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At least 19 recordsLinked to original sources
PubMed1986

Electrophysiological effects of amoxapine in untreated and in amoxapine-pretreated rat atria.

The effects of amoxapine (10(-7)-10(-4) M) have been studied in rat atrial fibres obtained from untreated animals and animals pretreated for 28 days with amoxapine (10 mg kg-1, i.p.). In untreated atria amoxapine reduced atrial rate, contractile force and df/dtmax, prolonged the sinus node recovery time and decreased atrial excitability. Amoxapine also decreased amplitude and Vmax of the upstroke, prolonged the duration of the action potential (APD) and effective refractory period (ERP) and reduced the resting membrane potential. During the treatment with amoxapine behavioural and cardiovascular adverse effects, including hypotension, tachycardia and prolongation of the Q-Tc, were observed. However, with the exception of the ERP which was significantly prolonged in pretreated atria, pretreatment with amoxapine did not modify the control values of the measured parameters compared to those obtained in untreated atria. Further addition of amoxapine produced similar changes in both pretreated and untreated atria. However, in contrast to untreated atria, in pretreated atria the prolongation of the ERP produced by amoxapine exceeded the prolongation of the APD and thus, the ERP/APD ratio increased. The decrease in atrial excitability was also more marked in pretreated than in untreated atria. Amoxapine inhibited the slow action potentials and contractions induced by isoprenaline in K-depolarized atria. It is concluded that the electrophysiological effects of amoxapine on rat atrial fibres are similar to those described for other tricyclic antidepressants. Possible explanations for the lower cardiodepressant activity of amoxapine are discussed.

Action Potentials↗
PubMed2000

Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats.

BACKGROUND: The dibenzoxazepine amoxapine was introduced as an antidepressant but has shown antipsychoticlike activity in a number of animal screening tests. A recent positron emission tomography study showed a 5-HT(2)/D(2) receptor occupancy profile of amoxapine that is very similar to that of established atypical antipsychotics. Schizophrenics display deficits in sensory gating mechanisms, such as prepulse inhibition (PPI) of the acoustic startle reflex. A similar deficit can be produced by dopamine (DA) and by 5-HT(2A/C) receptor agonists in rats. Antipsychotic compounds reverse this effect. METHODS: Effects of amoxapine on apomorphine- or 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced disruption of PPI were studied in adult male Sprague-Dawley rats. The extrapyramidal side effect (EPS) liability of amoxapine was assessed using the inclined grid catalepsy (CAT) test. Statistical analyses were performed by analysis of variance (ANOVA) for fully repeated measures (PPI) and by the Kruskal-Wallis one-way ANOVA by ranks (CAT). RESULTS: Apomorphine (0.5 mg/kg) produced a significant reduction in PPI compared with the case of rats in the saline control group. Pretreatment with amoxapine (10 mg/kg) significantly attenuated the apomorphine-induced disruption of PPI. DOI (0.5 mg/kg) significantly reduced PPI compared with saline controls. Pretreatment with amoxapine (5 or 10 mg/kg) produced a significant attenuation of the DOI-induced disruption of PPI. Amoxapine by itself did not alter PPI. Amoxapine (5 or 10 mg/kg) did not produce CAT. CONCLUSIONS: The DA D(2)/5-HT(2) receptor antagonist amoxapine produced an antipsychoticlike reversal of both apomorphine- and DOI-induced disruption of PPI. Furthermore, the same doses of amoxapine that reversed disruption of PPI did not produce CAT. The results confirm and lend further support to the results of previous studies on amoxapine, suggesting that amoxapine might possess antipsychotic activity with little propensity for producing EPS.

Acoustic Stimulation↗
PubMed1988

Biochemical evidence that high concentrations of the antidepressant amoxapine may cause inhibition of mitochondrial electron transport.

Overdosage with the antidepressant amoxapine causes metabolic acidosis and may lead to brain damage and death. To better understand the metabolic disturbances caused by amoxapine overdose, its effects on three simple systems were studied: growth of Saccharomyces cerevisiae, mitochondrial energy metabolism, and an electron transport system in microsomal membranes. Growth of yeast on all substrates except lactate was inhibited by amoxapine at 50-100 micrograms ml-1. Growth on lactate was observed at 200 micrograms ml-1 of amoxapine. In beef heart mitochondria, amoxapine at 100 micrograms ml-1 inhibited reactions involving large sections of the electron transport chain. Energy-linked reactions in submitochondrial particles were also inhibited. Electron microscopy showed some disruption of the mitochondrial internal structure by amoxapine and a change from orthodox to condensed conformation. Microsomal NADH-cytochrome b5 reductase was inhibited by amoxapine, but at higher amoxapine concentrations than mitochondrial reactions. The results suggest amoxapine disrupts reactions of membrane-associated enzyme complexes, and mitochondrial energy conservation may be one of the first systems affected. We speculate that lactic acid accumulation in patients with amoxapine overdose may be caused by loss of electron acceptor activity in tissues.

Amoxapine↗
PubMedDate not supplied

Evaluation of amoxapine.

The pharmacology, pharmacokinetics, clinical trials, side effects, and dosage of amoxapine are reviewed. Amoxapine is a tricyclic dibenzoxazepine antidepressant that is chemically similar to the antipsychotic agent loxapine. In animal tests, amoxapine and its metabolites block reuptake of the neurotransmitter norepinephrine, with little effect on serotonin. It is rapidly and virtually completely absorbed when administered orally; peak serum concentrations occur one to two hours after ingestion. Amoxapine is widely distributed throughout body tissues and is 90% bound to serum proteins. Aromatic hydroxylation in the liver produces two major metabolites, which are excreted in the urine primarily but also in the feces. Amoxapine's elimination half-life is eight hours; one of the metabolites has a long half-life (30 hours). In clinical trials, amoxapine has been compared with amitriptyline and imipramine in several types of depressed patients. In some studies, amoxapine's therapeutic effects were measurable earlier (at one or two weeks after initiation of therapy) than those of the amitriptyline or imipramine, but generally only a portion of the depression-rating scales yielded statistically significant differences. Side effects noted during amoxapine therapy include hypotension (42%), drowsiness (14%), xerostomia (14%), constipation (12%), blurred vision (7%), fatigue (5%), and vertigo (5%). Amoxapine is approved by FDA for use in patients with neurotic or reactive depressive disorders, endogenous or psychotic depression, and depression accompanied by anxiety or agitation. The usual adult dosage is 200-300 mg daily, either in divided doses or a single bedtime dose. Amoxapine is a safe and effective antidepressant with no striking advantages over other available agents.

Amitriptyline↗
PubMed2005

Amoxapine as an atypical antipsychotic: a comparative study vs risperidone.

Amoxapine is marketed as an antidepressant. However, its in-vitro profile, receptor occupancy and preclinical effects are very similar to atypical antipsychotics. Amoxapine has also shown efficacy as an atypical antipsychotic in open trials. The objective of this study was to compare the antipsychotic and side effect profile of amoxapine and risperidone in a randomised assignment, standardized dosing, double-blind trial of acutely psychotic patients with schizophrenia. A total of 48 schizophrenic patients were enrolled and randomized in a double-blind 6-week trial to receive either risperidone (up to 5 mg/day) or amoxapine (up to 250 mg/day). Positive, negative, affective symptoms and motor side effects were measured using standardized weekly assessments. Prolactin levels were also determined at baseline and at the end of the study. A total of 39 patients (amoxapine, n=22; risperidone, n=21) completed the trial. Both pharmacological treatments, amoxapine 228.0 mg/day (SD=34.6) and risperidone 4.5 mg/day (SD=0.7), showed equivalent improvement in positive, negative, and depressive symptoms. Amoxapine was associated with less EPS and less prolactin elevation than risperidone. These data support previous reports about the efficacy of amoxapine as an atypical antipsychotic. Since amoxapine is off-patent, it may be a valuable low-cost alternative to new atypical antipsychotics, particularly in low-income countries where the majority of the patients are still treated with typical antipsychotics.

Adolescent↗
PubMed1979

Comparison of efficacy of amoxapine and imipramine in a multi-clinic double-blind study using the WHO schedule for a standard assessment of patients with depressive disorders.

A multi-clinic double-blind controlled study on amoxapine in comparison with imipramine, using the WHO Schedule for a Standard Assessment of Patients with Depressive Disorders, was performed and the data were analyzed with 111 patients. The assessment of severity of illness and overall improvement indicated clearly the superiority of the antidepressive effect of amoxapine to that of imipramine. The onset of antidepressive effect of amoxapine was clearly more rapid than that of imipramine, and in more than half of the patients in the amoxapine group the improvement was seen within four days following the drug administration. Amoxapine was superior to imipramine in terms of safety and usefulness. The side-effects due to amoxapine appeared less frequently and were less serious than with imipramine. The difference between amoxapine and imipramine was especially remarkable for hypotensive effect. The antidepressive effect of amoxaphine was superior to that of imipramine for almost all symptoms and signs. Amoxapine displayed an especially remarkable effect on psychomotor retardation, depressive feeling, anxiety and tension, somatic complaints and sleep disturbance.

Amoxapine↗
PubMed1992

In rat brain amoxapine enhances dopamine metabolism: pharmacokinetic variations of the effect.

When rats were given i.p. amoxapine, the drug was biotransformed to 7-hydroxyamoxapine, but not to 8-hydroxyamoxapine. The maximal concentrations of amoxapine and 7-hydroxyamoxapine in the serum and brain were found 30 min after the single injection, and the concentration of the former in the brain was higher than that of the latter. During the chronic treatment the concentration of amoxapine in the brain was much higher than that of 7-hydroxyamoxapine. A single administration of amoxapine increased the brain levels of dihydroxyphenylacetic acid and homovanillic acid. Their highest levels were observed 6 h after the injection. Repeated administration reduced the increases; chronic treatment caused tolerance to the enhancing effects on dopamine (DA) metabolism. Tolerance was observed in both striatum and hippocampus, but not in frontal cortex and hypothalamus. Single or chronic injection did not appear to change the level of DA in the brain. Amoxapine itself could be chiefly responsible for the enhancement of DA metabolism. In addition, the level of 3-methoxy-4-hydroxyphenylethyleneglycol in brain decreased transiently right after the injection of amoxapine, but the norepinephrine level did not seem to change following single or chronic administration of amoxapine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity.

Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABAA-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of 36Cl- uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABAA receptor selective antagonist [3H]SR 95531 with an IC50 value of 3.45 microM and a pseudo Hill coefficient of 0.83. In contrast, 10 microM amoxapine inhibits [3H]flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15-1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABAA receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses.

Amoxapine↗
PubMed2003

Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study.

OBJECTIVE: Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. METHODS: Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. RESULTS: Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no treatment-emergent extrapyramidal side-effects, akathisia or weight gain. Prolactin elevation was observed. CONCLUSION: These clinical data lend support to the pre-clinical suggestions that amoxapine may be an atypical antipsychotic. Given its lack of weight gain and that it is considerably less expensive than current options, amoxapine could be a valuable alternative for some patients. These considerations strongly call for more systematic, double-blind studies of amoxapine as an atypical antipsychotic.

Adolescent↗
PubMedDate not supplied

The determination of amoxapine in human fatal overdoses.

Amoxapine, a recently introduced dibenzoxazepine, has been found effective in clinical studies for the treatment of various types of depression. Two amoxapine related deaths, a 53-year-old white male and a 21-year-old white female, have been investigated by this office. Both had been prescribed amoxapine for depression. Quantitation of amoxapine was by gas chromatography using a 3% OV-17 column with confirmation by ultraviolet spectrophotometry and thin layer chromatography. Blood amoxapine concentrations were found to be 18 mg/L in the first subject, and 6.7 mg/L in the second subject. These concentrations are many-fold higher than the therapeutic serum concentrations of up to 0.21 mg/L reported in a clinical study. These cases illustrate the potential lethality of amoxapine overdosage and the need for caution in prescribing amoxapine to patients with suicidal tendencies.

Amoxapine↗
PubMed1982

Systematic studies with amoxapine, a new antidepressant.

Amoxapine, a tricyclic dibenzoxazepine is an antidepressant which in the dosage range of 150-300 mg/day is notable for its rapid onset of action. Because of the rather long, approximately 30-hour, half-life of 8-hydroxyamoxapine, the active metabolite of amoxapine, the possibility was raised that amoxapine therapy may be carried out with single daily dosages. Such a dosage schedule may improve compliance and, if appropriately timed, decrease perception of some of the unwanted effects of the drug. To test the hypothesis that there may be no disadvantages and perhaps even advantages of a once-a-day regimen as compared to a divided dosage schedule, a 6-week double-blind clinical trial was carried out in 35 hospitalized patients with major (18 patients) and minor (17 patients) depressive disorders. While no statistically significant difference was found in overall therapeutic and adverse effects between the groups treated with single or divided daily doses, onset of therapeutic effect appeared a bit faster in the group treated with single daily doses. Of particular relevance for drugs which can be given in single daily doses is their effect on psychomotor performance tests. In view of the findings that a once-a-day dosage regimen with amoxapine may have advantages over divided daily doses, a second study was carried out in which the effects of amoxapine (50 and 100 mg) were compared to an inactive placebo and amitriptyline (50 mg) with and without ethanol in 8 normal male volunteers. The study was double-blind and followed a latin square design. Since the effects of amoxapine on motor reflex, visual-motor coordination and depth perception did not differ significantly from placebo, the results suggest that the effects of amoxapine on the performances measured are clinically insignificant. No significant interaction with ethanol was noted.

Adult↗
PubMed1991

[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats].

The effects of two antidepressant drugs, amoxapine and amitriptyline, that belong to distinct chemical classes, have been examined on various biochemical parameters related to serotoninergic and opioidergic neurotransmission in the rat brain and spinal cord. In vitro binding studies showed that both amoxapine and amitriptyline interact in the nanomolar range with 5-HT2 receptors labelled by [3H]ketanserin in cortical membranes. By contrast, neither amoxapine nor amitriptyline can be considered as possible ligands of 5-HT1A and 5-HT1B receptors because their affinities for these sites are in the micromolar range (or even worse). Interestingly, amoxapine binds with a good affinity (IC50 = 0.30 microM) to 5-HT3 receptors labelled by [3H]zacopride in cortical membranes. Complementary experiments using the 5-HT3-dependent Bezold-Jarisch reflex confirmed that amoxapine really acts in vivo as a 5-HT3 antagonist (IC50 = 50 micrograms/kg i.v.), whereas amitriptyline is essentially inactive on 5-HT3 receptors. The second part of this study consisted of looking for possible changes in central 5-HT receptors 24 h after either a single or a repeated (for 14 days) treatment with amoxapine (10 mg/kg i.p. each day) or amitriptyline (10 mg/kg i.p.). A marked decrease in the density of 5-HT2 receptors was found in the cerebral cortex in both treatment groups. By contrast, neither 5-HT1A nor 5-HT1B receptors were significantly affected in any brain region studied. Finally we explored whether acute and/or chronic administration of amoxapine or amitriptyline affected the levels of opioid peptides and the mu and delta classes of opioid receptors in various regions of the brain and the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMedDate not supplied

Amoxapine--an antidepressant with some neuroleptic properties? A review of its chemistry, animal pharmacology and toxicology, human pharmacology, and clinical efficacy.

Amoxapine, a new antidepressant, exhibits both antidepressant and neuroleptic effects in laboratory animals and in humans. Evidence from human studies (extrapyramidal reactions, hyperprolactinemia, and galactorrhea), animal screening tests, and neurochemical experiments support the contention that amoxapine or a metabolite occasionally produces neuroleptic-like effects. Amoxapine's neuroleptic activity may derive from 7-hydroxy-amoxapine, a minor metabolite in humans, which exhibits significant dopamine receptor-blocking activity. Evidence for an early antidepressant effect of amoxapine in the treatment of depressive illness has not been consistently demonstrated. In comparable doses (roughly twice the dose of imipramine or amitriptyline), amoxapine appears to be similar to reference antidepressants in efficacy, unwanted effects, and acute toxicity.

Amitriptyline↗
PubMed1984

Amoxapine fatalities: three case studies.

Amoxapine (Asendin), a recently introduced dibenzoxazepine, has been effective in clinical studies for the treatment of various types of depression. Three amoxapine-related deaths are reported. Quantitation of amoxapine was carried out by gas chromatography using 3% OV-17 column. Blood amoxapine concentrations were 11.5 mg/l, 2.8 mg/l, and 0.89 mg/l. The concentrations are many-fold higher than the reported therapeutic serum concentrations of 0.21 mg/l. These cases illustrate the potential toxicity and lethality of amoxapine overdose and the need for caution in prescribing a large amount of amoxapine to patients with suicidal tendencies.

Adult↗
PubMed1988

Effects of amoxapine on electrophysiological properties of rabbit sinoatrial node.

The effects of amoxapine on membrane potentials and membrane currents of rabbit sinoatrial node were studied using the double microelectrode voltage clamp method. Amoxapine (greater than 1 mumol.litre-1) decreased the heart rate and the maximum rate of rise and the rate of diastolic depolarisation in a dose dependent manner. Above 3 mumol.litre-1, amoxapine also decreased the action potential amplitude and prolonged the action potential duration at half amplitude. These electrophysiological changes induced by amoxapine were relatively reduced in a high calcium medium (extracellular calcium concentration 4.0 mmol.litre-1). In voltage clamp experiments amoxapine depressed the slow inward current, the time dependent potassium current, and the hyperpolarisation activated inward current. The major effect, however, was considered to be a reduction of the slow inward current. It is concluded that amoxapine produced an inhibitory action on the electrical activity of sinoatrial node, and this action is mainly explained by an inhibition of calcium influx through the cell membrane.

Action Potentials↗
PubMedDate not supplied

Toxicological findings in amoxapine overdose.

Tissue concentrations of amoxapine, a new antidepressant with antipsychotic properties, were determined in two cases in which amoxapine was taken in overdose. Two extractions and GLC procedures, UV spectra, and TLC properties of amoxapine are described. The concentrations of amoxapine are described. The concentrations of amoxapine in brain tissue (52 micrograms/g and 53.2 micrograms/g) were about equal to concentrations found in liver (77 micrograms/g and 50 micrograms/g) and higher than blood concentrations (6 micrograms/mL and 1.5 micrograms/mL). The two metabolites of amoxapine, 8-hydroxyamoxapine and 7-hydroxyamoxapine, were not detected by TLC or GLC.

Adult↗
PubMed1988

Inhibitory actions of amoxapine, a tricyclic antidepressant agent, on electrophysiological properties of mammalian isolated cardiac preparations.

1. The electrophysiological effects of amoxapine were examined in guinea-pig isolated papillary muscles and rabbit sinoatrial nodes using a conventional microelectrode technique. 2. In papillary muscles, amoxapine above 10 microM caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential and in the action potential amplitude (APA), whereas the action potential duration at 90% repolarization (APD90) was significantly prolonged. For a decrease in Vmax, amoxapine produced a negative shift of the curve relating Vmax to the resting potential (Em) along the voltage axis to more negative membrane potentials. 3. Amoxapine also decreased Vmax and the overshoot potential of K+-depolarized slow action potentials of papillary muscle preparations. 4. In spontaneously beating sinoatrial node preparations, amoxapine above 3 microM reduced the heart rate, Vmax, APA and the slope of phase 4 depolarization in a dose-dependent manner. 5. It was concluded that amoxapine exerts inhibitory actions on fast- and slow-response fibres of the heart and these actions can be mainly explained by inhibition of both fast Na+ and slow Ca2+ channels.

Action Potentials↗
PubMed1982

Amoxapine (Asendin, Lederle Laboratories).

Amoxapine is a tricyclic antidepressant agent, which is chemically related to the antipsychotic agent loxapine, but which appears to block selectively the neuronal reuptake of norepinephrine; it is qualitatively similar to desipramine. In studies of patients with mixed depressive illnesses, amoxapine is at least as effective as amitriptyline and imipramine and probably more effective than placebo in ameliorating depressive symptoms. Claims of more rapid onset of therapeutic effects are based on group mean data obtained from small samples of depressed patients with heterogeneous and imprecisely defined diagnostic types. Amoxapine has yet to be compared with desipramine or maprotiline, the most pharmacologically similar antidepressants. Biopharmaceutical and pharmacokinetic data are limited, and a relationship between serum concentrations and efficacy has not yet been shown. Acute toxicity and drug interaction documentation are also lacking. At this time, amoxapine represents a chemical alternative to traditional tricyclic antidepressants. There are no consistent data indicating superiority of amoxapine over any other antidepressant agent for any specific symptom constellation, in rate or extent of improvement, or in any particular diagnostic or demographic population. Studies in which amoxapine is compared with pharmacologically similar agents at therapeutically equivalent doses in diagnostically homogeneous groups are needed to establish the drug's true place in the treatment of depressions.

Amoxapine↗