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At least 19 recordsLinked to original sources
PubMed1980

Metabolism of nomifensine (Alival, Merital): isolation and identification of the conjugates of nomifensine-14C from human urine.

1 It can be stated in regard to the metabolism of nomifensine that the metabolites and also the starting compound are present in alkaline urine almost completely in conjugated form. 2 The metabolites M I-M III represent about 30% of the radioactivity excreted with urine. Two-thirds are N-glucuronides and one-third O-glucuronides. 3 Nearly the entire remainder of the renally eliminated radioactivity in nomifensine which is present in conjugated form as N-glucuronide. 4 Thus over 90% of the metabolites formed in man and excreted via urine have been identified.

Biotransformation↗
PubMed1977

Determination of nomifensine by a sensitive radioimmunoassay.

1. A radioimmunoassay (RIA) has been developed for determination of both nomifensine and total nomifensine (nomifensine + conjugated nomifensine) in serum, plasma, and urine. 2. Antibodies were prepared in rabbits by immunization with N-(8-Nomifensine) succinamic acid-bovine serum albumin. 3H-labelled drug was used as tracer. Separation of free from antibody-bound nomifensine was carried out using dextran-coated charcoal. For determination of total nomifensine, the acid-labile conjugate was split by acidification. 3. The limit of detection for nomifensine is 300 pg/ml plasma and the cross-reactivity of the metabolites is less that 1%. The influence of conjugated nomifensine on the results of nomifensine can be corrected. 4. Pharmacokinetics of nomifensine were determined in healthy volunteers after oral administration of 100 mg 14C-labelled drug. Peak levels of 14C radioactivity (2,150 ng/ml), total nomifensine (1,252 ng/ml) and nomifensine (53 ng/ml) appeared within 1.5-2 h; the half-life of elimination from plasma was 1.5-2 hours. The advantages of this routine method are high sensitivity, the requirement of small amounts of plasma, and simple handling.

Administration, Oral↗
PubMed1985

Binding characteristics of the dopamine uptake inhibitor [3H]nomifensine to striatal membranes.

Binding of the radiolabeled antidepressant [3H]nomifensine to rat and rabbit striatal membranes has been characterized. The specific binding of [3H]nomifensine to striatal membranes was stable, reversible and saturable. Saturation experiments indicated that [3H]nomifensine labeled a single site with an affinity (Kd) of 80 nM and a total number of binding sites (Bmax) of 6.5 pmoles/mg protein both in rat and rabbit striatal membranes. The affinity constants obtained from kinetic analyses and competition experiments were in fairly good agreement with those obtained in saturation experiments. Compounds known to inhibit [3H]dopamine uptake in vitro, such as nomifensine, 4-hydroxy-nomifensine, mazindol, amfonelic acid and benztropine, were the most potent competitors of nomifensine binding. Additionally, the absolute potencies of various drugs in competing for [3H]nomifensine binding to rat and rabbit striatal membranes correlated closely with their potencies in inhibiting [3H]dopamine uptake into striatal synaptosomes. Specific [3H]nomifensine binding was dependent on the presence of NaCl which is also consistent with its association with the dopamine uptake pump. The number, but not the affinity, of striatal [3H]nomifensine binding sites was reduced significantly following in vivo lesions with 6-hydroxydopamine. The number of [3H]nomifensine binding sites was found to be highest in areas rich in dopamine nerve terminals such as the striatum and olfactory tubercle. These results suggest that [3H]nomifensine binds to a site on dopaminergic nerve terminals associated with the dopamine uptake pump.

Animals↗
PubMed1987

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography.

In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C-nomifensine was administered i.v. in trace amounts (10-50 micrograms) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the time-course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

Aged↗
PubMed1982

The pharmacokinetics of nomifensine. Comparison of pharmacokinetics and pharmacodynamics using computer pharmaco-EEG.

Pharmacokinetics and pharmacodynamics of nomifensine infusions as compared with oral preparations were investigated in a double-blind place-controlled crossover study in 10 healthy normal volunteers. They received randomized in weekly intervals 75 mg nomifensine and placebo intravenously as well as placebo, 75 and 150 mg nomifensine orally. Blood samples, quantitative EEG evaluations, psychometric tests, blood pressure, pulse rate and side effects were obtained and monitored at the hours 0, 1, 2, 4, 6 and 8. Nomifensine serum levels were determined by a radioimmunoassay; peak levels occurred within the first 2 h, the elimination half-life was around 2 h, both results indicating fast absorption and elimination. While the evaluation of the total nomifensine demonstrated almost identical bioavailability of the oral and intravenous form, free nomifensine levels after 75 mg i.v. were more similar to those after 150 mg than 75 mg p.o. Digital computer period analysis of the EEG confirmed nomifensine as a drug with a significant effect on the CNS as compared with placebo, showing in fact an antidepressant 'pharmaco-EEG profile' similar to desipramine. Evaluation of dose-effect curves demonstrated that 75 mg i.v. was the most effective drug, being closer to 150 than 75 mg p.o. The latter oral dosage could be discriminated from placebo only in certain variables at certain times. Concerning time-effect, nomifensine was most effective around the 6th hour post-drug, which was similar to the psychometric findings, thus showing a considerable delay compared to the peak serum concentration. Relating pharmacodynamic findings to pharmacokinetic results it became evident that free nomifensine may be of far greater importance for the drugs encephalotropic and psychotropic properties than the total unconjugated and conjugated nomifensine--thus justifying the development of a parenteral preparation. Finally, the relationship of blood levels and CNS effects was found to have a characteristic 'hysteresis loop' shape suggesting a delay of pharmacodynamic effects as opposed to the serum concentrations. This delay may be due to a slowly formed active metabolite, the drug acting on deep compartment receptors or both.

Adult↗
PubMed1984

Kinetics and metabolism of nomifensine.

Metabolic and pharmacokinetic studies of nomifensine maleate, a tetrahydroisoquinoline derivative with antidepressant properties, are reviewed. Results of pharmacokinetic studies indicate that nomifensine has a short distribution phase and a large volume of distribution. It is rapidly metabolized to its N-glucuronide. Plasma levels of nomifensine-N-glucuronide are up to 100-fold higher than those of nomifensine, obviously because of a smaller volume of distribution. As nomifensine-N-glucuronide is extremely unstable and cleaved to nomifensine, determinations of nomifensine are easily falsified. It is therefore recommended only to determine the sum of nomifensine and its N-glucuronide (total nomifensine) in clinical trials. Kinetics of total nomifensine can best be described by the open two-compartment model: Maximum plasma levels are obtained 1-2 hours postadministration; mean elimination half-life is 2 hours. Excretion is almost entirely by the kidneys, with approximately 88% of an oral dose excreted within 24 hours.

Animals↗
PubMed1986

Disposition of nomifensine after acute and prolonged dosing.

The pharmacokinetics of nomifensine were studied after single oral and intravenous doses. The effect of prolonged oral dosing on the pharmacokinetics of nomifensine was also evaluated. Nomifensine was rapidly absorbed from the gastrointestinal tract. The peak concentration of free nomifensine (0.18 mumol/L) was reached at 1.13 hours after dosing. The highest concentration after the intravenous dose was 1.21 mumol/L. The elimination t1/2 after a single dose was about 4 hours regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The main reason for limited bioavailability seems to be extensive first-pass metabolism during the absorption process. The AUC of free nomifensine decreased substantially (from 0.78 to 0.32 hr X mumol/L) and the elimination t1/2 was shortened (from 4.39 to 2.11 hours) after a 2-week dosing period. These effects suggest marked induction of the metabolizing enzymes. An increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect.

Administration, Oral↗
PubMed1982

Pharmacology of nomifensine.

Nomifensine, a representative of a new class of chemical substances, is a compound of low toxicity and of wide therapeutical range. Nomifensine is absorbed very well, has a rapid onset of action, has no sedative effect and does not prolong alcohol-induced anaesthesia. In studies on thymoleptic activity, nomifensine showed a good and persistent activity, particularly after oral treatment. It had a better quantitative effect than the tricyclic reference compounds from which it differs by the lack of distinct anticholinergic activity. The efficacy of nomifensine does not decrease during long-term treatment. The mechanism of action of nomifensine, whose thymoleptic activity resembles that of a tricyclic antidepressant, may be explained by the influence on the catecholamine metabolism, but contrary to tricyclic compounds, nomifensine also influences the dopamine uptake. The increase in motility induced by nomifensine is based on a different mechanism as that induced by phenylalkylamines. Particularly noteworthy are the lack of a systemic effect, the remarkably slight influence on the cardiovascular system, and the slight cardio-toxicity in comparison with reference compounds. Nomifensine showed an interesting activity component in the protective influence on stress-induced ulcers. The results of kinetic studies of nomifensine in animals explain the rapid onset of action and indicate an easy use in therapy.

Animals↗
PubMedDate not supplied

Nomifensine maleate: a new second-generation antidepressant.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and formulary recommendations for nomifensine maleate are reviewed. Nomifensine is a potent inhibitor of norepinephrine but has little effect on serotonin. It is unique in that it is a potent reuptake inhibitor of dopamine. Nomifensine is rapidly and completely absorbed and is widely distributed throughout the body. The major route of elimination is through the kidneys. Because of its short half-life and resultant lack of accumulation, nomifensine is usually given in divided doses. Nomifensine is approved for the treatment of depression. In clinical trials with imipramine, amitriptyline, nortriptyline, maprotiline, and various investigational antidepressant drugs, it has been found to be as effective as the standard antidepressant agents. In general, nomifensine has been well tolerated by patients and has caused few side effects. It also has not been associated with serious toxic effects in overdose situations. The usual effective dose of nomifensine maleate is 100-200 mg daily given in divided doses. It appears to be a good choice for patients with profoundly retarded depression and for those who cannot tolerate the side effects of traditional antidepressant drugs. Nomifensine should not be used alone in patients with schizoaffective disorders or in patients with agitated depression. Nomifensine is a safe and effective antidepressant with a fairly unique pharmacological profile. Because the drug is relatively safe and causes little sedation, it may offer substantial advantages over the more traditional antidepressants and should be considered for formulary addition.

Chemical Phenomena↗
PubMed1985

The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia.

Nomifensine is an antidepressant drug (widely used in Europe, but not yet available in the United States), which has been linked to intravascular hemolysis. We studied 19 patients (18 women and 1 man) with acute intravascular hemolysis due to nomifensine-dependent antibodies. Transitory renal insufficiency developed in at least seven patients, and four required temporary dialysis. To investigate the antibodies, we used nomifensine, its three main metabolites, and its ex vivo antigens (urine samples from a volunteer collected 1.5 to 16 hours after the ingestion of 100 mg of nomifensine). We found an extraordinary heterogeneity of antibody response. Only five antibodies appeared to be primarily reactive with nomifensine. The remaining antibodies reacted either optimally or exclusively in the presence of one or more of the metabolites. Three of the metabolite-specific antibodies were positive only in the presence of ex vivo antigens, indicating specificity for as-yet-unidentified early and late metabolites of nomifensine. All the antibodies were capable of activating complement and belonged to the IgG or IgM class or both. Two serum samples also contained weak IgA antibodies. In addition to a variable degree of cross-reactivity of the antibodies, at least one serum sample had two drug-dependent red-cell antibodies (IgG against nomifensine and IgM against metabolites), and one sample had a drug-dependent IgM red-cell antibody and an IgG platelet antibody. Despite their serologic heterogeneity, all the antibodies were strongly reactive with ex vivo antigens. We recommend the use of ex vivo antigens as the technique of choice for the detection of nomifensine-dependent (and probably other drug-dependent) antibodies.

Acute Disease↗
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↗
PubMed1979

Effects of nomifensine on the isolated vas deferens of the rat.

The effects of nomifensine on the rat isolated vas deferens was studied. Nomifensine (7.60 X 10(-11) molar--7.60 X 10(-8) molar) enhanced the stimulant effects of dopamine and prevented the inhibitory action of pimozide on dopamine-induced contractions. Higher concentrations of nomifensine blocked the effects of dopamine noncompetitively (pD2' = 7.25 +/- 0.12). Nomifensine (7.60 X 10(-9) molar--3.80 X 10(-6) molar) enhanced noradrenaline-induced contractions and reduced phentolamine-induced antagonism of noradrenaline. Higher concentrations of nomifensine blocked the effects of noradrenaline competitively (pA2 = 5.50 +/- 0.06). Guanethidine induced supersensitivity of the vas to noradrenaline and further enhanced the potentiating effect of nomifensine. The effect of 5-HT was reduced competitively by nomifensine (pA2 = 7.50 +/- 0.10). Desipramine produced a similar preferential enhancement of dopamine-induced contractions and antagonized dopamine at higher concentrations. It is concluded that nomifensine may act prejunctionally by inhibiting uptake of the amines and postjunctionally by blocking the receptors.

Animals↗
PubMed1984

The pharmacokinetics and bioavailability of nomifensine maleate in healthy men.

Two studies were conducted in normal male volunteers to establish the pharmacokinetic parameters for nomifensine maleate and to determine the bioavailability of the drug from the Merital capsule intended for U.S. marketing. Single oral doses of 25, 100, and 200 mg of nomifensine maleate as aqueous solutions were administered to 24 men in the open-label Latin-square design pharmacokinetic study. In the bioavailability study, 24 men received single oral 50 mg doses of nomifensine maleate in a capsule or as an aqueous solution. Plasma levels of nomifensine were determined by radioimmunoassay and urinary levels of total nomifensine and its metabolites were assayed by thin-layer chromatography. There was a proportional increase in the area under the curve (AUC) with increasing dose, while peak plasma levels and amounts of total nomifensine and its metabolites excreted in the urine rose as dose increased. The pharmacokinetics of nomifensine are considered linear over the dose range tested. Nomifensine maleate was equally bioavailable from the 50 mg aqueous solution and the Merital capsule formulation.

Administration, Oral↗
PubMed1976

Methylphenidate-like effects of the new antidepressant drug nomifensine (HOE 984).

Nomifensine (HOE 984) belongs to a chemically new class of drugs with reported antidepressant properties. Nomifensine, like methylphemidate, d-amphetamine and apomorphine, induces strong, intense stereotypes behaviour in the rat. The nomifensine-induced stereotyped behaviour was completely antagonized by pretreatment with reserpine (7.5 mg/kg, 18 h) but not by short-time pretreatment with alpha-methyltyrosine (250 mg/kg, 2 h.) Nomifensine thus differs from d-amphetamine and apomorphine but resembles methylphenidate on stereotyped behaviour. Nominfensine, M1 (8-amino-2-methyl-4-(4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline fumarate) (Hoechst), methylphenidate and d-amphetamine induced a strong increase in the brain level of homovanillec acid (HVA), whereas the dopamine uptake inhibitor benztropine induced no changes in HVA and cocaine induced only a small increase. Nomifensine and the M1 metabolite, like methylphenidate, also increased 3,4-dihydroxyphenylacetic acid (DOPAC) whereas amphetamine, apomorphine, benztropine and cocaine decreased this dopamine metabolite. This suggests that the stereotyped licking and/or biting activities in the rat are related to dopamine releasing properties of nomifensine, methylphenidate and amphetamine. This is further supported by an inverse relationship between the in vitro dopamine uptake inhibitory concentrations and the sterotypy-inducing dose levels of nomifensine and d-amphetamine. Amphetamine caused a strong, and nomifensine and apormorphine a week increase in brain 3-methoxy-4-hydroxyphenylglycol (MOPEG).

Animals↗
PubMed1987

Effects of acute and chronic treatment with an atypical antidepressant drug, nomifensine, on the sleep-wake activity in rats.

After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of neonatal nomifensine exposure on adult behavior and brain monoamines in rats.

The aim of the study was to examine the effects of early postnatal exposure to nomifensine, an inhibitor of catecholamine uptake, on concurrent active (REM) sleep, on later alcohol related behavior and on monoamine concentrations in various brain regions of rats. For these purposes rats were given daily injections of 10 mg/kg nomifensine s.c. between the 7th and the 18th postnatal days. During the nomifensine exposure active sleep, expressed as a percentage of total sleeping time, was reduced. At one month of age, the nomifensine rats showed increased ambulation and had lower defecation scores in the open-field than the controls. Neonatal exposure to nomifensine increased voluntary intake of 10% (v/v) alcohol when the rats were 2-3 months of age. The rats, however, did not exhibit preservation in the T-maze, and similarly to control rats suppressed drinking 0.1 M lithium chloride even when thirsty. Measurement of cerebral monoamine concentrations at the age of 3 months suggested that neonatal nomifensine treatment interferes with the noradrenergic and serotonergic systems in several regions of the brain. Concentrations of noradrenaline and 5-hydroxyindoleacetic acid (5-HIAA) were decreased in the cerebral cortex and frontal cortex, concentration of 5-HIAA was decreased in the neostriatum, and concentrations of noradrenaline, 5-hydroxytryptamine (5-HT) and 5-HIAA were elevated in the lower brain stem. Taken together, these findings show that exposure to nomifensine during the 2nd and 3rd postnatal weeks suppresses neonatal active sleep, causes changes in the adult open-field behavior, and increases voluntary alcohol intake, perhaps due to a long-lasting alteration in brain monoamines.

Aging↗
PubMed1985

Psychopharmacological effects of nomifensine enantiomers.

The effects of enantiomers of nomifensine were compared in five psychopharmacological tests in which (+/-)-nomifensine is active. In mice, (+)-nomifensine increased motor activity at 16 mg/kg, 8 mg/kg reduced the hypothermia and ptosis induced by reserpine and antagonized the hypothermia induced by 16 mg/kg of apomorphine. (+)-Nomifensine 4 mg/kg potentiated yohimbine toxicity. (-)-Nomifensine 4,8, or 16 mg/kg was inactive in all these tests. In rats, (+)-nomifensine 8 mg/kg induced stereotyped movements whereas (-)-nomifensine 64 mg/kg did not produce stereotypies.

Animals↗