Combination Of Imipramine Research Articles

Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.

SummaryGlioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.

Pharmacologically Induced Ex Copula Ejaculation in Horses and Donkeys.

Pharmacologically induced ex copula ejaculation is a method used for collection of semen when the traditional methods of semen collection are not feasible. Common indications for this method include health issues that either preclude the physical act of mating or result in impaired erection and ejaculation. The method also offers an alternative when there is a lack of equipment and facilities required for semen collection using the conventional artificial vagina method. A variety of pharmacological protocols for ex copula ejaculation in stallions have been evaluated in both research and clinical settings with no serious side-effects reported. In general, these protocols included tricyclic antidepressants, alpha-2 adrenergic receptor agonists, and smooth muscle stimulators, either individually or in combination. Although there is a lot of variation in the ejaculatory rates among studies, a combination of imipramine and xylazine appears to be an effective option for inducing ejaculation in stallions. In cases where this protocol is not successful, collections should be reattempted using a combination of imipramine, detomidine, and oxytocin. Regardless of the protocol used, a quiet environment with minimal disturbance is associated with a better outcome. In contrast to the body of literature available on pharmacologically induced ex copula ejaculation in horses, only a few studies have been published so far on this topic in donkeys. Further studies are warranted to investigate whether pharmacologically induced ex copula ejaculation is an effective method of semen collection in jacks and to compare different pharmacological protocols for inducing ejaculation in jacks.

Differential impact of imipramine on thapsigargin- and tunicamycin-induced endoplasmic reticulum stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells

The aim of our work was to study effect of antidepressant imipramine on both thapsigargin- and tunicamycin-induced ER stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells. ER stress in SH-SY5Y cells was induced by either tunicamycin or thapsigargin in the presence or absence of imipramine. Cell viability was tested by the MTT assay. Splicing of XBP1 mRNA was studied by RT-PCR. Finally, expression of Hrd1 and Hsp60 was determined by Western blot analysis.Our findings provide evidence that at high concentrations imipramine potentiates ER stress-induced death of SH-SY5Y cells. The effect of imipramine on ER stress-induced death of SH-SY5Y cells was stronger in combination of imipramine with thapsigargin. In addition, we have found that treatment of SH-SY5Y cells with imipramine in combination of either thapsigargin or tunicamycin is associated with the alteration of ER stress-induced IRE1α-XBP1 signalling. Despite potentiation of ER stress-induced XBP1 splicing, imipramine suppresses both thapsigargin- and tunicamycin-induced expression of Hrd1. Finally, imipramine in combination with thapsigargin, but not tunicamycin, aggravates ER stress-induced mitochondrial dysfunction without significant impact on intracellular mitochondrial content as indicated by the unaltered expression of Hsp60.Our results indicate the possibility that chronic treatment with imipramine might be associated with a higher risk of development and progression of neurodegenerative disorders, in particular those allied with ER stress and mitochondrial dysfunction like Parkinson's and Alzheimer's disease.

Combination of Imipramine, a sphingomyelinase inhibitor, and β-caryophyllene improve their therapeutic effects on experimental autoimmune encephalomyelitis (EAE)

Multiple Sclerosis (MS) is one of the most common inflammatory diseases with the essential role of immune system in the demyelination, damage and inflammation of the central nervous system neurons (CNS). β-Caryophyllene (BCP), a natural and selective CB2 agonist, possesses several protective effects. In the present study, we evaluated the protective effects of low dose of BCP (5 mg/kg), sphingomyelinase (SMase) inhibitor imipramine (IMP, 10 mg/kg), and the combination of BCP (2.5 and 5 mg/kg) with IMP in the treatment of experimental autoimmune encephalomyelitis (EAE) mice as a known model of chronic MS. These effects were assessed on the levels of pro- or anti-inflammatory cytokines as well as the polarization of spleen lymphocytes and microglia, in EAE mice. Our results indicated that low dose of BCP, IMP and BCP combined with a SMase inhibitor IMP exert protective effects in treatment of EAE mice. We also found that they reduced the clinical and pathological defects in EAE mice through modulation of both local (microglia) and systemic (lymphocytes and blood) immunity from inflammatory (Th1/Th17/M1) towards anti-inflammatory (Th2/Treg/M2) phenotypes. Therefore, it can be suggested that a low dose of BCP alone or combined with IMP as a known SMase inhibitor deserve a therapeutic position for treatment of MS.

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole.

BackgroundImipramine, a tricyclic antidepressant widely used clinically, has other pharmacological effects, such as antileishmanial activity. Tricyclic antidepressants interact with lipid bilayers, and some studies have shown that imipramine inhibits methyltransferases. Leishmania spp. produces compounds with an ergostane skeleton instead of a cholesterol skeleton, and the inhibition of enzymes of the sterol biosynthesis pathway is an interesting therapeutic target. Among these enzymes, C-24 methyltransferase has been suggested to play an essential role, as its inhibition kills the parasites. In this context, we investigated whether imipramine alters the biosynthesis of sterols in L. amazonensis and evaluated the efficacy of imipramine alone and in combination with miconazole, a classical inhibitor of another step in this pathway.MethodsTo analyze the interference of imipramine with sterol metabolism, promastigotes of L. amazonensis were cultured with medium alone, 15 or 30 μM imipramine or 4 μM miconazole, and their lipids were extracted with methanol/chloroform/water (1:0.5:0.4 v/v) and analyzed by GC/MS. To assess the antileishmanial activity of the treatments, promastigotes of L. amazonensis were incubated with various concentrations of imipramine up to 100 μM and up to 24 μM miconazole. Promastigotes were also treated with the combination of imipramine and miconazole at concentrations up to 12.5 μM of imipramine and 24 μM of miconazole. Parasite growth was evaluated by the MTT assay. The fractional inhibitory concentration index (FICI) was calculated to determine whether there were synergistic effects. Peritoneal macrophages with and without L. amazonensis infection were treated with miconazole (0 – 16 μM) or imipramine (0 to 50 μM) for 72 hours. For assays of the combined treatment in amastigotes, the concentration of imipramine was fixed at 12.5 μM and various concentrations of miconazole were used up to 16 μM. The infection rate was determined by counting the infected macrophages under a light microscope.FindingsPromastigotes treated with imipramine accumulated cholesta-5,7,22-trien-3β-ol and cholesta-7-24-dien- 3β-ol, sterols that normally increase after treatment with classical inhibitors of C-24 methyltransferase. The IC50 of miconazole in promastigotes decreased when it was used in combination with imipramine, resulting in an additive effect, with a FICI value of 0.83. Imipramine also showed activity against intracellular amastigotes and enhanced the activity of miconazole, without apparent toxicity to the host cells.ConclusionsImipramine was confirmed to have antileishmanial activity in both forms of the parasite, affecting the sterol biosynthesis of the organisms. Using imipramine in combination with azoles may be advantageous for the treatment of leishmaniasis.

Imipramine and pregabalin combination for painful polyneuropathy

Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs. This was a randomized, double-blind, placebo-controlled, crossover, multicenter trial consisting of four 5-week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/d vs pregabalin 300 mg/d vs combination therapy vs placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20 to 85 years, pain intensity ≥4 on a 0- to 10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial. A total of 262 patients were screened for participation, 73 patients were randomized, and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (-1.67 NRS points, P < 0.001), imipramine (-1.08 NRS points, P < 0.001), and pregabalin (-0.48 NRS points, P = 0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (P = 0.009), combination vs pregabalin (P < 0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of side effects. Combination of moderate doses of the tricyclic antidepressant imipramine and pregabalin could be considered as an alternative to high-dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue.

Role of urine osmolality as a predictor of the effectiveness of combined imipramine and desmopressin in the treatment of monosymptomatic nocturnal enuresis

Background: We examined the usefulness of urine osmolality, as a predictive factor in the treatment of monosymptomatic nocturnal enuresis (NE) with combination therapy of imipramine and desmopressin. Methods: From May 2014 to April 2015, 59 monosymptomatic NE patients participated in this study. Early morning urine osmolality was measured at 1 week and 1 day before combination therapy of imipramine and desmopressin, and at 1 week and 2 weeks after therapy. The response to combination therapy was evaluated at 3 months after treatment. The mean period of combination therapy was 6.4± 4.2 weeks. Therapeutic response was classified as complete (0-1 wet night/week), partial (over 50% reduction of night) and non-responders (less than 50% reduction of night). Results: The cumulative rate of the complete and partial responders was 76.3%. Among the 3 groups, the statistically lowest value of pre-treatment urine osmolality was observed in the complete responder group (p<0.001). Urine osmolality increased in all groups after treatment, however, statistically the greatest difference between pre and post-treatment urine osmolality was observed in the complete responder group (p=0.024). No serious side effects were observed. Conclusion: Early morning urine osmolality and change of urine osmolality between pre and post-treatment have predictive values in the response to combined imipramine and desmopressin for treatment of monosymptomatic NE.

Imipramine exploits histone deacetylase 11 to increase the IL-12/IL-10 ratio in macrophages infected with antimony-resistant Leishmania donovani and clears organ parasites in experimental infection.

The efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kala-azar patients infected with antimony-resistant Leishmania donovani (Sb(R)LD). Previously we showed that MDR-1 upregulation in Sb(R)LD infection is IL-10-dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children, inhibits IL-10 production from Sb(R)LD-infected macrophages (Sb(R)LD-Mϕs) and favors accumulation of surrogates of antimonials. It inhibits IL-10-driven nuclear translocation of c-Fos/c-Jun, critical for enhanced MDR-1 expression. The drug upregulates histone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from Sb(R)LD-Mϕs. It abrogates Sb(R)LD-mediated p50/c-Rel binding to IL-10 promoter and preferentially recruits p65/RelB to IL-12 p35 and p40 promoters, causing a decrease in IL-10 and overproduction of IL-12 in Sb(R)LD-Mϕs. Histone deacetylase 11 per se does not influence IL-12 promoter activity. Instead, a imipramine-mediated decreased IL-10 level allows optimal IL-12 production in Sb(R)LD-Mϕs. Furthermore, exogenous rIL-12 inhibits intracellular Sb(R)LD replication, which can be mimicked by the presence of Ab to IL-10. This observation indicated that reciprocity exists between IL-10 and IL-12 and that imipramine tips the balance toward an increased IL-12/IL-10 ratio in Sb(R)LD-Mϕs. Oral treatment of infected BALB/c mice with imipramine in combination with sodium stibogluconate cleared organ Sb(R)LD parasites and caused an expansion of the antileishmanial T cell repertoire where sodium stibogluconate alone had no effect. Our study deciphers a detailed molecular mechanism of imipramine-mediated regulation of IL-10/IL-12 reciprocity and its impact on Sb(R)LD clearance from infected hosts.

Evaluation of anti-depressant effect of lemon grass (&amp;lt;i&amp;gt;Cymbopogon citratus&amp;lt;/i&amp;gt;) in albino mice

Background: Depression is a common serious psychiatric disorder and the available anti-depressant treatments are associated with many unwanted side-effects. Thus, various herbal products have been tried. The advantages of herbal treatments would include its complementary nature to the conventional treatment, thus making the latter a safer and cheaper option for depressive disorders. The objective of the present study was to evaluate the anti-depressant activity of lemon grass ( Cymbopogon citratus ) in albino mice and compare it with Imipramine. Methods: A total of 60 Swiss albino mice weighing around 20-40 g of either sex were divided into 10 groups (n=6). They were orally administered with tween 80, as a control, 20 mg/kg imipramine (standard), 5 mg/kg and 10 mg/kg C. citratus (test drugs), and combination of imipramine (10 mg/kg) and C. citratus (10 mg/kg). Duration of immobility was observed for last 4 mins of total 6 mins period in groups 1-5 for forced swimming test (porsolt test) and groups 6-10 for tail suspension test each on 1st, 8th and 15th day and recorded as mean±standard error of the mean. Results were analyzed by one-way analysis of variance, followed by Tukey’s post-hoc test. Results: Lemon grass at the above doses significantly reduced the immobility time in both the tests compared with the control (<0.05). The reduction in the duration of immobility at the dose of 10 mg/kg was comparable to imipramine. Conclusions: The essential oil of lemon grass ( C. citratus ) has significant anti-depressant activity comparable to imipramine.

The Influences of Reserpine and Imipramine on the 5-HT2 Receptor Binding Site and Its Coupled Second Messenger in Rat Cerebral Cortex

An investigation on the molecular mechanism of depression state, less attention was focused on changes at the intracellular messenger level. In this study the effects of reserpine, a monoamine depletor, and imipramine, an antidepressant, on serotonin-2 (5-HT2) receptor binding and its second messenger system of rat cerebral cortex were studied. The level of inositol 4-monophosphate (IP1) accumulation elicited by 100 microM 5-HT via activation of the 5-HT2 receptor on cerebral cortical slices at twelve hours after a single dose of reserpine (2 mg/kg, i.p.) was significantly higher in treated rats, when compared to that of saline-treated rats; this significant level lasted for at least four days. The level of IP1 accumulation in rat cerebral cortical slices elicited by 100 microM serotonin was higher in the group pretreated with reserpine (0.25 mg/kg/day) sub-chronically for seven days than the group pretreated with normal saline. In the receptor binding study, the maximum binding (B(max)) of 5-HT2 receptor binding was increased, when compared to the corresponding controls; whereas, the dissociation equilibrium constant (K(d)) value of the 5-HT2 receptor was found unchanged in the reserpine treated group. Increases in the sensitivity of phosphoinositol (PI) turnover coupled with the 5-HT2 receptor were also found in the long-term (21 days) low dose (0.1 mg/kg/day) administration of reserpine. However, a long-term administration of imipramine (10 mg/kg/day) reduced the function of the PI turnover coupled with the 5-HT2 receptor. Results obtained from the combined use of reserpine and imipramine demonstrated that this combination was able to antagonize the super-sensitivity of the second messenger responses in 5-HT2 receptor induced by long-term treatment with reserpine. Long-term treatment with reserpine but not imipramine also caused an increase in the B(max) of the 5-HT2 receptor. This up-regulation of the 5-HT2 receptor by reserpine could be antagonized by imipramine, if a combined treatment was employed. However, this combination of imipramine with an additional phospholipid liposome did not enhance or decrease the imipramine's effect on the 5-HT2 receptor, or on its coupled second messenger level. In summary, reserpine induced up-regulation of the postsynaptic monoamine receptor and its coupled second messenger responses (such as IP1 formation). Imipramine was capable of antagonizing these same events in a depression animal model with reserpine. This study demonstrated the dynamic changes and adaptability of the receptor system, followed by changes in PI turnover. The results provide an explanation at the molecular level for the bases of depression and the role of antidepressant drugs effects on those pathological linking elements.

Neurogenic Bladder: Current Pharmacologic Trends

Several studies have investigated the many pharmacologic therapies to treat neurogenic bladder. Our aim with this review is to provide an update on the current clinical and basic science literature pertaining to pharmacotherapy for this condition. Advances have been made in pediatric and adult pharmacotherapy. The most notable include the safety and effective use of tolterodine and transdermal oxybutynin in the treatment of pediatric neurogenic bladder. Also, recently, the safe and effective triple drug therapy consisting of an antimuscarinic, an α-blocker, and imipramine in combination has been shown to significantly improve bladder compliance and detrusor pressures.

Combination therapy of imipramine and melatonin: Additive antidepressant effect in mouse forced swimming test

Although there are tools to treat depressive patients, a considerable amount of the cases remains to be untreated. These drug-resistant patients need new drugs or drug combinations to overcome this problem. Thus, the potential synergistic effect of melatonin on a classical drug, imipramine was evaluated in the present study. To test this hypothesis, porsolt swim test, a test predictive of antidepressant-like action, was conducted in mice. Imipramine at doses of 20 and 40 mg/kg caused no alteration and statistically significant reduction in the duration of immobility in forced swim test, respectively. While 5 mg/kg melatonin had no effect, 10 mg/kg melatonin slightly reduced the duration of immobility. When sub-effective doses of imipramine and melatonin (20 and 5 mg/kg, respectively) were co-administered, there was no alteration in responses compared with those of each drug alone. Likewise, the effective dose of melatonin (10 mg/kg) did not cause any increase in responses to 20 mg/kg imipramine. Although combination of imipramine (40 mg/kg) and melatonin (5 mg/kg) did not exert an antidepressant effect above that of imipramine alone, co-administration of the effective doses (10 and 40 mg/kg for melatonin and imipramine, respectively) displayed an additive effect. There were no significant differences between groups in relation with locomotor activity test. The results show that co-administration of imipramine and melatonin exhibits an additive effect and that there seems to be no interaction between the drugs.

Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test

The activation of cell-mediated immunity and the hypothalamic-pituitary-adrenal axis may play a role in the pathophysiology of depression, especially a treatment-resistant one, and antidepressant treatments may exert their effect by suppressing this activation. In our previous studies we described synergistic, antidepressant-like effects of a combination of amantadine (10 mg/kg) and imipramine (5 mg/kg) - drugs otherwise ineffective when given separately in such doses - in the forced swimming test (FST), an animal model of depression. Moreover, preliminary clinical data show that the above-described combination has beneficial effects on treatment-resistant patients. However, it is still unknown whether these positive effects of combined treatment with amantadine and imipramine on behavioural depressive changes are accompanied with normalization of immunoendocrine parameters. Therefore, the present study was aimed at ascertaining whether the antidepressive effect of a combination of amantadine and imipramine was accompanied with a decrease in some immunoendocrine parameters. The antidepressant activity was accompanied with a reversal of the stress-induced increase in the proliferation of splenocytes in response to concanavalin A (ConA). Imipramine, amantadine and a combination of amantadine and imipramine enhanced the production of the negative immunoregulator IL-10 in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with imipramine or amantadine (a combination of imipramine and amantadine causes reduction within the margin of error). In summary, the antidepressive efficacy of a combination of amantadine and imipramine given in suboptimal doses may be related to their negative immunoendocrine effects.

Potentiation of imipramine-induced antinociception by nicotine in the formalin test

In this study, the effect of cholinergic agents on imipramine antinociception in mice, in the formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of imipramine (2.5, 5, 10, 20 and 30 mg/kg) or nicotine (0.25, 0.5, 0.75 and 1 mg/kg) induced a dose dependent antinociception in both the first and second phases of the formalin test in mice. The combination of imipramine with doses of 0.5 and 0.75 mg/kg of nicotine showed a potentiated response, in both phases of the test. However, neither hexamethonium (5 and 10 mg/kg), atropine (0.25 mg/kg) or mecamylamine (0.25 mg/kg) altered the antinociception induced by imipramine. It is concluded that nicotinic receptor activation but not the cholinergic muscarinic mechanism is involved in the imipramine-induced antinociception.

Imipramine-Induced Antinociception in the Formalin Test

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10–40 mg/kg) and 0.5–3 min of swim stress (17°C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through α₂-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.

Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: a double-blind, randomized trial

Depression is a major health problem and is not only underrecognized and undertreated but is associated with significant morbidity and mortality. Lavandula angustifolia Mill. (Lamiacae) is used to treat depression. Many medicinal plant textbooks refer to this indication, whereas there is no evidence-based document. Our objective was to compare the efficacy of tincture of L. angustifolia with imipramine in the treatment of mild to moderate depression and to evaluate the possible adjuvant effect of this tincture in a 4 week double-blind, randomized trial. Forty-five adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive lavandula tincture (1:5 in 50% alcohol ) 60 drops/day plus placebo tablet (Group A), tablet imipramine 100 mg/day plus placebo drop (Group B) and tablet imipramine 100 mg/day plus lavandula tincture 60 drops/day (Group C) for a 4-week study. In this small preliminary double-blind and randomized trial, lavandula tincture at this concentration was found to be less effective than imipramine in the treatment of mild to moderate depression ( F=13.16, df=1, P=.001). In the imipramine group, anticholinergic effects such as dry mouth and urinary retention were observed more often that was predictable, whereas headache was observed more in the lavandula tincture group. A combination of imipramine and lavandula tincture was more effective than imipramine alone ( F=20.83, df=1, P<.0001). As this study indicates, one of the advantages of this combination is a better and earlier improvement. The main overall finding from this study is that lavandula tincture may be of therapeutic benefit in the management of mild to moderate depression as adjuvant therapy. A large-scale trial is justified.

Effect of α-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice

In this study, the effects of adrenoceptor agonists and antagonists on antinociception induced by imipramine in sciatic-nerve-ligated mice were investigated. The response of different doses of morphine, imipramine and adrenoceptor agonists and antagonists was examined 14 days after unilateral nerve-ligation in the hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), imipramine (10, 20 and 40 mg/kg), the α 2-adrenoceptor agonist, clonidine (0.05, 0.1 and 0.2 mg/kg) or the α 1-adrenoceptor agonist, phenylephrine (2, 4 and 8 mg/kg) induced dose-related antinociception in both intact and nerve-ligated mice. The antinociception induced by morphine but not that of imipramine, clonidine or phenylephrine, in nerve-ligated mice was significantly less than that induced in intact animals. Imipramine in combination with clonidine tends to induce a higher response, but the combination of imipramine with phenylephrine did not lead to significant potentiation. The α 2-adrenoceptor antagonist, yohimbine, reduced the response induced by imipramine or imipramine plus clonidine in intact and nerve-ligated animals. However, the α 1-adrenoceptor antagonist, prazosin, did not alter imipramine response. It may be concluded that imipramine induced antinociception in both intact and nerve-ligated mice through an α 2-adrenoceptor mechanism(s).

Combination Therapy of Imipramine with Oxybutynin in Children with Enuresis Nocturna

Purpose: The treatment approach for enuresis is controversial due to the lack of consensus as to the exact causes of nocturnal enuresis. Despite various treatment modalities, pharmacotherapy still appears to be the common choice. The aim of this prospective study was the evaluation of the efficacy of combination therapy (imipramine and oxybutynin) in patients with enuresis nocturna. Patients and Methods: This prospective study was done with 77 monosymptomatic nocturnal enuretics between July 1996 and December 1998. Results: Even though there is no statistically significant difference between combination therapy (imipramine plus oxybutynin) and monotherapy, clinical data showed that combination therapy is more effective. Conclusions: We conclude that combination of imipramine with oxybutynin is a safe and new choice in the treatment of nocturnal enuresis.

Case study: The combined use of imipramine and behavior modification to reduce aggression in an adult male diagnosed as having autistic disorder

AbstractThe present study examined the behavior decelerative effects of combined imipramine (tofranil) and behavior modification in a severely retarded, depressed autistic man. A simple interrupted time‐series design was conducted and the primary data analytic techniques consisted of modified trend analyses and dependent samples t‐tests. Consistent with previous theory and scant empirical research, results indicated that combined imipramine and behavior modification significantly reduced daily episodes of self‐directed and other‐directed aggression. Specifically, controlling for the effects of time, the combined treatment regimen led to significant reductions in both level and slope across three topographies of aggressive behavior. Limitations of the present study and recommendations for future research were discussed. It was concluded that combined imipramine and behavior modification may be an effective strategy for reducing aggression in the developmentally disabled.

Electrophysiological Effects of the Combination of Imipramine and Desipramine in Guinea Pig Papillary Muscles

The electrophysiological effects of imipramine and its active metabolite desipramine, alone or in combination, were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) of the action potential was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, imipramine alone (5 x 10(-6) M), desipramine alone (5 x 10(-6) M), or their combination had no effect on action potential characteristics. However, in the presence of imipramine or desipramine, trains of stimuli at rates between 0.5 and 3 Hz led to a frequency-dependent Vmax block that was augmented at higher stimulation rates. At each driving rate, the Vmax block produced by desipramine was significantly greater than that produced by imipramine. The combination of imipramine and desipramine increased the onset rate of the frequency-dependent Vmax block, but the total amount of Vmax block was similar to that produced by desipramine alone. In the presence of imipramine alone, the recovery of Vmax was a monoexponential process, the time constant (tau re) being 2.3 +/- 0.4 s, whereas in the presence of desipramine, it was better defined by a biexponential function (tau re = 1.5 +/- 0.4 and 15.8 +/- 2.8 s). In the presence of the combination, the recovery process was also defined by a biexponential function and the tau re values were similar to those found in the presence of desipramine alone. Thus, according to their onset and offset kinetics of the frequency-dependent Vmax block, imipramine and desipramine can be classified as sodium channel blockers with intermediate and slow kinetics, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)