Doses Of Imipramine Research Articles

Antidepressant-like effect of the hydroethanolic leaf extract of Alchornea cordifolia (Schumach. & Thonn.) Mull. Arg. (Euphorbiaceae) in mice: Involvement of monoaminergic system

Ethnopharmacological relevanceThe leaf of Alchornea cordifolia (Euphorbiaceae) is used in traditional African medicine in the treatment of various neurological and psychiatric disorders including depression. Previous studies have shown its potent antidepressant-like effect in the forced swimming test (FST). Hence, this study sought to investigate the involvement of monoaminergic systems in the antidepressant-like effect elicited by hydroethanolic leaf extract of Alchornea cordifolia (HeAC) in the FST. Materials and methodsHeAC (25–400mg/kg, p.o.) was administered 1h before the FST. To investigate the contribution of monoaminergic systems to antidepressant-like effect, receptors antagonists were injected 15min before oral administration of HeAC (200mg/kg) to mice and 1h thereafter, subjected to FST. ResultsHeAC (200 and 400mg/kg, p.o.) produced dose dependent and significant (P<0.001) antidepressant-like effect, in the FST, without accompanying changes in spontaneous locomotor activities in the open-field test. The anti-immobility effect of HeAC (200mg/kg) in the FST was prevented by pretreatment of mice with SCH 23390 (0.05mg/kg, s.c., a dopamine D1 receptor antagonist), sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist), and GR 127993 (5-HT1B receptor antagonist). Similarly, 3 days intraperitoneal injection of p-chlorophenylalanine (pCPA, 150mg/kg, i.p., an inhibitor of serotonin synthesis) prevented the antidepressant-like effect elicited by HeAC. The combination of subeffective doses of imipramine (5mg/kg, p.o.) or fluoxetine (5mg/kg, p.o.), with HeAC (25mg/kg, p.o., subeffective dose) produced a synergistic antidepressant-like effect in the FST. ConclusionThe hydroethanolic extract of Alchornea cordifolia possesses antidepressant-like effect mediated through interaction with dopamine (D1 and D2), noradrenergic (α1 and α2 adrenoceptors), and serotonergic (5HT1B receptors) systems. Also, the potentiation of the anti-immobility effect of conventional antidepressants (fluoxetine and imipramine) by Alchornea cordifolia suggest potential therapeutic effect in depression.

Studying the Effect of Imipramine on Morphometric and Histopathological Changes of Ovary in Adult Female Rat

Purpose and background: the aim of this study was investigating intraperitoneal injection of different doses of Imipramine on the number of follicles in the adult female rat. Infertility that occurs as a result of taking drugs is an important clinical issue. Rate of infertility that has been reported as a result of taking antidepressant drugs is 60%, in spite of its popularity a slight amount of studies has been formed to clarify the mechanism of action on these drugs, this study has written about Imipramine. forty female wistar 180 ± 20 g, selected and distributed them into groups experimental 1, 2, and 3. And they injected 6.25, 12.5, and 25 mg/kg bodyweight Imipramine respectively for 4 weeks, control group receives nothing, and sham group receives distilled water, at the end the samples of ovary tissue were taken to the laboratory for slice preparation, and slides of different parts of ovary made us available to count total number of follicles in each ovary. Results showed that this drug has no effect on bodyweight, ovary and primitive, secondary, graffian and atretic follicles. Different doses of imipramine, number of primary follicles, also 25 mg/kg dose of this drug has caused Corpusluteum to decrease.

The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice.

There is a close relationship between chronic stress, glucocorticoids and depression. Psychiatric and cognitive symptoms resembling major depression have been observed in patients experiencing elevated glucocorticoid levels, and a high percentage of people suffering from depression have undergone a stressful event/events prior to the onset of this mental disorder. In our study, we investigated whether acute and chronic treatment of dexamethasone induces depression-like behavior in mice and if dexamethasone therapy influences the activity of antidepressant drugs with diverse modes of action. The antidepressant-like effect was assessed by the forced swim test in adult mice. The depressogenic-like activity of dexamethasone turned out to be dose-dependent: only the highest tested dose of the glucocorticoid (i.e., 64μg/kg) given as a single injection increased immobility time, whereas 16μg/kg/day of dexamethasone (but not 4μg/kg/day) administered repeatedly induced a significant alteration in animal behavior. These depressogenic doses of dexamethasone (i.e., 64μg/kg and 16μg/kg/day for an acute and repeated administration, respectively) diminished the antidepressant potential of the therapeutic doses of imipramine (10mg/kg), amitriptyline (10mg/kg), tianeptine (25mg/kg), mianserin (10mg/kg), citalopram (15mg/kg) and moclobemide (25mg/kg). Two main findings of our study should be particularly underlined: (1) both single and repeated administration of dexamethasone evoked a depression-like behavior of mice, (2) both single and repeated administration of dexamethasone were able to modify the activity of the antidepressant agents from various pharmacological groups, which may lead to a considerable reduction in the efficacy of pharmacotherapy prescribed for patients with mood disorders.

Phloroglucinol Derivatives Present an Antidepressant-like Effect in the Mice Tail Suspension Test (TST)

The antidepressant-like effects of phloroglucinol and seven synthetic related derivatives were investigated using the tail suspension test (TST) in mice. Compounds 2-methyl-1-[2,4,6-trihydroxy-3-(2-methylpropanoyl)phenyl] propan-l-one (5), 1-(2,4,6-trihydroxyphenyl)ethan-l-one (6), 1-(3-acetyl-2,4,6-trihydroxyphenyl)ethan-l-one (7), 2-methyl-1 -[2,4,6-trihydroxy-3-(2-methylpropanoyl)-5-{ [2,4,6-trihydroxy-3,5-bis(2-methylpropanoyl)phenyl]methyl phenyl] propan-1-one (9) and 1-{3-acetyl-5-[(3,5-diacetyl-2,4,6-trihydroxyphenyl)methyl]-2,4,6-trihydroxyphenyl}ethan-1-one (10), containing acyl groups, decreased the immobile behavior of mice treated orally with equimolar doses of imipramine 20 mg/kg, with no alterations in locomotor activity as assessed by the open-field test. These results suggest that these phloroglucinol derivatives could represent a new molecular model in the search for antidepressant drugs.

Antidepressant-like activity of beta-carotene in unstressed and chronic unpredictable mild stressed mice

The antidepressant-like activity of beta-carotene in Swiss young male albino mice subjected to chronic unpredictable mild stress was evaluated. Beta-carotene (50 and 100mg/kg, p.o.) and imipramine (15mg/kg, p.o.) per se were administered for 21 successive days to separate groups of unstressed and stressed mice. Higher dose (100mg/kg) of beta-carotene and imipramine significantly decreased immobility period of mice in tail suspension test. These compounds significantly restored the reduced sucrose preference in stressed mice. There was no significant effect on locomotor activity of mice by the drugs. Beta-carotene significantly reversed stress-induced increase in brain catalase, monoamine oxidase (MAO-A), thiobarbituric acid-reactive substances (TBARS); and plasma nitrite and corticosterone levels; and increased stress-induced decrease in reduced glutathione levels. Thus, beta-carotene showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of MAO-A and oxidative stress. Its antidepressant-like activity in stressed mice might also be due to decrease in plasma corticosterone levels.

Mechanisms of Neuroprotective Action of Imipramine against Dexamethasone Neurotoxicity

Imbalances in the corticosteroid millieu have been implicated in several neuropsychiatric disorders and neuronal damage. Administration of the high therapeutic doses of the glucocorticoids also induces neuronal damage. We investigated the early electrophysiological manifestations of neurotoxic action of the glucocorticoids. Administration of the toxic doses of dexamethasone (7 and 20 mg/kg) per 24 hours before the electrophysiological studies of rats hippocampal slices induced a dose-dependent decrease of reactivity of the glutamatergic synapses in CA1 pyramidal and granular neurons of dentate gyrus. This neurotoxic action of dexamethasone (at the dose of 7 mg/kg) was reinforced by a co-agonist of NMDA receptors glycine (50 mg/kg) and a administration of single dose of antidepressant imipramine (25 mg/kg). The neurotoxic effect of studied glucocorticoid was decreased by a noncompetitive blocker of the NMDA receptors ketamine (30 mg/kg), an inhibitor of tyrosine phosphoprotein phosphatases sodium ortovanadate (15 mg/kg) and chronic over two weeks administration of imipramine (25 mg/kg). It can be supposed that dexamethasone neurotoxicity is a result of the glutamate accumulation in brain extracellular spaces and intensive activation of NMDA receptors as well as of the inhibiton of providing survival of the neurons tyrosine phosphorilation of the neuronal protein substrates, which produced by the different activators of tyrosine protein kinases. Chronic administration of imipramine probably decreases the both components of dexamethasone neurotoxicity.

A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients

ObjectiveTo compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients in a randomized double-blind study. MethodsThe study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression (HAM-D) score ≥ 17.Patients were randomized to imipramine or venlafaxine. The dose of imipramine was adjusted for each patient to a predefined blood level of 200–300 ng/ml. The dose of venlafaxine was increased gradually to 300–375 mg/day. Efficacy was evaluated after 7 weeks of treatment. ResultsThe mean age of the study group was 54.5 (range 29–82) years. There was no significant difference according to the primary outcome criterion of a ≥50% reduction on the HAM-D score: 17 of 43 (39.5%) patients on imipramine were responders compared to 21 of 42 (50%) patients on venlafaxine. When considering remission as outcome criterion (HAM-D score ≤ 7), 10 of 43 (23.3%) patients on imipramine were remitters compared to 15 of 42 (35.7%) patients on venlafaxine; again, no significant difference. When analysing a subpopulation of patients without psychotic features, with remission as outcome criterion, a significant difference was found: 5 of 34 (14.7%) patients on imipramine were remitters compared to 12 of 31 (38.7%) patients on venlafaxine. ConclusionsThe present study used optimal doses in depressed inpatients and showed that venlafaxine is at least equal in efficacy to imipramine. The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine.

Interactive effects of N-acetylcysteine and antidepressants

N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression.

The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test

The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 μg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.

Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants

It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.

Chronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels

Several animal models are currently utilised in the investigation of major depressive disorder; however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100μg/day; 14 days) blocks the immobility-reducing ‘antidepressant’ effects of a single dose of imipramine (10mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100μg/day; 14 days) blocks the antidepressant effects of imipramine (10mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.

A study on evaluation of antidepressant effect of Imipramine adjunct with Ashwagandha and Bramhi

Introduction: Depressive disorders increases the risks of self-harm or even suicide in patients. Indigenous drugs are being tried to treat such patient along with conventional antidepressant drugs. Objective: To investigate the antidepressant action of Ashwagandha and Bramhi and also to confirm its efficacy in the behavioural despair animal model of depression. Material and methods: Normal saline as control (5ml/kg), imipramine as standard (16,32,64 mg/kg) and ashwagandha (50,100,150 mg/kg), bramhi (20,40,80 mg/kg) as test drugs were introduced to the albino rats weighing between 200-250gm for 2 weeks, 1 hr before electric shock in Learned helplessness test (LHT) and swimming in Forced swimming test (FST). Effects of individual drugs as well as their combination were evaluated. Result: Avoidance response, escape failure and immobility period in case of imipramine and ashwagandha showed highly significant (p<0.01) result on individual use. There was no significant result in case of Bramhi used alone except in escape failure and immobility period (FST), where at higher doses it showed significant (p<0.01) result . But combination of Bramhi and ashwagandha in low doses with low dose of imipramine gave a highly significant result (p<0.01) in all the parameters. Conclusion: Ashwagandha had significant antidepressant action, but bramhi had not when used alone. Combination of these two indigenous drugs with imipramine showed high efficacy in animal model.

The effect of different antidepressant drugs on oxidative stress after lipopolysaccharide administration in mice.

This study investigated the effect of the serotonin selective reuptake inhibitors (SSRIs) fluoxetine, sertraline, fluvoxamine and the tricyclic antidepressant (TCA) impiramine on oxidative stress in brain and liver induced by lipopolysaccharide administration in mice. Each drug was administered subcutaneously at doses of 10 or 20 mg/kg, for two days prior to intraperitoneal (i.p.) administration of lipopolysaccharide E (LPS: 200 µg/kg). Mice were euthanized 4 h after administration of the lipopolysaccharide. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) concentrations were measured in brain and liver. Results: The administration of lipopolysaccharide increased oxidative stress in brain and liver; it increased brain MDA by 36.1 and liver MDA by 159.8 %. GSH decreased by 34.1 % and 64.8 % and nitric oxide increased by 78.7 % and 103.8 % in brain and liver, respectively. In brain, MDA decreased after the administration of sertraline and by the lower dose of fluoxetine or fluvoxamine, but increased after the higher dose of imipramine. Reduced glutathione increased after sertraline, fluvoxamine and the lower dose of fluoxetine or imipramine. Nitric oxide decreased by sertraline, fluoxetine, fluvoxamine and by the lower dose of imipramine. In the liver, all drugs decreased MDA and increased GSH level. Nitric oxide is decreased by sertraline, fluvoxamine and by the lower dose of fluoxetine or imipramine. It is concluded that, during mild systemic inflammatory illness induced by peripheral bacterial endotoxin injection, the SSRIs fluoxetine, sertraline and fluvoxamine reduced, while the TCA impiramine increased oxidative stress induced in the brain. The SSRIs as well as imipramine reduced oxidative stress due to lipopolysaccharide in liver tissue.

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: A promising new molecular pattern for the development of antidepressant drugs

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 μg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC 50 = 90 ± 38 nM), serotonin (IC 50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Metabolism of Amyloid-β Protein May Be Affected in Depression

Epidemiologic studies have demonstrated that a history of depression increases the risk of developing Alzheimer's disease, particularly among individuals with early-onset depression. On the other hand, recent studies have suggested that a higher amyloid-β protein (Aβ)40 to Aβ42 ratio may be associated with the future onset of Alzheimer's disease. Our objective was to assess whether the pathophysiology of early-onset depression may involve or affect Aβ metabolism. In this extension of a case-control pilot study, 193 inpatients with DSM-IV major depressive disorder (MDD) (mean age = 55.9 years) from the Juntendo Koshigaya Hospital, Saitama, Japan, and 413 healthy controls from the community (mean age = 56.6 years) were recruited between May 2004 and April 2009. Serum Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratio, and other clinical and biological factors were compared between controls and patients in 3 age groups: young (< 40 years), middle-aged (≥ 40 to < 65 years), and elderly (≥ 65 years). Depressive symptoms were assessed with the Hamilton Depression Rating Scale. All patients were receiving antidepressant medication at the time of the study, and doses of current antidepressants were converted to an equivalent imipramine dose. The serum Aβ40/Aβ42 ratio was significantly higher in MDD patients than controls in all age groups (young: P = .003; middle-aged: P < .001; elderly: P = .006). These differences were also observed in noncarriers of the apolipoprotein E ε4 allele. Our findings suggest that Aβ metabolism may be affected in depression; these findings also possibly answer the question of why even early-onset depression is a risk factor for developing Alzheimer's disease.

Diminished conditioned responding to the nicotine stimulus by antidepressant drugs with differing specificity for the serotonin and norepinephrine transporter

People diagnosed with depression also tend to have a co-morbid nicotine addiction. Thus, there is interest in whether medications used to treat depression alter the effects of nicotine. This study assessed whether the antidepressant drugs citalopram, imipramine, and reboxetine, with differing specificity for the serotonin and norepinephrine transporter, altered responding controlled by the conditional stimulus (CS) effects of nicotine. Rats received intermixed 20-min nicotine (0.4mg base/kg, SC) and saline sessions. On nicotine sessions, rats had intermittent access to sucrose; no sucrose was available on saline sessions. After discrimination performance stabilized and a nicotine generalization curve (0.025–0.4mg/kg) was established, the antidepressant drugs were assessed. In these tests, rats were pretreated with citalopram (1–17mg/kg), imipramine (1–17mg/kg), or reboxetine (1–30mg/kg) before the training dose of nicotine and placement in a chamber for a 4-min extinction test. At the higher doses, all three antidepressant drugs blocked responding evoked by the nicotine CS and decreased nicotine-induced hyperactivity. When these higher doses of citalopram, imipramine, and reboxetine were tested alone (no nicotine), they decreased chamber activity and/or dipper entries. Nevertheless, all three drugs produced partial or complete blockade of the CS effects of nicotine at doses that produced no effect on dipper entries or chamber entries. This finding suggests that both neurotransmitters play a role in the CS effects of nicotine and that modifications in these systems by antidepressants may be clinically relevant.

Strain-Dependent Effect of Imipramine on Responses of Mechanosensitive Pelvic Nerve Afferent Fibers to Bladder Distension

Background: This study evaluated the effect of imipramine, which inhibits colonic afferents, on responses of the peripheral afferent nerve innervating bladder to noxious urinary bladder distension in different strains of rats [Sprague-Dawley, spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY)]. Methods: Rats were anesthetized with sodium pentobarbital and single-afferent nerve fibers in the L6 dorsal root were teased for recording the inhibitory response to urinary bladder distension (60 mmHg, 30s) following intravenous injection of accumulative doses of imipramine. Results: The stimulus-response functions of mechanosensitive afferent nerves were not enhanced in SHR. Intravenous injection of imipramine significantly reduced responses of mechanosensitive afferent nerves to urinary bladder distension, on all afferent fibers. Interestingly imipramine showed strain-dependent suppressions on afferent fibers, with strong suppression in SHR (ID50 2.96 mg/kg) and weak in WKY (10 mg/kg, to 6 ± 7% of control in SHR vs. 72 ± 9% of control in WKY). Conclusion: The effects of imipramine in bladder dysfunction/pain are likely due to direct actions on afferent fibers. The enhanced inhibitory effect of imipramine in the SHR suggests that a different mechanical encoding mechanism is involved in the regulation of bladder afferent nerve activity in SHR.

A Randomized, Double-Blind, Placebo-Controlled Trial of Low Dose Imipramine for Treatment of Refractory Functional Dyspepsia (FD)

G A A b st ra ct s to assess dose response. Funnel plot analysis was performed to test for publication bias. Results: Systematic review identified 3,403 citations. Detailed evaluation identified 18 potentially relevant journal articles/abstracts, of which 5 fulfilled our inclusion criteria. Of the 1803 IBS patients randomized, 96% had non-constipated IBS. Meta-analysis of data from 5 studies demonstrated that rifaximin was superior to placebo for global symptom improvement (p=0.0038, see table). Raw data was available from 4 studies for the secondary endpoint of bloating. For this endpoint, the response rate with rifaximin was significantly higher than with placebo (p<0.0001). Based on data from 4 studies, rifaximin significantly reduced abdominal pain scores compared to placebo. Data from 3 studies demonstrated that rifaximin significantly improved stool consistency compared to placebo. A logistic regression model showed no linear trend for a dose response. Funnel plot analysis revealed no evidence of publication bias. The most common AEs (≤10%) with rifaximin were headache, upper respiratory infection, urinary tract infection, nausea, vomiting, & diarrhea which were similar to placebo. Serious AEs with rifaximin were rare (<2%) and similar to placebo. There were no confirmed reports of C. difficile associated diarrhea. Conclusion: In high quality studies, rifaximin was more effective than placebo at improving global symptoms and bloating in patients with IBS. Rifaximin was well tolerated in short term trials. Efficacy and safety data beyond 10 weeks of therapy are not available.

Effect of phenobarbitone on the distribution and elimination of imipramine in rats.

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg-1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot,b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t1/2) and Vdss significantly decreased to approximately 23-40% while CLtot,b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were less than 1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.

Effect of Imipramine on the Membrane Anisotropy and on the Phospholipid Methylation in the Central Nervous System of the Rat

An ex-vivo and in-vitro study of the effects of imipramine on the membrane anisotropy and phospholipid methylation in the rat cortical membranes was carried out. A comparative study of the membrane fluidity in various brain regions indicated different basal anisotropy of the areas and different reaction of these membranes to imipramine. It was found that imipramine when given to rats chronically (14 x 10 mg kg-1, i.p.) or added externally to the cortical membranes of naive rats or rats treated with a single dose of imipramine (10 mg kg-1, i.p.) decreased the anisotropy of cortical membranes. Chronic imipramine produced some changes of the membrane architecture in the cortex, whereas imipramine in different concentrations did not fluidize these membranes in-vitro. Imipramine in concentrations corresponding to its mean concentration in the rat brain after administration at a dose of 10 mg kg-1 i.p., potentiated phospholipid methylation in the cortical membranes of naive rats and rats receiving imipramine in a single dose of 10 mg kg-1 i.p. in an in-vitro study, whereas the prolonged administration of imipramine decreased the sensitivity of phospholipid methyltransferases to the stimulating effect of the drug in-vitro.