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PubMed1991

Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline.

The concentrations of maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of MAP in rats. MAP was eliminated in a biexponential manner from the serum and monoexponentially from the brain. The DMAP declined monoexponentially from the serum and brain regions. No significant difference was observed in elimination among the eight brain regions examined. In the brain, MAP distributed unevenly after chronic administration, whereas DMAP showed an even distribution. In the acute administration, the AUCbrain: AUCserum ratio of MAP was similar to that of DMAP, and the AUCDMAP: AUCMAP ratio in the serum was almost equal to that in the brain, indicating equivalent ability of MAP and DMAP to penetrate into the brain. After chronic administration, the AUCDMAP value in the serum increased 4.1 times, whereas no marked change was observed for MAP. There was no evidence of enhanced N-demethylation activity from in vitro metabolism study, suggesting that the enhanced AUCDMAP value was not attributable to the enhancement of drug metabolizing activity. Although the AUCMAP value in the brain, as well as in the serum, increased slightly, the AUCDMAP in the brain increased 2.3 times, showing less increase than that in the serum. These findings suggest inhibited distribution of DMAP into tissue, including brain regions, after chronic administration. The pharmacokinetics of the demethylated metabolite DMAP is affected more than that of MAP by chronic administration of MAP.

Animals↗
PubMed1992

Pharmacokinetic analysis of maprotiline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of maprotiline.

Compartmental model analysis by simultaneous curve fitting was used to ascertain the pharmacokinetic relationship between maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and brain of rats after single or multiple oral administrations of MAP. The extent of bioavailability and the fraction metabolized to DMAP after acute oral administration were 0.202 and 0.065, respectively, indicating first-pass metabolism of MAP. Although the estimated transfer rate constants to and from the brain (k(in) and k(out)) of MAP were higher than those of DMAP, the k(in):k(out) ratio for MAP was similar to that for DMAP. These findings indicate the equivalent ability of MAP and DMAP to penetrate into the brain after acute oral administration. The estimated values of bioavailability and fraction metabolized to DMAP increased 2.6 and 1.7 times, respectively, after chronic administration of MAP. These findings are attributable to inhibited distribution in tissue. The k(in) and k(out) values of MAP decreased, whereas those of DMAP showed no marked change. Therefore, the k(in):k(out) ratio for MAP decreased, whereas that for DMAP did not change. These results suggest that the permeability of MAP into the brain might be affected and that of DMAP is not modified by chronic administration of MAP.

Administration, Oral↗
PubMed1990

Response to total sleep deprivation before and during treatment with fluvoxamine or maprotiline in patients with major depression--results of a double-blind study.

To test the hypothesis that the antidepressant effects of total sleep deprivation (TSD) are linked to the serotonergic and/or noradrenergic system the authors carried out a double-blind study (fluvoxamine versus maprotiline) in 42 inpatients with endogenous depression (ICD). Patients were randomized to a four-week treatment with either fluvoxamine (100-300 mg/day) or maprotiline (100-300 mg/day). In addition, patients underwent a TSD procedure before and after one week of antidepressant medication. There was a statistically significant reduction of depression ratings (HDRS) in both the fluvoxamine and maprotiline group. The day-1 response to TSD before antidepressive medication was not associated with a clear relationship to the outcome after four weeks of treatment with either fluvoxamine or maprotiline. On the other hand, the day-2 response to TSD was significantly correlated with a good outcome to subchronic treatment with maprotiline. Furthermore, the results of the authors' data suggest that a favorable short-term outcome of TSD may be connected to antidepressants enhancing the serotonergic neurotransmission. The global comparison between fluvoxamine and maprotiline revealed that the group of patients treated with fluvoxamine had a significantly higher efficiency index (CGI) than the maprotiline group; fluvoxamine was rated to be tolerated excellently in 70% of the patients whereas this percentage was only 43% in the maprotiline group. There was also significantly more vertigo and dry mouth in the maprotiline group whereas the fluvoxamine group was rated to have significantly more sleep disturbances during the trial.

Adult↗
PubMed1975

[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.

Aggression↗
PubMedDate not supplied

Chemistry, pharmacology, pharmacokinetics, adverse effects, and efficacy of the antidepressant maprotiline hydrochloride.

Maprotiline, a tetracyclic antidepressant with sedative properties, exhibits strong inhibitory effects on norepinephrine uptake across nerve cell membranes but interferes relatively little with serotoninergic mechanisms. The biological half-life of unchanged maprotiline in blood averages 43 hours. Though several studies suggest a more rapid onset of antidepressant effects with maprotiline than with amitriptyline or imipramine, this issue remains unresolved. The adverse effect profile of maprotiline is similar to that of the tricyclic antidepressants, except that rashes are about twice as frequent with maprotiline as with amitriptyline or imipramine. The most frequent adverse reactions are anticholinergic effects and sedation. Data suggest less frequent and severe anticholinergic side effects with maprotiline than with amitriptyline. Maprotiline may be less likely to induce orthostatic hypotension and tachycardia than standard tricyclic antidepressants, but clinically important differences in cardiovascular effects remain to be conclusively demonstrated. Many patients benefit from the convenience of once daily dosing. Maprotiline is comparable in antidepressant efficacy to the tricyclic antidepressants.

Anthracenes↗
PubMed1980

GLC-mass spectrometric determination of maprotiline and its major metabolite using stable isotope-labeled analog as internal standard.

A quantitative GLC-mass spectrometric assay was developed for the determination of maprotiline and its major metabolite, desmethylmaprotiline, in animal and human plasma. The assay utilizes selective-ion focusing to monitor, in a GLC effluent, the fragment ions and the base peaks of maprotiline and desmethylmaprotiline trifluoroacetamides generated by electron-impact ionization. Maprotiline-d3 was the internal standard. The assay can measure 2 ng of maprotiline (and the metabolite)/ml of plasma with approximately 5% precision. The curves relating the amounts of maprotiline and the metabolite added versus the amounts experimentally found over a large concentration range were linear with nearly zero intercepts and slopes of 0.99 +/- 0.01 and 0.98 +/- 0.02, respectively. The method was used to study the pharmacokinetic pattern of the drug in rabbits as well as to analyze intact maprotiline and the metabolite in patients maintained on therapeutic doses of maprotiline. Assay specificity was confirmed by complete consistency of the mass spectra of maprotiline and desmethylmaprotiline with those of the authentic materials.

Animals↗
PubMed1983

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.

Animals↗
PubMed1983

Lack of interaction between the tetracyclic antidepressant maprotiline and the centrally acting antihypertensive drug clonidine.

The well known interaction between tricyclic antidepressants and the centrally acting antihypertensive drug clonidine, namely impairment of the antihypertensive effect of clonidine, is thought to be related to blockade of noradrenaline uptake or competition at central alpha-receptors. The tetracyclic antidepressant maprotiline has been shown to be a potent inhibitor of noradrenaline uptake and it might, therefore, interfere with the antihypertensive action of clonidine. The possible interaction of clonidine and maprotiline was studied in 8 healthy subjects using doses in the therapeutic range. The study followed a double-blind, cross over design, in which clonidine alone (0.3 mg p.o.), clonidine (0.3 mg p.o.) plus maprotiline (100 mg in 4 divided doses over 22 h), maprotiline alone (100 mg in 4 divided doses over 22 h) and placebo were given by the double-dummy technique. Several pharmacodynamic parameters were measured for 12 h after administration of the drugs (supine and erect blood pressure, heart rate, saliva production and sedation). Concurrent administration of maprotiline did not alter the effect of clonidine and neither the size nor the time of the maximal response after clonidine were influenced by maprotiline. It is concluded that [1] blockade of noradrenaline uptake is not associated with the interaction of tricyclic antidepressants and clonidine, and [2] maprotiline should be preferred to tricyclic antidepressants in hypertensive patients on clonidine therapy if a concomitant depressive illness has to be treated.

Adult↗
PubMed1979

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.

Amitriptyline↗
PubMed1975

Pharmacological studies of drug action on CNS, with special reference to effects of maprotiline.

The effects of maprotiline, mainly on the CNS, were examined and compared with those of imipramine, methamphetamine and chlorpromazine. In the repeated administration and the stroboscope studies, maprotiline exhibited actions to increase behavioral activities of animals, just like amphetamine and imipramine. This appears to attest to pharmacological effects of maprotiline as an anti-depressant. It is noted, however, that whereas maprotiline shows a slight anti-apomorphine action in dogs and an inhibition of the spinal reflex action potential in cats, such actions are not recognized in other anti-depressants of the tricyclic groups including imipramine, amitriptyline, etc. These differences suggest the tranquilizing action of maprotiline at work, probably forming a specific pharmacological feature of maprotiline. Also, maprotiline increases body weight of rats strikingly, which seems to offer a wide range of clinical applications of this drug.

Action Potentials↗
PubMed1991

Prophylactic efficacy of maprotiline on unipolar depression relapse.

BACKGROUND: Although antidepressant medications have been in use for about 30 years, the question remains about their utility in the prophylaxis of recurrent depression. The purpose of this study was to evaluate the efficacy of maprotiline, a tetracyclic antidepressant, for depression prophylaxis. METHOD: We conducted a vast, prospective, multicenter, double-blind, placebo-controlled study of 1141 outpatients suffering from depression and treated with maprotiline or placebo for 1 year. The very large size of the study population allowed for the testing of two drug doses. The study design included a pre-inclusion treatment phase that assured that all study patients had recently suffered from a depressive episode and were in remission at the time they were randomized into two treatment groups (1 and 1/2 tablet of maprotiline 75 mg) and two control groups (1/2 and 1 tablet of placebo). RESULTS: The actuarial relapse rate at 1 year was 16% for maprotiline 75 mg, 1 tablet; 23.8% for maprotiline 75 mg, 1/2 tablet; 31.5% for 1 tablet placebo, and 37.5% for 1/2 tablet placebo. The difference between each group is statistically significant, except for the difference between the two placebo groups. The actuarial incidence of adverse drug reactions during the year was not statistically significant between the treatment and control groups. CONCLUSIONS: This study demonstrates maprotiline's prophylactic effectiveness for depressive relapses, the 75-mg dose being more effective than the 37.5-mg dose. The patients' tolerance of maprotiline therapy was satisfactory at both doses with prolonged prescription.

Adolescent↗
PubMedDate not supplied

[Recurrence of unipolar depression and efficacy of maprotiline].

Although antidepressive treatments have been used for about thirty years, the question of their duration remains controverted. In fact, among the large number of therapeutic trials, only about fifteen control studies versus placebo, have evaluated the prophylactic advantage of a long-term antidepressive treatment. In order to complete the small number of products evaluated for this indication (imipramine, amitriptyline, zimelidine, nomifensine, fluoxetine), we have undertaken a vast multicenter study (130 psychiatrists), including 1,141 patients suffering from depression and treated with maprotiline, double-blind versus placebo, in ambulatory, for 1 year. The controlled trial was preceded with a pre-inclusion period in which 1,339 patients suffering from depression were treated, in an open study, with maprotiline at a dose of 75 to 150 mg. Only patients who were clinically improved during this preliminary study (MADRS less than 10), were included in the prophylactic evaluation phase, and divided into four groups: maprotiline 75 mg, maprotiline 1/2 tablet of 75 mg, placebo 1 tablet or placebo 1/2 tablet. The relapse was defined by a score exceeding 27 on the MADRS or exceeding 25 during two separate work-ups of 8 days or according to the experimenter's judgment. The actuarial relapse rate at 1 year was: 16% with 75 mg of maprotiline, 23.8% with 37.5 mg of maprotiline, 31.5% with one placebo tablet and 37.5% with 1/2 tablet of placebo, the difference being statistically significant between the 4 groups except for the "placebo" groups between them. In addition, the tolerance of maprotiline was satisfactory with prolonged prescription.

Adult↗
PubMed1986

Maprotiline: an antidepressant with an unusual pharmacological profile.

Maprotiline, which differs from other typical tricyclic antidepressants for its tetracyclic structure, is a highly selective inhibitor of norepinephrine reuptake. Despite its in vitro and in vivo inhibitory activity on NE uptake, 21 repeated daily injections of maprotiline (20 mg/kg i.p.) neither attenuated the norepinephrine-stimulated cAMP accumulation nor reduced the number of beta adrenergic recognition sites in rat frontal cortex. Also, the number of brain serotonin2 recognition sites labeled by [3H]ketanserin remained virtually unchanged in rats receiving 21 daily injections of maprotiline. [3H]Desmethylimipramine and [3H]mianserin specific binding sites were also unmodified by repeated maprotiline injections. However, after 3 weeks of daily administrations, maprotiline elicited a significant decrease in the number of [3H]flunitrazepam binding sites and a decrease in the apparent affinity of [3H]beta-carboline ethylester binding to crude synaptic membranes prepared from hippocampal and hypothalamic homogenates. These changes appear to be unrelated to modifications in the concentration of endogenous gamma-aminobutyric acid present in the membrane preparation, since the addition of 100 microM bicuculline to the incubation mixture decreases [3H]flunitrazepam binding to the same extent in saline- and maprotiline-treated rats. It is suggested that repeated maprotiline injections may elicit an increase in the hypothalamic and hippocampal tissue levels of an endogenous substance(s) which binds to the benzodiazepine/beta-carboline recognition sites.

Animals↗
PubMed1980

[The problem of hemoperfusion in poisonings: ineffectiveness in maprotiline poisoning].

A case of self-poisoning with maprotiline presenting with coma stage III was treated by resin hemoperfusion for 9 hours using an XAD-4 resin cartridge. Plasma levels of about 800 ng/ml maprotilin were initially found. After 5 hours of hemoperfusion progredient clinical improvement was noticed without decreasing tendency of the blood drug levels. The theoretical extraction efficiency calculated from the maprotiline blood levels and the perfusion rate yielded 50 mg for maprotiline and 16 mg for desmethylmaprotiline and was in good agreement with 60.5 mg of maprotiline and 17.3 mg of desmethylmaprotiline recovered from the resin cartridge at the end of the hemoperfusion. The in vitro binding capacity for maprotiline was estimated to be 230 mg per g of resin. These results demonstrate that XAD-4 resin efficiently binds maprotiline. However, because of the very low blood concentrations due to the large volume of distribution, whole body concentrations are minimally affected by resin hemoperfusion. Main complications consisted in thrombocytopenia extending over 24 hours after stopping hemoperfusion, anemia, a short initial decrease of blood pressure and an episode of premature ventricular beats.

Anthracenes↗
PubMed1990

Comparative effects of antidepressants, amitriptyline, and maprotiline on intraventricular conduction, effective refractory period, and incidence of ventricular arrhythmias induced by programmed stimulation in dog hearts after myocardial infarction.

The effects of amitriptyline and maprotiline, standard tricyclic and tetracyclic antidepressants, on intraventricular conduction, the effective refractory period (ERP), and the incidence of ventricular arrhythmias induced by programmed stimulation were studied and compared in dog hearts after myocardial infarction. Amitriptyline at doses of 1-3 mg/kg significantly slowed ventricular conduction of the infarcted zones in a frequency-dependent and dose-dependent manner. Amitriptyline at doses of 2 and 3 mg/kg slowed conduction slightly in normal zones. The ERP was prolonged by amitriptyline at a dose of 2 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. Maprotiline at doses of 1-3 mg/kg slowed conduction in infarcted zones to a lesser extent as compared with amitriptyline, although severely depressed conduction in the infarcted zone was obviously slowed by maprotiline. Maprotiline did not increase the incidence of ventricular arrhythmias significantly. From the present results, maprotiline appears to have less cardiac toxicity than amitriptyline, although maprotiline produces a slight decrease in conduction of infarcted zones.

Action Potentials↗
PubMed1988

A double-blind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes.

Seventy patients with idiopathic syndromes were treated with maprotiline, a noradrenaline reuptake inhibitor, or clomipramine, a serotonin reuptake inhibitor in a 6-week, double-blind, randomized, multicenter trial. Fifty-two patients completed the double-blind phase. Overall, 50% of the patients improved. Significant decreases were seen not only in the levels of pain but also in bodily discomfort, sadness an inner tension (determined by visual analogue scales, VAS). A decrease was also found in the frequency of sleep disturbances, intellectual and emotional inhibition, irritability, guilt feelings, retardation, sadness and suicidal ideas (observed ratings). Sixty-three percent of the subjects showed an overall improvement during treatment with clomipramine as compared to 36% during treatment with maprotiline (p less than 0.05). During clomipramine treatment significant decreases were seen on all the six VAS: sadness, bodily discomfort, inner tension, concentration difficulties, memory disturbances and pain. Bodily discomfort and pain were significantly reduced during maprotiline treatment. The effects produced by clomipramine were also significantly greater than the effects caused by maprotiline as concerns psychic anxiety and inhibition (VAS). The overall reduction in VAS was significantly greater with clomipramine when compared to maprotiline. The most important side effects were dry mouth (both drugs) and sweating (clomipramine). However, in the clomipramine group, 8 patients were excluded due to side effects as compared to 1 patient in the maprotiline group. Thus, the results indicate that antidepressants reduce not only pain but are also of clinical value in the treatment of patients with idiopathic pain syndromes. Drugs with pronounced effects on the serotonin reuptake are to be preferred.

Adult↗
PubMed1976

A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders.

A double-blind prospective study was carried out comparing the prophylactic effect of maprotiline and lithium carbonate over a period of one year in patients suffering from recurrent affective disorders. The average Affective Morbidity Index was lower, but not significantly so, in patients treated with lithium. A further analysis, based on dividing patients into those with no affective morbidity and those who showed some affective morbidity during the study, demonstrated lithium carbonate to be significantly superior to maprotiline both in the group as a whole and in unipolar depressives. A correlation between high plasma maprotiline concentration and low morbidity was observed and was in line with an earlier report. A highly significant negative correlation (r=-0-97; p less than 0-001) was found between plasma maprotiline concentration and body weight. Although the results showed lithium carbonate to be superior to maprotiline in the study, it should be emphasized that the plasma levels of lithium were constantly monitored and maintained at what is considered to be its optimum concentration, whereas the maprotiline treated patients were kept on a fixed dosage regime irrespective of plasma levels.

Adult↗
PubMed1988

Electrophysiological effects of maprotiline, a tetracyclic antidepressant agent, on isolated cardiac preparations.

We studied the effects of maprotiline, a tetracyclic antidepressant agent, on transmembrane potentials recorded from papillary muscles of guinea pigs and sinoatrial nodes of rabbits, using standard microelectrode techniques. Maprotiline (10-100 microM) produced dose-dependent decreases in the maximum rate of rise (Vmax) and action potential duration in papillary muscles, while the resting potential (Em) was not significantly affected. Maprotiline also shifted the Vmax-Em relation to more negative potentials. The slow action potentials of papillary muscles elicited by high [K+]o were also depressed by the drug application. In sinoatrial node cells, maprotiline (above 10 microM) reduced heart rate, Vmax, and action potential amplitude, and increased the action potential duration at half-amplitude. The slope of the phase 4 depolarization was decelerated by the drug. These results suggest that maprotiline depresses not only the fast inward sodium current but also the slow inward calcium current, and that relatively high concentrations of maprotiline exert an inhibitory effect on the electrical activity of the fast- and slow-response fibers of the hearts.

Action Potentials↗