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At least 19 recordsLinked to original sources
PubMed1975

Effects of iprindole on responses of single cortical and caudate neurones to monoamines and acetylcholine.

1 The technique of microelectrophoresis was used to study the effects of iprindole on single neurones in the cerebral cortex and caudate nucleus of the rat. 2 Iprindole, when applied for a brief period, did not affect the firing rate of the vast majority of neurones tested. 3 Both potentiation and antagonism of neuronal responses to noradrenaline, dopamine, and 5-hydroxytryptamine could be observed after a brief application of iprindole. Potentiation and antagonism often occurred after the same application of iprindole, antagonism always preceding potentiation. 4 Responses to acetylcholine were affected by iprindole similarly: both potentiation and antagonism of the responses could be observed. 5 Responses to glutamate were not affected by iprindole. 6 It is concluded that the potentiation of responses to monoamines by iprindole cannot be explained on the basis of uptake blockade; this potentiation may be due to the blockade of masked receptors on the post-synaptic cell. 7. It is suggested that the common pharmacological action of the tricyclic antidepressants may be the ability to block both monoamine and acetylcholine receptors in the brain.

Acetylcholine↗
PubMed1986

Antidepressants and protein kinases: inhibition of Ca2+-regulated myosin phosphorylation by fluoxetine and iprindole.

The effects of several antidepressant and antipsychotic agents on Ca2+-calmodulin-regulated myosin light chain phosphorylation were evaluated. At a concentration of 100 microM, the antidepressant agents buproprion, mianserin and maprotiline were ineffective; zimelidine, desipramine and imipramine produced 40-50% inhibition; and iprindole and fluoxetine produced 75-90% inhibition. The efficacies of iprindole and fluoxetine were similar to the phenothiazine antipsychotics chlorpromazine and trifluoperazine. Clozapine, an atypical antipsychotic and the butyrophenone haloperidol were relatively ineffective as myosin light chain phosphorylation inhibitors. IC50 values of the most effective agents were: trifluoperazine 16 microM, fluoxetine 28 microM, chlorpromazine and iprindole 56 microM. As with trifluoperazine, inhibition of myosin phosphorylation by iprindole was completely attenuated in the presence of exogenous calmodulin. However, a significant component (30%) of the inhibitory effect of fluoxetine was not reversible with calmodulin. These results show that some antidepressant agents, most notably iprindole and fluoxetine, are capable of antagonizing a calmodulin-regulated protein kinase through calmodulin inhibition; and in the case of fluoxetine, through an additional calmodulin-independent mechanism.

Animals↗
PubMed1988

Is iprindole an indirect betamimetic drug?

Iprindole, an active antidepressant in clinical use, has no effect on norepinephrine reuptake and does not bind to receptors of the noradrenergic system. Iprindole weakly antagonizes reserpine hypothermia and potentiates yohimbine toxicity. This effect is antagonized by propranolol but not by atenolol or metoprolol. In an acute dose, iprindole potentiates the effect of maprotiline on yohimbine toxicity. Beta 2-adrenergic agonists and antagonists specifically modify the effect of iprindole on spontaneous motility. These results indicate that iprindole has an indirect beta 2-mimetic effect.

Adrenergic beta-Agonists↗
PubMed1991

Structural characterization of the urinary metabolites of iprindole in rat.

1. The in vivo metabolism of iprindole in rat is described. Each rat received a single dose of iprindole (10 mg/kg) and urine was collected for 48 h. 2. Fourteen metabolites of iprindole were isolated from rat urine after enzymic hydrolysis and their structures were determined by a computerized g.l.c.-mass spectrometric technique, before and after appropriate chemical derivatization. 3. Three concurrent metabolic pathways have been identified for iprindole in rat; aromatic ring hydroxylation is a minor pathway. 4. This is the first reported comprehensive study on the in vivo metabolism of iprindole in rat.

Animals↗
PubMed1979

Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.

Adjustment Disorders↗
PubMed1986

Chronic treatment with iprindole reduces immobility of rats in the behavioural 'despair' test by activating dopaminergic mechanisms in the brain.

Iprindole, 10 mg kg-1 i.p., once daily for 21 days, enhanced the metabolism of dopamine in the frontal cortex and striatum of rats with no effect in the nucleus accumbens 1 h after the last injection. Noradrenaline metabolism in the brainstem and telencephalon was also increased in these conditions. No effect on dopamine or noradrenaline metabolism was seen 24 h after the last injection. The same repeated treatment schedule with iprindole markedly reduced the immobility of rats in the behavioural 'despair' test 1 h after the last injection and the effect was prevented by 0.5 mg kg-1 i.p. haloperidol and 100 mg kg-1 i.p. sulpiride but not by 3 mg kg-1 s.c. prazosin or 5 mg kg-1 i.p. (+/-)-propranolol. The data show that enhanced metabolism of brain dopamine and noradrenaline is associated with the presence of iprindole during repeated treatment and the effect on dopamine mechanism is important in iprindole's ability to reduce rats' immobility in the behavioural 'despair' test.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Iprindole reverses the lamellar body deficiency of cultured L-2 cells. Possible implications in the reversal of surfactant deficiency.

Type II alveolar epithelial cells in long-term culture typically lose the ability to synthesize surfactant together with a loss of the characteristic lamellar bodies in the cytoplasm of the cells. Iprindole, a cationic amphiphilic drug, induces lamellar body formation in cultured L-2 cells, a cell line derived from rat Type II cells, but devoid of lamellar bodies. With concentrations of 10(-7)-10(-5) M iprindole, which approximate therapeutic plasma concentrations in human subjects, the drug induced the formation of lamellar bodies within 8 hours of incubation. This effect on cell morphology was rapidly lost after withdrawal of the drug. At concentrations of iprindole which induced lamellar body formation, there was a significant increase in phospholipid content of the L-2 cells as well as an increase in disaturated phosphatidylcholine, an important constituent of surfactant. These studies suggest that the use of drugs such as iprindole may represent a novel approach in the augmentation of phospholipid (and possibly surfactant) content of Type II cells in the lung.

Animals↗
PubMed1978

Decrease in brain NE turnover after chronic DMI treatment; no effect with iprindole.

Previous studies have suggested that chronic treatment with tricyclic antidepressants alters brain NE turnover. This action is more likely a biochemical correlate of their clinical effect than is the blockade of amine reuptake, because the latter occurs with acute administration, whereas tricyclics must be given chronically for clinical improvement. In this paper the effects of chronic treatment with the tricyclics desmethylimipramine (DMI) and iprindole (a clinically effective tricyclic that does not potently block amine reuptake) on rat brain NE turnover, as measured by the Conversion Index, was studied. Chronic DMI, but not iprindole, decreased NE turnover. These results are discussed regarding the proposed mechanism of action of tricyclics and the 'catecholamine hypothesis of affective disorders'. Chronic DMI also tended to decrease endogenous brain NE, and chronic treatment with either DMI or iprindole tended to decrease brain and plasma tyrosine.

Animals↗
PubMed1989

Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of enkephalin-degrading peptidases.

The implication that opioid peptides are involved in the action of the antidepressants imipramine and iprindole was investigated in mice by using the forced swimming test as an experimental model of depression. Both the drugs were found to shorten the immobility time in this test. This effect of imipramine and iprindole was reversed by the opiate antagonist naloxone. Moreover, when subeffective doses of either imipramine or iprindole were given together with an intracerebroventricular injection of an inhibitor of their degradation (thiorphan or bestatin), the immobility time was again decreased. Interestingly, the reduction of the time of immobility was found to be not related to the effect of the drugs on locomotor activity. These data might be taken as further evidence for the involvement of opioid peptides in the pharmacological action of antidepressant drugs.

Animals↗
PubMed1991

Interactions of iprindole with fenfluramine metabolism in rat brain and liver.

An assay procedure utilizing electron-capture gas chromatography was developed for simultaneous analysis of fenfluramine and norfenfluramine. This method was applied to brain and liver samples from rats which had been injected with fenfluramine with or without pretreatment with iprindole. The tissues from rats treated with fenfluramine showed extensive formation of norfenfluramine, consistent with findings reported previously in the literature. Pretreatment with iprindole led to an increase in brain and liver levels of fenfluramine, and, unexpectedly, to a marked decrease in levels of norfenfluramine in these tissues. These findings suggest that iprindole blocks N-deethylation and that it may be a useful tool with which to study the effects of fenfluramine in the absence of norfenfluramine. The results also emphasize the importance of considering drug-drug interactions in future research on fenfluramine.

Animals↗
PubMed1992

MK801 antagonism of the prolonged depletion of striatal dopamine by amphetamine in iprindole-treated rats.

The administration of amphetamine to rats pretreated with iprindole to inhibit the metabolism of amphetamine results in a long-lasting depletion of striatal dopamine and its metabolites, DOPAC and HVA. Pretreatment with MK801, a noncompetitive antagonist of the NMDA (N-methyl-D-aspartate) subclass of excitatory amino acid receptors, antagonized the depletion of striatal dopamine, DOPAC and HVA 3 days after a single dose of amphetamine in iprindole-treated rats. MK801 pretreatment was effective up to 4 hours but not at 8 or 24 hours in preventing amphetamine effects on striatal dopamine, DOPAC and HVA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat.

1. Absorption of a single oral dose of [14C]iprindole was rapid in rats, rhesus monkeys, miniature swine, dogs and human volunteers. In all species except the rat, most of the radioactivity in the blood resided in the plasma. Small amounts of unchanged iprindole were detected in the plasma of rats and rhesus monkeys but not in man and miniature swine. 2. Radioactivity was excreted mainly in the urine of man, miniature swine and rhesus monkey, but in the faeces of rat and dog. 3. Urinary radioactivity was associated with basic (free and conjugated), acidic and highly polar, water soluble metabolites. At least 20 metabolites as well as small amounts of unchanged drug were detected in the basic fractions of each species' urine. 4. Many of these metabolites were common to all species; however, qualitative as well as quantitative differences were apparent. Mass-spectrometric analysis of several metabolites indicated N-demethylation and oxidation of the alicylic ring or a combination of both pathways.

Animals↗
PubMed1976

Alterations in peripheral nerves of rats treated with chlorphentermine or with iprindole.

This study deals with the effects of two amphiphilic lipidosis-inducing drugs (chlorphentermine, iprindole) upon the ultrastructure of peripheral nerves of rats. After prolonged drug treatment the preterminal and terminal axoplasm of motor and sensory nerves within skeletal muscles contain numerous abnormal inclusions (osmiophilic conglomerates, autophagic vacuoles, lamellated bodies). By contrast, the axons within large peripheral nerves are little effected. The present observations are tentatively interpreted as resulting from interference with catabolic processes involved in the normal turnover of axoplasmic constituents at the nerve terminal. The exact pathogenesis and the functional significance of these alterations remain to be elucidated.

Animals↗
PubMed1977

Axonal and cellular alterations in the inner ear of rats treated with chlorphentermine or iprindole.

An electron-microscopic study was carried out on the inner ear of rats, which had been treated with the anorectic drug chlorphentermine and the antidepressant drug iprindole, two cationic amphiphilic compounds known to induce a generalized lipidosis. After chronic drug treatment the following vestibular and cochlear alterations were observed: a) numerous lamellated and crystalloid cytoplasmic inclusion bodies in various cell types, typical of drug-induced lipidosis; b) axonal balloonings predominantly affecting preterminal sensory endings which were filled with masses of coarse osmiophilic inclusions and autophagic vacuoles. With prolonged treatment degeneration of nerve fibers below the sensory epithelium was observed in increased numbers. Axonal changes are tentatively interpreted to result from drug-induced interference with certain catabolic processes involved in the normal degradation of axoplasmic constituents.

Animals↗
PubMed1976

Myopathy in rats treated with chlorphentermine or iprindole.

Muscular lesions were induced in rats by prolonged administration of chlorphentermine and iprindole. The alterations consisted of longitudinal fibre splitting, fibre degeneration and necrosis, and of formation of dense cytoplasmic inclusions and large cytoplasmic vacuoles. The soleus muscle was more severely affected than were extensor digitorum longus (EDL), gastrocnemius, and lumbrical muscles. This myopathy closely resembles that induced by chloroquine. The pathogenesis of the muscular lesions, and causal relationship between myotoxic and lipidosis-inducing effects of the drugs under study remain to be elucidated.

Animals↗
PubMed1985

Agonist interactions with beta-adrenergic receptors following chronic administration of desipramine or the atypical antidepressants, iprindole and mianserin.

Desipramine (DMI), decreased the maximum number of beta-adrenergic receptors by approximately 10, 20, 30, and 20% in groups of rats treated i.p. with 5 mg/kg for 14 days or 10 mg/kg for 7, 14, or 21 days, respectively. In studies of agonist competition for beta-adrenergic receptors labelled with [125I]-CYP, chronic DMI administration caused a selective decrease in those receptors normally found in the high affinity conformation in proportion to the dose of DMI administered. No change was observed in either the number of receptors in the agonist low affinity conformation or in the affinity of any drug for the high or low affinity conformations of the receptors. Therefore, chronic DMI caused a selective decrease in the beta-adrenergic receptors linked to adenylate cyclase but did not appear to change other properties of the receptors that would be manifested as a change in their ability to interact with adrenergic agonists. Neither iprindole (15 mg/kg i.p., 14 days) nor mianserin (10 mg/kg i.p., 14 days) decreased the number of receptors, the proportions of agonist high or low affinity receptors, or the affinity of competitor drugs for these receptors, suggesting a different mechanism for the reported loss of adenylate cyclase activity following these drugs than the down-regulation of receptors observed with chronic DMI treatment.

Adrenergic beta-Agonists↗
PubMed1991

Effect of iprindole on the metabolism of trimipramine in the rat.

Major metabolites of trimipramine in young male Sprague-Dawley rats are the result of alicyclic and aromatic ring oxidation. The four major urinary metabolites have been identified as 10-oxotrimipramine, 2-hydroxytrimipramine, 2-hydroxynortrimipramine, and 2-hydroxy-10-oxotrimipramine. When iprindole was administered to rats prior to trimipramine, the effect on trimipramine metabolism was profound. The formation of both 10-oxo metabolites was virtually completely inhibited; the production of 2-hydroxytrimipramine was significantly reduced while the metabolic formation of 2-hydroxynortrimipramine was increased. It is apparent from these preliminary results that metabolic alicyclic and aromatic hydroxylations are catalyzed by different cytochrome P450 isozymes and more than one P450 isozyme is involved in the aromatic ring oxidation of trimipramine and nortrimipramine.

Animals↗