Acute toxicity profile of maprotiline in the rat.

The aim of the present study was to examine the toxic effects of single oral administrations of the antidepressant maprotiline at 150 mg/kg or 300 mg/kg using female Sprague-Dawley rats. Body-weight gain was significantly reduced in the group receiving 300 mg/kg on days 1-5 of the study (P<0.01). A significant reduction in food and water intake was observed on days 1 and 2 of the study (P<0.01) in the 300 mg/kg group and on day 1 in the 150 mg/kg group (P<0.05). There was a significant decrease in nocturnal home cage activity over the first five days of the study in the 300 mg/kg group (P<0.01). A significant hypothermic response was observed in both 150 and 300 mg/kg groups at 1, 2 and 4 hr after dosing (P<0.01), that had returned to control values within 8 hr following administration. This study demonstrates that a multi-parameter approach is appropriate for the investigation of high doses of antidepressants in rodents.

Acute lung failure induced by tricyclic antidepressants.

Overdosing of several drugs, such as tricyclic antidepressants, salicylates, and opiates, is known to induce effects like those seen in patients with adult respiratory distress syndrome. By exposing isolated perfused and ventilated rat lungs via the perfusate to six different tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, mianserine, and maprotiline), we investigated possible effects on ventilation (conductance and dynamic compliance), lung perfusion flow, and edema formation. The effects of these substances were pronounced and appeared within 15 min after exposure. Amitriptyline was studied in greater detail and caused a dose-related (0.01-1.0 mM) reduction in ventilation and perfusion flow. At the highest drug concentration pronounced lung edema was observed. Morphological studies were conducted with a transmission electron microscope. The microscopic preparations showed dose-related edema (amitriptyline 0.1 and 1.0 mM). The effects noted in our experimental studies are similar to those described in patients who have taken an overdose of tricyclic antidepressants. This emphasizes the possibility of a noncardiogenic edema component in these patients.

Structure-activity relationships of tricyclic antidepressants and related compounds in the wing somatic mutation and recombination test of Drosophila melanogaster.

Four antidepressants and one neuroleptic drug were tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Three-day-old larvae trans-heterozygous for two linked recessive wing hair mutations (multiple wing hairs and flare) were fed the test compounds in water or solvents mixed with a standard dry food for 48 h. Wings of the emerging adult flies were scored for the presence of spots of mutant cells which can result from either somatic mutation or mitotic recombination. The tricyclic antidepressant clomipramine, which is closely related to imipramine (previously shown to be genotoxic in somatic cells of Drosophila), was clearly genotoxic at concentrations above 10 mM. The structurally related antidepressants lofepramine and mianserin were positive only at 100 mM which is the maximum tolerated dose. The antidepressant maprotiline and the antipsychotic chlorpromazine, which are distinguished from the other compounds by a 6-membered central ring instead of a 7-membered one, were not genotoxic in the same dose range. These results lend further support for the hypothesis that an N atom in the heterocyclic 7-membered ring of the tricyclic molecule is responsible for the genotoxic property of the compounds in Drosophila.

[Comparative study of age-related effectiveness of tri- and tetracyclic antidepressants]. / Sravnitel'no-vozrastnoe izuchenie éffektivnosti trekh- i chetyrekhtsiklicheskikh antidepressantov.

A comparative age-associated study of the efficacy and side effects of amitriptyline and maprotyline was carried out in a group of 93 patients over 50. The health status of the patients was assessed with the aid of Hamilton's depression scale and the scale of side effects on days 0, 7 and 28 of the therapy. It has been discovered that on day 28 maprotyline caused a more complete reduction of depressive disorders as compared to amitriptyline. Maprotyline produced a more intensive action on the anxious component of depression. There were differences in the intensity and range of side effects evoked by amitriptyline and maprotyline. Unlike maprotyline, the antidepressive effect of amitriptyline developed in a group of patients over 70, at later stages of the therapy. Therefore, it is more advisable that tetracyclic antidepressants be used for the treatment of senile patients.

The effect of antidepressants on immune function in mice.

Depression or its treatment with antidepressant agents may have an impact on the normal function of the immune system. To address this issue in an animal model, we studied the effect of maprotiline and desipramine treatment of mice on several immunological activities associated with host resistance to cancer and infections. Our results indicate that chronic maprotiline treatment depressed natural killer (NK) cell function, measured in vivo as clearance of tumor cells from the lung or in vitro as cytolytic activity. Cell-mediated immunity, measured as delayed hypersensitivity in vivo and T and B lymphocyte proliferative responses in vitro, was largely unaffected. Although antidepressant toxicity at high concentrations inhibited T, B, and NK cell activity, it is unlikely that this is the basis for the in vivo effects.

Relative acute cardiovascular toxicity induced by maprotiline, mianserin and nomifensine in conscious rabbits.

The relative acute cardiovascular toxicity among three novel antidepressants: maprotiline, mianserin and nomifensine, has been assessed in conscious rabbits ip injected at 50 mg/kg, throughout a 150 min observation period. No death was observed in mianserin rabbits (n = 6), but 3 in the maprotiline rabbits (n = 8) and 1 death in the nomifensine group (n = 8), within the 2 hours. Cardiac output and renal blood flow were determined by the radioactive Sephadex microspheres method. Cardiac output values were significantly lowered (-29%) at 120 min only in mianserin rabbits, whereas renal blood flow values were reduced by 46.8% (mianserin, 35.8% (maprotiline) and 28% (nomifensine) at 120 min. In mianserin and maprotiline rabbits left ventricular pressure and mean arterial pressure fell significantly, but remained unchanged in nomifensine group. ECG disturbances consisting of ventricular and supraventricular extrasystoles were seen in all the injected rabbits, but QRS widening and right bundle branch block were solely observed after maprotiline and mianserin. Nomifensine rabbits experienced severe seizures with hypocapnia and metabolic acidosis. The drug myocardial/plasma ratio ranged between 59.3 (maprotiline) 13.25 (mianserin) and 0.92 (nomifensine). A rise in plasma catecholamines (epinephrine) was documented after mianserin but not after nomifensin and maprotiline. Nomifensine exhibited much lesser cardiotoxicity than mianserin and maprotiline at this dose (50 mg/kg), but induced more convulsions.

The relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in rabbits in vivo.

1. Conscious or barbiturate-anaesthetized rabbits were slowly infused intravenously with solutions of amitriptyline, imipramine, maprotiline or mianserin, usually until death occurred. 2. Amitriptyline produced death at the lowest dose, imipramine and maprotiline were intermediate while much higher doses of mianserin were required. 3. Convulsions were induced by the antidepressants in all conscious rabbits and the order of potency of the drugs in producing this effect was amitriptyline greater than or equal to imipramine greater than maprotiline greater than mianserin. 4. All four drugs produced a reduction in heart rate and blood pressure in the anaesthetized rabbits and the order of potency in this respect was amitriptyline greater than imipramine greater than maprotiline greater than mianserin. 5. All four drugs produced significant changes in the ECG compared with control rabbits. The P-R interval was lengthened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin) and the QRS complex was widened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin). 7. It is concluded that all four drugs show the toxic effects classically associated with tricyclic antidepressants but the relative toxicity amongst these agents varies considerably and is in the order amitriptyline greater than imipramine greater than maprotiline greater than mianserin.

Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin after intravenous infusion in conscious rabbits.

1. Amitriptyline, imipramine, maprotiline and mianserin were administered intravenously to conscious rabbits. 2. Of the four compounds, mianserin was the least toxic, as assessed by the occurrence of convulsions, cardiotoxicity and eventual death. 3. The applicability of the results from this test system to man is debatable, but the indications are that the relative toxicity of mianserin may be low.

[Behavior pharmacology of maprotiline, a new antidepressant].

The effect of maprotiline (N-methyl-9, 10-ethanoanthracene-9 (10H)-propylamine) on animal behavior was investigated in mice and rats and compared with those of amitriptyline and imipramine. Maprotiline inhibited reserpine hypothermia in mice and tetrabenazine ptosis in rats, while it potentiated the effects of methamphetamine, L-DOPA and apomorphine in mice, in a similar manner to that of amitriptyline and imipramine. Maprotiline was more potent than anitriptyline and imipramine in antagonizing haloperidol-induced catalepsy as well as in suppressing muricide induced by either olfactory bulbectomy or delta-9-tetrahydrocannabinol in rats. Maprotiline potentiated anesthesia induced by thiopental or ether in mice to a lesser degree than did amitriptyline, and failed to counteract the lethal effect of physostigmine or oxotremorine tremor in mice, indicating that this drug has no central anti-cholinergic effect. Maprotiline markedly inhibited hyperemotionality of the rat with either septal lesions or olfactory bulb ablations, suggesting that it does have a tranquilizing effect. Inhibition of conditioned avoidance response of the rat in the shuttle box and reduction of methamphetamine group toxicity with maprotiline were similar to those with amitriptyline. Maprotiline exaggerated pentetrazol convulsion, decreased muscle tone and impaired coordinated motor activity in mice to a much lesser degree than amitriptyline and imipramine. LD50 of maprotiline was approximately twice that of imipramine and three times that of amitriptyline. These results indicate that maprotiline is a new type of antidepressant, has a low toxicity and shares both potent antidepressant and some tranquilizing effect, without possessing central anticholinergic action.