There is little evidence that anxiolytics aid smoking cessation. Some antidepressants (bupropion and nortriptyline) can aid smoking cessation. It is not clear whether these effects are specific for individual drugs, or a class effect.
Physiologically based pharmacokinetic (PBPK) models were developed for design and optimization of liposome therapy for treatment of overdoses of tricyclic antidepressants and local anesthetics. In vitro drug-binding data for pegylated, anionic liposomes and published mechanistic equations for partition coefficients were used to develop the models. The models were proven reliable through comparisons to intravenous data. The liposomes were predicted to be highly effective at treating amitriptyline overdoses, with reductions in the area under the concentration versus time curves (AUC) of 64% for the heart and brain. Peak heart and brain drug concentrations were predicted to drop by 20%. Bupivacaine AUC and peak concentration reductions were lower at 15.4% and 17.3%, respectively, for the heart and brain. The predicted pharmacokinetic profiles following liposome administration agreed well with data from clinical studies where protein fragments were administered to patients for overdose treatment. Published data on local cardiac function were used to relate the predicted concentrations in the body to local pharmacodynamic effects in the heart. While the results offer encouragement for future liposome therapies geared toward overdose, it is imperative to point out that animal experiments and phase I clinical trials are the next steps to ensuring the efficacy of the treatment.
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In 14 patients by bilateral retroperitoneal lymph node dissection for nonseminoma tumors of the testes, several sexual functions before and after node dissection were compared. All patients had normal sexual function before the operation. After the operation, antegrade ejaculation was found to have disappeared completely in 12 patients, retrograde ejaculation was demonstrable in ten of these patients. In ten patients, antegrade ejaculation was restored after treatment with 25 mg imipramine twice daily by mouth. In the two patients who still showed antegrade ejaculation, albeit diminished, imipramine medication led to an increased number of spermatoza. During imipramine medication, the partners of five patients became pregnant. The preliminary conclusion from these findings is that ejaculation disorders, which most males develop after bilateral retroperitoneal lymph node dissection, can be successfully treated with daily oral doses of 25-50 mg imipramine in the majority of patients who still desire children.
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The purpose of this work was to examine the number and function of alpha 2-adrenoceptors and the number of serotonin uptake sites in depressed patients and controls. Platelet alpha 2-adrenoceptors and platelet serotonin uptake sites were labelled with [3H]yohimbine and [3H]imipramine respectively. Central alpha 2-adrenoceptor function was assessed by growth hormone and other responses to challenge with the alpha 2-agonist clonidine. No overall difference in the binding parameters was observed between the control and depressed groups, but the results highlight the importance of drug-free interval, menopausal status and membrane protein concentration within the binding assays in the interpretation of such studies. The growth hormone response to clonidine tended to be blunted in depressed females and was significantly blunted in the subgroup of depressives who failed to suppress plasma cortisol concentrations in response to dexamethasone. Depressed subjects also showed a smaller decrease in diastolic blood pressure and a smaller increase in sedation than control subjects.
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3H-Imipramine binding in relation to serotonergic function was studied in patients hospitalized following a suicide attempt. Comparison with a control group showed a highly significant difference in Bmax values. The results suggest, at least a posteriori, a biological alteration as the basis of suicidal behaviour. Although it is impossible to attribute a suicidal attempt to the alteration or to a predisposing pre-existent condition, this biological marker may be useful in evaluating suicidal risk and also short- and long-term prognosis.
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Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg-1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg-1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in-vivo.
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Down-regulation of cortical beta-adrenoceptors is observed in laboratory animals following chronic treatment with many clinically effective antidepressant therapies. [3H]Dihydroalprenolol (DHA) binding to cortical beta-adrenoceptors was examined in mice treated with the functional NMDA antagonists 1-aminocyclopropane-carboxylic acid (ACPC) and MK-801. ACPC and MK-801 reduced [3H]DHA binding by 19 (P less than 0.05) and 21% (P less than 0.05), respectively, while imipramine produced a 23% (P less than 0.05) reduction. No corresponding changes in the KD of [3H]DHA were observed. These findings are consistent with the observation that functional NMDA antagonists are active in animal models commonly used to evaluate antidepressants and may represent a novel approach to the treatment of depression.
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It is shown that a long experience of defeats in daily zoosocial collisions (ZC) elicits changes in the structure of submissive behaviour. Male mice of C57BL/6J line after 20 defeats demonstrated poses of passive subordination instead of active defence and run away which they manifested in the first ZC. Moreover, new immobile poses appeared which were rare in the first ZC. Submissive animals (CA) demonstrated a decrease of travels in the open field test and an increase of immobility time in the Porsolt test. Chronic administration of imipramine (10 mg/kg, i.p., twice a day during two weeks against the background of repeated ZC) prevented an increase of depressivity, estimated in Porsolt test. Changes were noted in the content of serotonin and 5-HIAA in some brain structures of subordinated mice in comparison to control animals (five days of isolation). The data are discussed from a position of the development of depression in SA of C57BL/6J line as a result of a long nonavoided zoosocial stress.
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This study investigated the involvement of NMDA receptors and the L-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl(2), 30 and 10-30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl(2) in the FST was prevented by pre-treatment of animals with guanosine 5'-monophosphate (GMP), ascorbic acid, L-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with D-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl(2)+MK-801 was not different from the result obtained with ZnCl(2) or MK-801 alone, but ZnCl(2)+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl(2) prevented the anti-immobility effect of MK-801, ketamine, GMP, L-arginine or N(G)-nitro-L-arginine (L-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the L-arginine-NO pathway.
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All randomised trials of desmopressin for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive desmopressin compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were reported. Trials focused solely on daytime wetting were excluded.
In addition to supporting traditional claims and previously reported antidepressant properties for POEE, this study shows that POEE prevents stress-induced HPA hyperactivity.
Repeated antidepressant treatment attenuates the step-down passive avoidance deficit which is induced by olfactory bulbectomy in rats. Using a shuttlebox passive avoidance procedure, the effects of antidepressants were investigated after various drug withdrawal intervals. Imipramine, amitriptyline, doxepin, bupropion and mianserin were effective at 48 and usually 72 hours after withdrawal, but no significant attenuation of the deficit was seen 4 hours after withdrawal from any antidepressant tested. At least 4 to 7 days of imipramine treatment were required for efficacy. A high dose of d-amphetamine (5 mg/kg) produced similar results while tranylcypromine and haloperidol were inactive at all withdrawal intervals tested. The olfactory bulbectomy syndrome may reflect functional serotonin deficiency, which would be ameliorated through antidepressant-induced alterations in serotonin receptor sensitivity.
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A test procedure, inducing a defined state of vigilance in rats, has been investigated to ascertain its usefulness for EEG monitoring of the effects of drugs. In order to prevent spontaneous fluctuations in the level of vigilance, rats were trained to walk in a slowly rotating treadwheel. The level of vigilance recorded under these conditions could be shifted by amphetamine, 1.0 mg/kg p.o., to a higher state of arousal, as shown by a reduction in power in all frequency bands, and by diazepam, 0.3 mg/kg p.o., to a lower state of arousal, as indicated by a rise in the activity at low frequencies. Imipramine (1.0, 3.0 and 10.0 mg/kg p.o.) caused a dose-related reduction in power in the intermediate frequency bands (3-18 Hz).
The effect of joint administration of imipramine (IMI) and magnesium (Mg) on antidepressant-like activity was studied in mice using forced swim test (FST). Mg doses ineffective per se (5 and 10 mg/kg) given jointly with IMI also at ineffective doses (10 and 15 mg/kg) resulted in a potent reduction in the immobility time. Since these combined treatments did not influence locomotor activity, the antidepressant-like activity was not due to non-specific behavioral activation. Moreover, we estimated the effect of joint administration of magnesium and IMI in FST on serum and brain magnesium, IMI and its active metabolite desipramine (DMI) concentrations in mice. Swim stress (mice subjected to FST) increased the magnesium concentration in serum and decreased it in the brain compared to naive animals. Moreover administration of IMI increased (normalized) magnesium brain concentration, without influence on the serum level. Joint administration of IMI and magnesium did not influence magnesium (compared with FST) or IMI and DMI (compared with IMI treatment alone) concentrations in both examined tissues. The present data demonstrated an enhancement of the antidepressant-like effect by joint administration of IMI and magnesium in the FST, and further indicate the particular role of magnesium in the antidepressant action. Since there was no increase in IMI, DMI or magnesium concentration after joint administration of magnesium and IMI, the data suggest that pharmacodynamic rather than pharmacokinetic interaction between magnesium and IMI is accountable for behavioral effect in the FST.
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The hallmark of agoraphobia is the spontaneous panic attack, a reaction of extreme fearfulness and impending doom with cardiorespiratory symptoms. The end result can be a patient who is housebound. The basic therapeutic principle is confrontation with the avoided object or activity. Controlled clinical experiments demonstrate that both imipramine and phenelzine, the drugs of choice for this prevalent and disabling disorder, have a specific antipanic effect.
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Retrograde ejaculation (RE) is one of the complications of diabetes mellitus. Different therapeutic approaches are present, whether medical or surgical, with limited success rates.
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Rat blood exhibited a significant quinone-dependent N-oxide reductase activity towards imipramine N-oxide. The reduction mediated by the blood proceeded in the presence of both NAD(P)H and menadione under anaerobic conditions. When menadione was replaced with 1,4-naphthoquinone or 9,10-phenanthrenequinone, similar results were obtained. The reduction was also mediated by the combination of rat erythrocytes and plasma. The reducing activity was inhibited by dicumarol and carbon monoxide. When boiled plasma was combined with untreated erythrocytes, the N-oxide reducing activity was abolished. In contrast, when boiled erythrocytes were combined with untreated plasma, the activity was unchanged. These results suggest that the activity is caused by the heme of hemoglobin in erythrocytes and quinone reductase in plasma. In fact, erythrocytes and hemoglobin have the ability to reduce the N-oxide when supplemented with DT-diaphorase purified from rat liver in the presence of both NAD(P)H and menadione. Hemoglobin also exhibits N-oxide reductase activity with reduced menadione (menadiol). Furthermore, hematin exhibits a significant reducing activity in the presence of menadiol. The reduction appears to proceed in two steps. The first step is enzymatic reduction of quinones to dihydroquinones by quinone reductase(s) with NADPH or NADH in plasma. The second step is nonenzymatic reduction of imipramine N-oxide to imipramine by the dihydroquinones, catalyzed by the heme group of hemoglobin in erythrocytes. Cyclobenzaprine N-oxide and brucine N-oxide are similarly transformed to the corresponding amines by the above reducing system in blood. These results suggest that blood plays an important role in the reduction of tertiary amine N-oxides to tertiary amines.
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Sodium bicarbonate has been recommended for the treatment of arrhythmias induced by tricyclic antidepressants. It is unclear, however, whether this therapy is effective only in the presence of acidosis. A case is presented in which there was an immediate response to sodium bicarbonate in three episodes of ventricular tachycardia despite the presence of alkalosis on two of the three occasions. Given the poor response to conventional therapy of arrhythmias induced by tricyclic antidepressants the use of sodium bicarbonate may be reasonable even in the presence of alkalosis. However, in the presence of pre-existing respiratory or metabolic alkalosis, such therapy is not without risk, and it is suggested that it be reserved for life-threatening situations when the arrhythmia has failed to respond to hyperventilation or antiarrhythmics or both.
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Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.
The phosphorylation of substrate proteins by protein kinases plays a key role in signal transduction and function of neurons. Protein kinases have been associated with several physiological and pathological states including depression. The aim of the present study was to investigate the effect of imipramine and electroconvulsive treatment (ECS), both clinically effective treatments of depression, on the activity of calcium/calmodulin dependent protein kinase II (CaM-KII) in the hippocampus. Our results indicate that repeated (but not acute) imipramine and ECS administration significantly decreased CaM-KII activity by 65 and 70%, respectively, in the soluble fractions from hippocampus. This decreased enzyme activity was accompanied by a proportional decrease (60-70%) of the amount of a-CaM-KII in the same fraction. A single and repeated administration of imipramine produced a significant increase in the activity of CaM-KII (50 and 337%, respectively) in the particulate fraction from hippocampus. Similarly, a single and repeated ECS produced an increase in the enzyme activity by 22 and 240%, respectively. The amount of a-CaM-KII in the particulate fraction was not significantly affected by repeated antidepressant administration. It is postulated that changes in CaM-KII activity following chronic antidepressant treatment might represent and important step in expression of its antidepressive action.