels of chlorimipramine and its demethyl metabolite during treatment of depression. Clin Pharmacol Ther 26: 600–610PubMedGoogle Scholar
  17. Westerlund D, Nilsson LB, Jaksch Y (1979) Straight phase ionpair chromatography of zimelidine and similar divalent amines. Part I: Bioanalysis. J Liquid Chromatogr 2: 373–405Google Scholar

Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • L. Bertilsson
    • 1
  • J. R. Tuck
    • 1
  • B. Siwers
    • 1
  1. 1.Departments of Clinical Pharmacology and Psychiatry, Karolinska InstitutetHuddinge HospitalHuddingeSweden

Personalised recommendations