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[Contribution to the effect of tri and tetracyclic antidepressive agents on the heart and blood circulation].

In 47 patients ECG tracings were recorded and cardiovascular values determined before therapy, during treatment with antidepressive agents after it had been in progress for at least 3 weeks, and 4 weeks after withdrawal of therapy. In a further 19 patients in whom antidepressive therapy could not be withdrawn, the same test battery was repeated after an average period of 13 months. No serious disturbances of cardiac rhythm were detected and certain changes in ECG criteria (prolongation of PR interval, widening of QRS complex, prolongation of QTc time and T-wave flattening) proved to be reversible. There was no difference between tricyclic and tetracyclic antidepressive agents. We are nevertheless of the opinion that ECG and cardiac function should be carefully monitored in elderly patients and in those on prolonged therapy with high doses of antidepressives. The results of this study are discussed and compared with previously published findings.

Adolescent

Metabolic fate of 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone), a new antidepressant agent, in man.

1. In man, the antidepressant agent 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone) on oral dosing was mainly eliminated in urine (80% dose in 12 h). 2. Plasma concn. of total radioactivity was max (5.8 micrograms equiv./ml) at 30 min to 1 h after administration and declined rapidly (t1/2, 1.25 h). Unchanged drug accounted for 48, 32 and 13% of plasma radioactivity at 15 min, 1 h and 6 h, respectively. 3. The drug was extensively metabolized. The major urinary metabolites were 3-(3-carboxyphenyl)-5-hydroxymethyl-2-oxazolidinone and a glucuronide of toloxatone. A minor urinary metabolite, characterized as a phenolic derivative, was also excreted conjugated.

Adult

Effects of antidepressant agents on the synthesis of brain monoamines.

The effect of seventeen established or possible antidepressant agents on the synthesis of 5-HT, noradrenaline and dopamine in rat brain has been investigated by measuring the accumulation of 5-hydroxytryptophan and DOPA induced by an inhibitor of the aromatic L-aminoacid decarboxylase (3-hydroxybenzylhydrazine hydrochloride, 100 mg/kg i.p.). All the established inhibitors of 5-HT, noradrenaline and dopamine uptake were found to inhibit the synthesis of the respective monoamines, presumably by influencing a receptor-mediated feedback mechanism. A close correlation appears to exist between blockade of transmitter uptake and inhibition of transmitter synthesis. The results support current ideas on the mode of action of antidepressant agents.

5-Hydroxytryptophan

[Anticalcium activity of several antidepressive agents].

In experiments in white mice and rats the antidepressants pyrazidol (pirlindole), moclobemide and especially tetrindole possess anticalcium activity in tests of calcium chloride-induced lethality in mice and arrhythmia in rats. Tetrindole is as active as verapamil. Imipramine, azaphen and incazane were not active in these experiments. In vitro on isolated intestinal segments of guinea-pigs tetrindole exerts anticalcium action, but in less degree than verapamil. In all probability the anticalcium activity of tetrindole may play some role in the mechanism of action of this compound on the central nervous system.

Animals

[Inhibition and antidepressive agents].

The author distinguishes inhibition as a symptom from inhibition as a processus in the three following situations: a) Antidepressants and melancholic inhibition: the action on inhibition is studied referring to Kielholz classification of antidepressants. The author points out the risk of suicide by suppressing inhibition. b) Antidepressants and chronical psychoses: the author compares effects of antidepressants and stimulating neuroleptics in these syndroms. He thinks that with the two types of psychotropic drugs, one can obtain a desinhibitory effect. But antidepressants can be better used in paranoid personnalities, loss of ego boundaries, and some schizophrenic-like syndroms, when neuroleptics seem to be more desinhibitory in hebephrenics. The author stresses the depressive core in these psychotic personnalities. c) The antidepressant effect has been studied in neurotic depressions. The author describes essentially cases with reinforcement of inhibition as a negative therapeutic reaction by antidepressants. It deals with neurotic depressions evoluting on narcissic personnality back ground.

Adjustment Disorders

Benzo[b]thiophenes, II: Novel benzo[b]thienylhydrazine and 1,3,4-oxadiazole derivatives as potential antidepressant agents.

Three novel series of benzo[b]thiophene derivatives bearing various hydrazone, hydrazine and 1,3,4-oxadiazole moieties were synthesized as potential antidepressant agents. 22 Compounds were evaluated for their in vitro inhibitory effect on monoamine oxidase enzyme (MAO) type A. Several compounds inhibited MAO stronger than pargyline hydrochloride. Maximum inhibitions of 83% and 90% were observed with 1-benzyl-2-(3-chlorobenzo[b]thienyl-2-carbonyl)hydrazine (24) and 1-[2-(4-chlorophenyl)ethyl]-2-(3-chlorobenzo[b]thienyl-2- carbonyl)hydrazine (35), respectively.

Animals

[Postsynaptic attack of tricyclic antidepressive agents in the circulatory system].

Tricyclic antidepressives (TA) exert differential effects on the circulatory system, though all of them have one principle in common: inhibition of back resorption of noradrenaline in the adrenergic synapses. Of more importance, however, seems to be the dose rather than the type of substance used. Smaller doses were found to potentiate the pressoric effects of noradrenaline, while higher doses frequently had an inhibitory action. In rats pretreated with 6-OH-dopamine, only an inhibitory action has been established. It is concluded that the TA must have a postsynaptic influence that becomes effective either through the membrane receptors and/or other factors within the cell.

Amitriptyline