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Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients
Author(s) -
Siwers Bo,
Ringberger Vivi-Ann,
Tuck J. Richard,
Sjöqvist Folke
Publication year - 1977
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1977212194
Subject(s) - homovanillic acid , tryptamine , metabolite , serotonin , monoamine neurotransmitter , chemistry , pharmacology , dopamine , endocrinology , medicine , biochemistry , receptor
The bicyclic compound Z‐1‐(4‐bromophenyl)‐1‐(3‐pyridyl)‐3‐dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5‐hydroxytryptamine (5‐HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice dailyfor about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5‐HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawnfrom the patients; and (3) the concentrations of the main metabolites of serotonin (5‐HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5‐hydroxyindoleacetic acid (5‐HIAA), indoleacetic acid (IAA), 4‐hydroxy‐3‐methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5‐HT uptake compared to NE uptake. The inhibitory effect on 5‐HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5‐HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5‐HIAA levels. The e.fects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5‐HT uptake in central monoamine neurons and is there.fore an interesting pharmacologic tool in future central nervous system (CNS) research.