SEARCH · PubMed Health

Results for “Lofepramine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1987

A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review.

The effects of the novel tricyclic antidepressant lofepramine were compared with that of its principal metabolite desipramine. In double-bind clinical trials, lofepramine has been shown to be as effective as desipramine and other comparator tricyclic antidepressants in the treatment of endogenous and reactive depression, but there are some differences between them. Thus the acute toxicity of lofepramine is approximately one-fifth that of its metabolite; lofepramine is a less potent muscarinic receptor antagonist than desipramine (verified by clinical studies in volunteers and depressed patients); lofepramine is less likely to produce conduction defects than desipramine. Neurochemical studies show that both lofepramine and its metabolite are potent noradrenaline uptake inhibitors in vitro and evidence is presented to suggest that lofepramine may release this amine following chronic administration in vivo; both drugs slightly increase serotonin turnover under these conditions and down-regulate cortical beta-adrenoceptor function. Unlike desipramine and most clinically effective antidepressants, lofepramine was inactive in attenuating the hyperactivity of olfactory bulbectomized rats in the "open field" apparatus, and in reversing acute clonidine induced hypomotility. From such tests it appears unlikely that the active metabolite, desipramine, is formed in the brain in sufficient concentrations after chronic lofepramine administration to make a substantial contribution towards the pharmacological activity of the parent compound.

Animals↗

PubMed1977

Effect of lofepramine and other antidepressants on the uptake of 5-hydroxytryptamine and noradrenaline into rat brain monoaminergic neurons.

Lofepramine, (N-methyl-N-[4-chlorobenzoylmethyl]-3-[10,11-dihydro-5H-dibenz(b,f)-azepin-5-yl]-propylamine hydrochloride), is a new antidepressant with low toxicity and no peripheral anticholinergic activity. Its effect on 5-hydroxytryptamine (5-HT) and noradrenaline uptake into rat brain monoaminergic neurons was studied and compared with that of other antidepressants, particularly with that of imipramine and desipramine. Lofepramine inhibited both 5-HT and noradrenaline uptake into synaptosomal fractions in vitro but was 4 times more potent in inhibiting noradrenaline than 5-HT uptake, indicating the effect resembles that of desipramine. Noradrenaline uptake was also preferentially inhibited in synaptosomes from brain of rats treated previously with lofepramine or desipramine (i.p.). Pretreatment with SKF 525A (i.p.) did not diminish the effect of lofepramine, but rather potentiated it. Therefore it is suggested that the formation of desipramine is not necessary for lofepramine to exhibit, the effect on amine uptake in vivo. Both lofepramine and desipramine inhibited intraventricular noradrenaline uptake into synaptosomes without any effect on 5-HT uptake. These results suggest that lofepramine is qualitatively similar to desipramine with respect to preferential inhibition of noradrenaline uptake into central noradrenergic neurons.

Animals↗

PubMed1987

A double-blind comparison of the pharmacodynamic effects of single doses of lofepramine, amitriptyline and placebo in elderly subjects.

In a double-blind five-way cross-over study, six drug free healthy elderly subjects received single oral doses of lofepramine (70 mg, 105 mg and 140 mg), amitriptyline (50 mg) and matched placebo tablets. A dose related increase in plasma drug levels and pharmacological effects of lofepramine was observed. Lofepramine (140 mg) improved psychomotor performance (choice reaction time and letter cancellation), but no such change was seen with lower dose regimes or placebo. No significant differences between lofepramine and placebo were observed in other parameters measured. Amitriptyline, as expected, reduced salivary volume, produced drowsiness and impaired psychomotor performance. These changes correlated with plasma amitriptyline levels. The incidence of subjective side-effects with amitriptyline was also higher than that of lofepramine or placebo. In the dosage used, lofepramine exhibited no deleterious effect on the peripheral cholinergic system or psychomotor performance. This drug therefore is likely to be a relatively safe antidepressant for the elderly, but further investigations during long-term medication are required to verify these observations.

Aged↗

PubMed1995

Simultaneous determination of lofepramine and desipramine by a high-performance liquid chromatographic method used for therapeutic drug monitoring.

A simple reversed-phase HPLC method with ultraviolet detection for the simultaneous measurement of lofepramine and desipramine is described. Only a single alkaline extraction was used, with clomipramine as internal standard. The column used was a Supelco PCN column, and the mobile phase was acetonitrile-methanol-0.015 M phosphate buffer (120:35:100, v/v). The average recoveries were 78.8% for desipramine and 103.8% for lofepramine, and limits of quantitation were 25 and 5 nmol/l, respectively. The inter-assay C.V.s for lofepramine and desipramine were 6.0 and 7.6%, respectively. The method is specific and has excellent accuracy, and has been used for therapeutic drug monitoring of patients with depressions treated with lofepramine. Mean steady-state plasma concentrations found for lofepramine and desipramine were 8.5 +/- 6.1 and 123.6 +/- 120.6 nmol/l, respectively. It is concluded that lofepramine in itself has an antidepressive effect.

Chromatography, High Pressure Liquid↗

PubMed1989

Pharmacokinetics of lofepramine and amitriptyline in elderly healthy subjects.

Pharmacokinetics of 3 doses (70 mg, 105 mg and 140 mg) of lofepramine were compared with amitriptyline (50 mg) in 6 healthy drug free elderly subjects aged between 65 and 72 years. Pharmacokinetics of lofepramine in the elderly appear to be similar to young adults as published before. Peak plasma lofepramine and amitriptyline concentrations were achieved at about 1 h and 3 h of dosing respectively. Elimination half-life of lofepramine was 2.5 h and that of amitriptyline was 31 h. A 24-fold inter-individual variation in peak plasma lofepramine concentrations was observed, but amitriptyline levels in plasma showed less variation. Pharmacokinetic parameters of amitriptyline were comparable to other published studies involving elderly people. Compared to placebo and lofepramine, amitriptyline produced drowsiness and dry mouth, reduced salivary volume and increased movement reaction time. These effects correlated with the plasma amitriptyline levels.

Aged↗

PubMed1994

The effect of low dose lofepramine in depressed elderly patients in general medical wards.

A double-blind randomised controlled trial of the effect of low dose lofepramine (70 mg once daily) against placebo was carried out on depressed elderly inpatients on general medical wards for the elderly, comparing measures of depression and side-effects between the randomised groups. Patients were identified for the study using the Geriatric Depression Scale (GDS) and the Brief Assessment Schedule Depression Cards (BASDEC). Sixty-three subjects were randomised: 46 patients completed the entire trial of 28 days treatment. BASDEC and GDS were administered on day 8 post-admission, and depressed patients were randomised double-blind to either low dose lofepramine (70 mg daily) (n = 23) or placebo (n = 23). Assessment of changes in depressive states were made using the Montgomery Asberg Depression Rating Scale (MADRS) on days 8, 18 and 36 post-admission. Both groups improved by a similar amount during the trial. Lofepramine tended to be more effective than placebo in those patients who were more depressed (GDS > or = 18). On the other hand, subjects who were less depressed (i.e. GDS < 18) improved more on placebo than lofepramine. Low dose lofepramine may prove useful in moderately or severely depressed patients treated for only 4 weeks. However, low dose lofepramine is not indicated for mild (GDS 15-18) depression.

Administration, Oral↗

PubMed1982

A double blind comparison of lofepramine, imipramine and placebo in patients with depression.

The results of double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group. In particular, for severe and/or moderate occurrences of dry mouth, the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 (8 lofepramine vs 21 imipramine patients).

Adolescent↗

PubMed1989

Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission. The overall therapeutic efficacy of lofepramine is comparable to that of imipramine, amitriptyline, clomipramine, maprotiline and mianserin in patients with depression of varying severity, and coexisting anxiety. Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose. Thus, providing its apparent favourable side effect profile is confirmed in practice, lofepramine may be a valuable alternative for treatment of the depressed patient where a tricyclic is indicated.

Clinical Trials as Topic↗

PubMed1982

Metabolism of lofepramine by rat liver microsomes.

1. The metabolism of lofepramine in vitro by rat liver microsomes was studied. The enzyme system involved was dependent on cytochrome P-450 and the main metabolites were desmethylimipramine (DMI), formaldehyde and p-chlorobenzoic acid. 2. Microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene showed enhanced lofepramine metabolizing activity. The induction was reflected in increased Vmax values, whereas Km values were not changed. 3. Pretreatment of rats with lofepramine or DMI did not alter the rate of aniline hydroxylation, aminopyrine demethylation or lofepramine metabolism per mg microsomal protein. Nor was the amount of cytochrome P-450 changed. 4. Lofepramine, imipramine and DMI inhibited competitively the microsomal hydroxylation of aniline in vitro. Lofepramine was the most potent inhibitor, which probably reflects the higher lipophilicity of this compound.

Aniline Hydroxylase↗

PubMed1976

Pharmacokinetics of lofepramine in man: relationship to inhibition of noradrenaline uptake.

The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desemthylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rats irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimipramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formed in vivo in man affect neuronal uptake is this amine. Lofepramine belongs to the group of tricyclic antidepressants which preferentially inhibit noradrenaline uptake.

Administration, Oral↗

PubMed1993

Effect of lofepramine on 5-HT function and sleep.

We studied the effect of the tricyclic antidepressant lofepramine (140-210 mg daily for 16 days) on 5-hydroxytryptamine 1A (5-HT1A) receptor sensitivity in healthy volunteers, using a buspirone neuroendocrine challenge paradigm (30 mg orally). We also studied the effect of lofepramine on platelet 5-HT content and sleep architecture. Lofepramine treatment did not alter the hypothermic, endocrine or amnesic effects of buspirone but significantly lowered platelet 5-HT content and decreased rapid eye movement sleep. Our findings suggest that at clinically used doses, lofepramine inhibits the uptake of 5-HT and produces changes in sleep architecture characteristic of tricyclic antidepressants. However, lofepramine does not appear to alter the sensitivity of 5-HT1A receptors.

Adult↗

PubMed1988

Behavioural and neuropharmacological properties of the dibenzazepines, desipramine and lofepramine: studies on the olfactory bulbectomized rat model of depression.

1. Lofepramine was compared with its major desipramine for its effects on adaptation to novel objects in the home cage (neophobia) and exploratory behaviours in both sham operated and olfactory bulbectomized rats. 2. In the test for neophobia (marble burying), the aversive response of bulbectomized rats differed from that of the sham operated animals, the bulbectomized rats showing a diminished aversive response. This response was unaffected by either antidepressant. 3. Of two tests for exploratory activity, the "open field" test clearly differentiated the bulbectomized rats treated with desipramine from those treated with lofepramine. In the lower doses used (1 and 10 mg/kg), only desipramine treatment significantly attenuated the hypermotility of the bulbectomized rats. In high doses (30 mg/kg), lofepramine also attenuated the hypermotility of the bulbectomized rats; this could have been due to the presence of high concentrations of the desipramine metabolite. In a non-stressful novel environment ('hole board'), neither drug significantly affected the behaviour of sham operated or olfactory bulbectomized rats. Neither antidepressant had noticeable anticholinergic properties as indicated by the number of faecal boli deposited. 4. Acute clonidine administration was found to attenuate the activity of rats in the 'open field' apparatus. This effect was attenuated following the chronic administration of desipramine but not lofepramine. It may be concluded that the pharmacological activity of lofepramine is independent of its metabolism to desipramine in vivo.

Animals↗

PubMed2002

The effect of lofepramine and other related agents on the motility of Tetrahymena pyriformis.

Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression, they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn, normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium. The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50s for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocaine had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values.

Amitriptyline↗

PubMed1990

Lofepramine overdosage.

Data presented show that lofepramine has lower acute toxicity for animals than other antidepressants tested. Review of 55 case reports of acute lofepramine overdose in man shows that hypotension was rare and convulsions did not occur, although in some cases large overdoses of several grams of drug had been taken. No deaths have been recorded due to overdose with lofepramine alone, and the fatal toxicity index for lofepramine (deaths per million prescriptions, England, Wales and Scotland, 1982-1986) is significantly lower than the mean of all antidepressants (P less than 0.001). It thus appears that the low toxicity of lofepramine in animal experiments applies also to man, and that this drug has a favourable safety profile when taken in acute overdose.

Adolescent↗

PubMed1989

Effects of lofepramine on human sleep: a pilot study.

The influence on objective and subjective sleep variables and tolerance of lofepramine (140 mg) given as a single night time dose was compared with placebo in a double-blind cross-over study. Four healthy male volunteers on the same 2 nights of 2 consecutive weeks took either lofepramine or placebo in a randomized order. On 2 successive mornings of the third week all subjects took 140 mg lofepramine after breakfast. The main variables were electrophysiological measures of all night sleep. Supplementary, scores on a sleep questionnaire after each night, and scores on a side-effect questionnaire every morning and evening of the experiment were obtained. Lofepramine reduced paradoxical sleep and increased REM latency. There was a tendency for more intra-sleep restlessness but no relevant changes in sleep continuity variables. In these subjects lofepramine did not change subjective judgement of sleep quality and of feeling refreshed after sleep. No side-effects were reported.

Adult↗

PubMed1981

Actions of lofepramine, a new tricyclic antidepressant, and desipramine on electrophysiological and mechanical parameters of guinea pig atrial and papillary muscles.

The effects of lofepramine on the isolated guinea pig atrial trabeculae were compared with those of desipramine. The preparations were taken from the same animal and mounted in the same tissue bath. All parameters were recorded in parallel. Lofepramine 10 microM was shown to exhibit minor changes in the transmembrane action potential duration only. The action potentials of the atrial trabeculae were prolonged, whereas they were shortened in the papillary muscles. Desipramine was about ten times more potent than lofepramine, but produced similar qualitative changes. Desipramine 10 microM and lofepramine 100 microM showed local anaesthetic properties: a decreased overshoot without a decreased resting potential, a decreased and rate-dependent Vmax, and a decrease in propagation velocity. After the addition of either drug in a lower concentration, a transient increase in force development and a concomitant increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) were recorded. The steady state effect on the force development was a decrease accompanied by a shortening of the action potential duration (papillary muscle). It is suggested that the action of lofepramine 100 microM and desipramine 10 microM on phase 0 of the action potential are produced by blockage of the fast sodium channel. The transient increase in developed force and the increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) could be caused by inhibition of the membrane re-uptake system for released noradrenaline. The steady state shortening and flattening of the plateau (papillary muscle) and the decrease in force development could be the cause of a block in the slow channel system.

Action Potentials↗

PubMed1979

A double-blind trial with amitriptyline and lofepramine in the treatment of endogenous depression.

A double-blind trial was undertaken to compare the antidepressant efficacy and the side effects of Lofepramine with those of Amitriptyline in the treatment of endogenous depression. The study involves 22 acutely ill endogenously depressive patients. 11 patients were treated with Lofepramine and the remaining 11 with Amitriptyline. The results demonstrate that both substances are effective in the treatment of depression. However, the therapeutical efficacy of Lofepramine is significantly greater than that of Amitriptyline. Furthermore, the tolerance of Lofepramine is better than that of Amitriptyline, and the side effects of Amitriptyline, especially in blood pressure dysregulation, are greater than those of Lofepramine.

Adult↗

PubMed1994

Metabolism of lofepramine and imipramine in liver microsomes from rat and man.

1. The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH-generating system in rat and human liver microsomes. 2. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI) and didesmethylimipramine (DDMI). 3. Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine. 4. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively. 5. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug.

Aminopyrine N-Demethylase↗