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Thermal burn injuries can result in significant morbidity and mortality. The combination of ethanol intoxication with thermal burn injury results in increased morbidity through an exaggerated inflammatory response involving many organs. Recent studies have linked involvement of the lipid mediator platelet-activating factor (PAF) in the pathology associated with intoxicated thermal burn injury (ITBI). The present studies tested the roles of PAF and the elevated levels of subcellular microvesicle particles (MVP) generated in response to ITBI in the subsequent multiorgan toxicity. First, thermal burn injury of HaCaT keratinocytes preincubated with ethanol resulted in augmented MVP release, which was blocked by inhibiting the PAF-generating enzyme cytosolic phospholipase A2 and the PAF receptor (PAFR). Second, ITBI of mice resulted in increased proinflammatory cytokine production and neutrophilic inflammation in multiple organs, which were not present in mice deficient in PAFRs or the MVP-generating enzyme acid sphingomyelinase (aSMase). Moreover, the increased bacterial translocation from the gut to mesenteric lymph nodes previously reported in murine ITBI was also dependent on PAFR and aSMase. MVP released from ITBI-treated keratinocytes contained high levels of PAFR agonistic activity. Finally, use of topical aSMase inhibitor imipramine following ITBI attenuated the widespread organ inflammatory response of ITBI, suggesting a potential therapeutic for this condition. These studies provide evidence for PAF-enriched MVP generated in skin, which then act on the gut PAFR, resulting in bacterial translocation as the mechanism for the multiorgan dysfunction associated with ITBI. Inasmuch as aSMase inhibitors are widely available, these studies could result in effective treatments for ITBI. [ABSTRACT FROM AUTHOR]

Simple Summary: In vivo microdialysis applied to rat submandibular glands showed that an increase in the norepinephrine and serotonin levels in the dialysate was primarily dependent on their release from the nerve endings. Either infusion of imipramine into interstitial fluids in rat submandibular glands through a dialysis probe or intraperitoneal administration of imipramine significantly and dose-dependently increased both norepinephrine and serotonin concentrations in the interstitial fluids. Xerostomia induced by antidepressants such as imipramine has long been thought to be due to their anticholinergic effects. However, even antidepressants with low anticholinergic effects may have a high incidence of xerostomia. In salivary glands, norepinephrine activates alpha-adrenergic receptors in blood vessels and beta-adrenergic receptors in acinar cells, respectively, causing a decrease in the blood flow and an increase in the protein secretion, resulting in the secretion of viscous saliva with low water content and high protein content. A previous study demonstrated that perfusion of the submandibular glands of rats with serotonin significantly decreased saliva secretion. The results of the present study revealed the following: (1) that norepinephrine and serotonin, but not epinephrine nor dopamine, were detected in the interstitial fluids in rat submandibular glands; (2) that norepinephrine and serotonin concentrations in the dialysate was 4.3 ± 2.8 nM and 32.3 ± 19.6 nM at stable level, respectively; (3) that infusion with imipramine, a reuptake inhibitor of norepinephrine and serotonin, significantly and dose-dependently increased both norepinephrine and serotonin concentrations in the dialysate; and (4) that intraperitoneal administration of imipramine significantly increased both norepinephrine and serotonin concentrations in the dialysate. These results suggested that one of the mechanisms of xerostomia induced by reuptake inhibitors of norepinephrine and serotonin involves the activation of adrenergic and serotonin receptors in the salivary glands, respectively. [ABSTRACT FROM AUTHOR]

Introduction and Hypothesis: Despite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method. Methods: In a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days' washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine. Results: All participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH2O (95% confidence interval [CI] 2.0–28.2 cmH2O, p = 0.03) in the resting state and 15.1 (95% CI 4.2–26.0 cmH2O, p = 0.01) cmH2O during squeezing. Conclusions: The findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function. [ABSTRACT FROM AUTHOR]

This study provides three prevalence-based metrics of potential harm, the fatal toxicity index (FTI), serious morbidity index (SMI) and healthcare utilization index (HUI) for fourteen of the most prescribed antidepressants in the US. For the years 2013–2020, adverse events for single drug exposures were obtained from the National Poison Data System. Prescription estimates were taken from the Agency for Healthcare Research and Quality's Medical Expenditure Survey. 95% confidence intervals were calculated using a Poisson distribution. Chi-square testing was used where significance was not clear. SSRIs and SNRIs had the lowest overall indices (FTI 0.02–0.26). Bupropion's FTI (0.27–0.43) was not statistically significantly different from that of imipramine (FTI 0–1.3, p =.62) or nortriptyline (FTI 0.25–0.78, p =.22), though its SMI and HUI were significantly greater. There was a statistically significant difference in all indices between TCAs (p <.0047). The difference between the FTI of all SSRIs did not remain significant after correction (p =.045). SSRIs and SNRIs are safer than alternative agents on all measures. Bupropion exposure was as likely to cause mortality, and more likely to cause morbidity or require treatment in a healthcare facility, than TCAs nortriptyline and imipramine. [ABSTRACT FROM AUTHOR]

Introduction: Doxazosin is an alpha-1 antagonist used for the treatment of benign prostatic hypertrophy (BPH) symptoms and hypertension. An α (1)-adrenergic receptor antagonist called Doxazosin is used to treat benign prostatic hyperplasia and excessive blood pressure. There is evidence linking peripheral α-adrenergic receptors to inflammation. Aim and Objective: To study the antidepressant effect of Doxazosin by an experimental model in swiss albino mice. Material and Methods: The study was conducted in the Department of Pharmacology & Therapeutics at King George’s Medical University, Lucknow. The present study was designed to evaluate antidepressant in an experimental model in Swiss albino mice. A total number of 18 female Swiss albino mice were included in the study. They were kept in the institutional animal house under standard conditions. They received normal pellet diet and water ad libitum. They were allowed to get acclimatized to the new environment for a period of 2 weeks. Mice were randomly divided into 3 groups, each group containing 6 mice. Results: In the present study antidepressant activity was observed by the period of immobility in Forced swim test. Each activity was conducted on 18 mice, 6 mice in each group (Group A: Vehicle, Group B: Doxazosin, Group C: Imipramine). Therefore on Day 1, period of immobility of mice in the above 3 groups was found to be comparable. On Day 11, period of immobility of mice in the above 3 groups was found to be comparable again. It was observed that there was a slight decrease in period of immobility indicating that Doxazosin (4 mg/kg) may have some weak antidepressant activity at Day 21. Decreasing period of immobility significantly more than control indicating that Doxazosin (4 mg/kg) may have moderate antidepressant activity at Day 31. Conclusion: Doxazosin (4 mg/kg) appeared to be a promising therapy option for patients presenting with depression. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathic pain is a result of damage/illness of the peripheral nerves. The mechanisms caused by its pathophysiology are not completely understood. Methods: Imipramine is a tricyclic antidepressant that is sometimes used to treat neuropathic pain. Moreover, citicoline is considered a novel adjuvant for painful disorders such as neuropathic pain. So, a possible interaction between imipramine and citicoline on pain behavior was examined in nerve-ligated mice using tail-flick and hot plate tests. Results: The results indicated that induction of neuropathic pain by sciatic nerve ligation caused hyperalgesia in nerve-ligated mice. On the other hand, intraperitoneal (i.p.) administration of citicoline (50, 75, and 100 mg/kg), and imipramine (2.5 and 5 mg/kg) induced anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Furthermore, citicoline potentiated the anti-hyperalgesic and anti-nociceptive effects of imipramine when they were co-administrated in nerve-ligated mice. Interestingly, there was an additive effect between imipramine and citicoline upon induction of anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Conclusion: Therefore, it can be concluded that citicoline (as an adjuvant substance) enhanced the efficacy of imipramine for the modulation of pain behavior in nerve-ligated mice [ABSTRACT FROM AUTHOR]

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains. [ABSTRACT FROM AUTHOR]

Objective To investigate the enhancing effect of zinc pretreatment on antidepressant effect of imipramine and to explore the underlying mechanism. Methods SD rats were randomly divided into the model group, zinc group, imipramine group, zinc + imipramine group, zinc + H89 + imipramine group, and control group. In the model group, zinc group, imipramine group, zinc + imipramine group, zinc + H89 + imipramine group, we constructed the learned helplessness depression models by using the electric box； the rats in the control group were also placed in the electric box, but no electric shock was given. After modeling, rats in the model group were intraperitoneally injected with normal saline； rats in the zinc group were intraperitoneally injected with zinc gluconate for 3 consecutive days； rats in the imipramine group were intraperitoneally injected with imipramine as a single dose； rats in the zinc + imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days and were given imipramine on the 4th day； rats in the zinc + H89 + imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days, and were injected with H89［ protein kinase A ( PKA） inhibitor］ injection after zinc administration on the first day and were given imipramine on the 4th day； rats in the normal control group were injected with normal saline. Depressive behaviors were assessed 24 h after the last administration using the shock shuttle-escape test and forced swimming test. Subsequently, the lateral habenular (LHb） was collected to evaluate the expression of cytochrome oxidase and Kir4. 1 protein in astrocytes. Results In the forced swimming test, the zinc group, imipramine group, zinc + H89 + imipramine group, and LH model group exhibited significantly longer immobility time compared with the control group. Similarly, in the shock shuttle-escape test, these groups showed more failure escape time compared with the control group. Notably, the zinc + imipramine group displayed significantly shorter immobility time and fewer failures in both tests compared with the model group, zinc group, imipramine group and zinc + H89 + imipramine group (all P<0. 01). The expression levels of cytochrome oxidase and Kir4. 1 in the zinc group, imipramine group, zinc + H89 + imipramine group, and model group were higher than those of the control group, the expression levels of cytochrome oxidase and Kir4. 1 in the zinc group, imipramine group, zinc + imipramine group were lower than those of the model group, and the zinc + imipramine group exhibited significantly lower expression levels of cytochrome oxidase and Kir4. 1 in comparison with those of the zinc group and imipramine group (all P<0. 01). Conclusion Zinc pretreatment can rapidly enhance the antidepressant effects of imipramine. Its mechanism of action may be related to regulating the expression of Kir4. 1 and inhibiting the clustered discharge of the LHb, and this effect can be blocked by the PKA inhibitor H89. [ABSTRACT FROM AUTHOR]

Background: Diarrhea-dominant irritable bowel syndrome (IBS-D) is a deliberating and chronic condition that can impair social activities. Determining proper medication with satisfactory outcomes has been a challenge. The 5-hydroxytryptamine 3 receptor antagonist (5-HT3 RA) drugs have demonstrated favorable outcomes on IBS-D in the last 3 decades. Ondansetron, also a 5-HT3 RA is known as an antiemetic. Our aim was to evaluate the efficacy of ondansetron in IBS-D. Methods: In this single-center, double-blind, randomized controlled trial, patients with IBS-D were recruited. Patients were randomized on a 1:1 ratio and assigned into two groups: imipramine 25 mg/daily plus ondansetron 4 mg/3 times per day and imipramine 25 mg/daily plus placebo. The primary endpoint was the frequency of diarrhea per day after 8 weeks of treatment. The secondary endpoints consisted of changes in the frequency of defecation urgency per day, the number of days with gastrointestinal pain and bloating, and the patients' overall satisfaction regarding bowel habits after 8 weeks of the treatment. Results: Data from 98 patients were analyzed. Ondansetron, compared to placebo, improved the primary outcome, and the stool consistency was increased significantly (3.29 ± 1.19 vs 4.55 ± 1.17, P < 0.001). Moreover, the response rate for the diarrhea frequency was significantly higher in the ondansetron group compared to the placebo (77.5% vs 34.7%, P < 0.001). In the ondansetron group, fewer urgencies were experienced, and pain severity and feeling of bloating declined as well (P < 0.01). Conclusion: Ondansetron can mitigate almost all IBS-D-related symptoms, which may indicate it as a drug of choice; however, further evidence is required to ascertain its safety. [ABSTRACT FROM AUTHOR]

Background: Nano-structure Lipid Carriers (NLCs) are small spheres extending in scale from 10 to 1000 nanometres comprised of biocompatible and biodegradable lipids. These spheres can encapsulate both hydrophilic and lipophilic drugs, preserving them from degradation and increasing their distribution to the intended place in the body. Imipramine, a tricyclic antidepressant, has been investigated in hamster model at 5-10 mg/kg for experimental leishmaniasis. The goal of this research is to develop Imipramine in a nano-structured lipid carrier formulation for targeting macrophage cells. Materials and Methods: Imipramine-loaded NLCs were created employing Glyceryl Monostearate (GMS) as the solid lipid constituent alongside oleic acid as the liquid lipid, while tween80 acted as the surfactant. The process of hot homogenization was employed to prepare the NLCs. The formulation was optimized using 2³ factorial designs using design expert software. The optimised formulation was further used for the preparation of mannose functionalized imipramine-loaded NLCs. Results: The IMP-NLC opt and M-NLC show a globule size of 348.5±0.81 nm and 459.4±0.28 nm with encapsulation efficiency of 61.6±0.326% and 64.48±0.408%, respectively. The drug release in vitro demonstrates a dual-phase pattern, featuring an early rapid sudden release followed by a gradual and slower release. The surface morphology, drug release kinetics and stability were also used to characterize the prepared NLCs. Conclusion: This study concludes that nanostructured lipid carriers demonstrate considerable encapsulation efficiency, release and stability for further pre-clinical investigation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory loss. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and antioxidant properties in the central nervous system. The aim of this study was to investigate the neuroprotective effects of imipramine on streptozotocin (STZ)-induced memory impairment. Male Wistar rats received an intracerebroventricular injection of STZ (3 mg/kg, 3 μl/ventricle) using the stereotaxic apparatus. The Morris water maze and passive avoidance tests were used to evaluate cognitive functions. 24 h after the STZ injection, imipramine was administered intraperitoneally at doses of 10 or 20 mg/kg for 14 consecutive days. The mRNA and protein levels of neurotrophic factors (BDNF and GDNF) and pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) were measured in the hippocampus using real-time PCR and ELISA techniques, respectively. In addition, real-time PCR was used to evaluate the mRNA levels of markers associated with neurogenesis (Nestin, DCX, and Ki67) and mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM). The results showed that imipramine, especially at a dose of 20 mg/kg, effectively improved STZ-induced memory impairment. This improvement was associated with an increase in neurogenesis and neurotrophic factors and a decrease in neuroinflammation and mitochondrial biogenesis dysfunction. Based on these results, imipramine appears to be a promising therapeutic option for improving cognitive functions in neurodegenerative diseases such as AD.

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep–wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep–wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep–wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: (1) what effects do imipramine and fluoxetine have on the sleep–wake cycle and the characteristics of sleep spindles in WAG/Rij rats and (2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep–wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of "slow" and "medium" spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep–wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data. [ABSTRACT FROM AUTHOR]

Knowledge of gender-specific drug distributions in different organs are of great importance for personalized medicine and reducing toxicity. However, such drug distributions have not been well studied. In this study, we investigated potential differences in the distribution of imipramine and chloroquine, as well as their metabolites, between male and female kidneys. Kidneys were collected from mice treated with imipramine or chloroquine and then subjected to atmospheric pressure matrix-assisted laser desorption ionization-mass spectrometry imaging (AP-MALDI-MSI). We observed differential distributions of the drugs and their metabolites between male and female kidneys. Imipramine showed prominent distributions in the cortex and medulla in male and female kidneys, respectively. Desipramine, one of the metabolites of imipramine, showed significantly higher (*** p < 0.001) distributions in the medulla of the male kidney compared to that of the female kidney. Chloroquine and its metabolites were accumulated in the pelvis of both male and female kidneys. Interestingly, they showed a characteristic distribution in the medulla of the female kidney, while almost no distributions were observed in the same areas of the male kidney. For the first time, our study revealed that the distributions of imipramine, chloroquine, and their metabolites were different in male and female kidneys. [ABSTRACT FROM AUTHOR]

Background: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. Methods: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Discussion: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and antimetastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. Clinical trial registration: https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17. [ABSTRACT FROM AUTHOR]

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo‐controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate‐certainty to low‐certainty evidence). Nonsteroidal anti‐inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate‐to‐severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided. • Serotonin transporter knockout rats can model patients with bipolar disorder. • Imipramine treatment increases signs of mania-like behavior in female model rats. • Imipramine activates the brain BDNF-TrkB-Akt pathway in female model rats. [ABSTRACT FROM AUTHOR]

Objectives: Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access. Interventions: Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations. Primary Outcomes: Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts. Results: Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified (N = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes. Conclusions: Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed. [ABSTRACT FROM AUTHOR]

This study sought to identify pathways affected by rat cortical RNA that were changed after treatment with fluoxetine or imipramine. We measured levels of cortical RNA in male rats using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (0.9% NaCl), fluoxetine (10 mg/kg/day) or imipramine (20 mg/kg/day) for 28 days. Levels of coding and non-coding RNA in vehicle treated rats were compared to those in treated rats using ANOVA in JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify pathways involving the changed RNAs. 18,876 transcripts were detected; there were highly correlated changes in 1010 levels of RNA after both drug treatments that would principally affect the metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding. Using our previously published data, we compared changes in transcripts after treatment with antipsychotic and mood stabilising drugs. Our study shows there are common, correlated, changes in coding and non-coding RNA in the rat cortex after treatment with fluoxetine or imipramine; we propose the pathways affected by these changes are involved in the therapeutic mechanisms of action of antidepressant drugs. [ABSTRACT FROM AUTHOR]

Tabernaemontana coronaria is an ornamental, evergreen, dichotomously branched shrub or small tree with large, shiny dark green leaves and white coloured flowers, pinwheel arrangement of petals, which are especially fragment at night. Stems exude milky latex when broken. The root is acrid, digestible with a bitter and bad taste. No specific environmental conditions are required for the growth of the plant. It can easily grow in garden and along roadsides. The plant is highly used in Chinese, Ayurvedic and Thai traditional medicine for the treatment of several diseases. Phytochemical studies revealed the bioactive chemical constituents of the plants such as monoterpene indole alkaloids, flavonoids, proteins, glycosides, carbohydrates, steroids, enzymes and phenolic acids from leaves, stems and roots of the plant. Pharmacological studies found that the plant extract has an anti-inflammatory, anticancer, antioxidant, antifertility, antifungal, antimicrobial, antidiabetic, antimalarial, cardiovascular effects, hypolipidemic, anticataract, antitussive, insecticidal, antidepressant, anxiolytic activity, local anaesthetic activity, anti-acetylcholinesterase activity, wound healing, hepatoprotective and gastroprotective properties. This article briefly describes the ethanomedicinal uses, pharmacognostical studies, phytochemical constituents and pharmacological activities of Tabernaemontana coronaria plant and it's bring the research up-to-date on the bioactive compounds produced by Tabernaemontana coronaria, directly or indirectly releated to the human health. [ABSTRACT FROM AUTHOR]

Depression, a global cause of disability and premature death, is often treated by traditional healers in Africa using medicinal herbs such as Ximenia americana (L.). With recent pharmacological studies showing the potential antidepressant properties of X. americana extract, this study aimed to evaluate the antidepressant-like effects of the compound(s) isolated from X. americana extract using the forced swim test (FST) and tail suspension test (TST) models predictive of depression. The extracts, administered orally within a dose range of 100–400 mg/kg, notably decreased the immobility time in both the FST and the TST. The most significant reduction occurred at the highest dose of 400 mg/kg, with a decrease of 117.66 s in FST and 53.5 s in TST. However, this reduction in immobility was not linked to changes in movements, as observed in an open-field test (OFT), suggesting that the effect of the extracts was not due to activation of locomotion. Subsequently, a sesquiterpene lactone, dehydrocostus lactone (1) was isolated through solubility-based fractionation and column chromatography of the active root bark extract of X. americana. Dehydrocostus lactone (400 mg/kg) demonstrated a 46.50 s reduction in immobility time in the FST, which was comparable to the positive control, imipramine (30 mg/kg). With a highly favorable docking score of −8.365 kcal/mol on an antidepressant target, monoamine oxidase A (MAO-A; pdb ID: 2BXS), dehydrocostus lactone (1) potentially outperforms the standard MAO-A inhibitor drug, isocarboxazid (−5.847 kcal/mol). Dehydrocostus lactone (1) displayed strong interactions involving hydrogen bond and hydrophobic and electrostatic interactions with specific MAO-A binding site residues. These findings highlight that the antidepressant-like activity of X. americana is partly attributed to the presence of dehydrocostus lactone. Additionally, it also supports the traditional medicinal use of the plant for treating depression. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is an intractable disease requiring long-term treatment. S-adenosyl-L-methionine (SAMe), a natural substance, has antidepressant effects, but the exact effect remains unclear. This study examines the evidence concerning the efficacy of SAMe as a monotherapy or in combination with antidepressants. The PubMed, EMBASE, and Cochrane electronic databases were searched for meta-analyses of randomized controlled clinical trials (RCTs) until June 30, 2023. We performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria, with the aim to compare the effects of SAMe to those of a placebo or active agents, or SAMe combined with other antidepressants in the treatment of MDD. Fourteen trials, with a total of 1522 subjects, were included in this review. The daily dose of SAMe varied from 200 to 3200 mg and the study duration ranged between 2 and 12 weeks. The results of SAMe versus placebo as a monotherapy, SAMe versus imipramine or escitalopram as a monotherapy, and SAMe versus placebo as an adjunctive therapy, showed no significant difference in depression with SAMe compared to the comparison treatment. SAMe may provide relief of depression symptoms similar to imipramine or escitalopram. However, the results of the comparisons should be interpreted with caution due to the small number of studies and the large range of SAMe doses that were used in the included trials. Therefore, we recommend that patients discuss treatment options with their doctor before taking SAMe. [ABSTRACT FROM AUTHOR]

The HSP70 and HSP90 family members belong to molecular chaperones that exhibit protective functions during the cellular response to stressful agents. We investigated whether the exposure of rats to chronic mild stress (CMS), a validated model of depression, affects the expression of HSP70 and HSP90 in the prefrontal cortex (PFC), hippocampus (HIP) and thalamus (Thal). Male Wistar rats were exposed to CMS for 3 or 8 weeks. The antidepressant imipramine (IMI, 10 mg/kg, i.p., daily) was introduced in the last five weeks of the long-term CMS procedure. Depressive-like behavior was verified by the sucrose consumption test. The expression of mRNA and protein was quantified by real-time PCR and Western blot, respectively. In the 8-week CMS model, stress alone elevated HSP72 and HSP90B mRNA expression in the HIP. HSP72 mRNA was increased in the PFC and HIP of rats not responding to IMI treatment vs. IMI responders. The CMS exposure increased HSP72 protein expression in the cytosolic fraction of the PFC and HIP, and this effect was diminished by IMI treatment. Our results suggest that elevated levels of HSP72 may serve as an important indicator of neuronal stress reactions accompanying depression pathology and could be a potential target for antidepressant strategy. [ABSTRACT FROM AUTHOR]

Background & Objective: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by changes in bowel movements and abdominal pain in the absence of structural disorders. Although effective treatment for irritable bowel syndrome is not yet available. One of the treatments is the low-dose antidepressants, depending on the type and severity of the disease. This study was performed to compare the effect of selective serotonin-norepinephrine reuptake inhibitors including duloxetine and imipramine from a tricyclic antidepressant Materials & Methods: forty-eight definitively diagnosed IBS patients (based on Rome III criteria) were examined in 2 groups of men and women. Patients in the control group were treated with Dicyclomine and Imipramine while the case group received dicyclomine and duloxetine. The outcomes were measured before and 3 months after treatment to determine and compare the improvement in responses (mainly diarrhea). Results: Duloxetine could significantly improve the symptoms such as abdominal pain in females (P-value: 0.01) and males (P-value: 0.001), bloating in females (Pvalue: 0.004) and incomplete defecation in females (P-value: 0.001) and in males (Pvalue: 0.007). The side effects of this drug were, however, higher than Imipramine. The introduction of more appropriate treatment requires further studies on a larger sample size to assess the symptoms and the side effects. Conclusion: Based on the effect of duloxetine on this clinical results, it is recommended as an effective treatment in controlling of abdominal pain, bloating, and incomplete defecation. [ABSTRACT FROM AUTHOR]

Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes. [ABSTRACT FROM AUTHOR]

Ether-a-go-go (EAG) channels are key regulators of neuronal excitability and tumorigenesis. EAG channels contain an Nterminal Per-Arnt-Sim (PAS) domain that can regulate currents from EAG channels by binding small molecules. The molecular mechanism of this regulation is not clear. Using surface plasmon resonance and electrophysiology we show that a small molecule ligand imipramine can bind to the PAS domain of EAG1 channels and inhibit EAG1 currents via this binding. We further used a combination of molecular dynamics (MD) simulations, electrophysiology, and mutagenesis to investigate the molecular mechanism of EAG1 current inhibition by imipramine binding to the PAS domain. We found that Tyr71, located at the entrance to the PAS domain cavity, serves as a "gatekeeper" limiting access of imipramine to the cavity. MD simulations indicate that the hydrophobic electrostatic profile of the cavity facilitates imipramine binding and in silico mutations of hydrophobic cavity-lining residues to negatively charged glutamates decreased imipramine binding. Probing the PAS domain cavity-lining residues with site-directed mutagenesis, guided by MD simulations, identified D39 and R84 as residues essential for the EAG1 channel inhibition by imipramine binding to the PAS domain. Taken together, our study identified specific residues in the PAS domain that could increase or decrease EAG1 current inhibition by imipramine binding to the PAS domain. These findings should further the understanding of molecular mechanisms of EAG1 channel regulation by ligands and facilitate the development of therapeutic agents targeting these channels. [ABSTRACT FROM AUTHOR]

Xerostomia induced by antidepressants such as imipramine has long been thought to be due to their anticholinergic effects. However, even antidepressants with low anticholinergic effects may have a high incidence of xerostomia. In salivary glands, norepinephrine activates alpha-adrenergic receptors in blood vessels and beta-adrenergic receptors in acinar cells, respectively, causing a decrease in the blood flow and an increase in the protein secretion, resulting in the secretion of viscous saliva with low water content and high protein content. A previous study demonstrated that perfusion of the submandibular glands of rats with serotonin significantly decreased saliva secretion. The results of the present study revealed the following: (1) that norepinephrine and serotonin, but not epinephrine nor dopamine, were detected in the interstitial fluids in rat submandibular glands; (2) that norepinephrine and serotonin concentrations in the dialysate was 4.3 ± 2.8 nM and 32.3 ± 19.6 nM at stable level, respectively; (3) that infusion with imipramine, a reuptake inhibitor of norepinephrine and serotonin, significantly and dose-dependently increased both norepinephrine and serotonin concentrations in the dialysate; and (4) that intraperitoneal administration of imipramine significantly increased both norepinephrine and serotonin concentrations in the dialysate. These results suggested that one of the mechanisms of xerostomia induced by reuptake inhibitors of norepinephrine and serotonin involves the activation of adrenergic and serotonin receptors in the salivary glands, respectively.

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains.

Abstract In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.

Brucellosis infection causes non-specific symptoms such as fever, chills, sweating, headaches, myalgia, arthralgia, anorexia, fatigue, and mood disorders. In mouse models, it has been associated with increased levels of IL-6, TNF-α, and IFN-γ, a decrease in serotonin and dopamine levels within the hippocampus, induced loss of muscle strength and equilibrium, and increased anxiety and hopelessness. Imipramine (ImiP), a tricyclic antidepressant, is used to alleviate neuropathic pain. This study evaluated the effects of ImiP on Balb/c mice infected with Brucella abortus 2308 (Ba) at 14- and 28-days post-infection. Serum levels of six cytokines (IFN-γ, IL-6, TNF-α, IL-12, MCP-1. and IL-10) were assessed by FACS, while the number of bacteria in the spleen was measured via CFU. Serotonin levels in the hippocampus were analyzed via HPLC, and behavioral tests were conducted to assess strength, equilibrium, and mood. Our results showed that mice infected with Brucella abortus 2308 and treated with ImiP for six days (Im6Ba14) had significantly different outcomes compared to infected mice (Ba14) at day 14 post-infection. The mood was enhanced in the forced swimming test (FST) (p < 0.01), tail suspension test (TST) (p < 0.0001), and open-field test (p < 0.0001). Additionally, there was an increase in serotonin levels in the hippocampus (p < 0.001). Furthermore, there was an improvement in equilibrium (p < 0.0001) and muscle strength (p < 0.01). Lastly, there was a decrease in IL-6 levels (p < 0.05) and CFU count in the spleen (p < 0.0001). At 28 days, infected mice that received ImiP for 20 days (Im20Ba28) showed preservation of positive effects compared to infected mice (Ba28). These effects include the following: (1) improved FST (p < 0.0001) and TST (p < 0.0001); (2) better equilibrium (p < 0.0001) and muscle strength (p < 0.0001); (3) decreased IL-6 levels (p < 0.05); and (4) reduced CFU count in the spleen (p < 0.0001). These findings suggest the potential for ImiP to be used as an adjuvant treatment for the symptoms of brucellosis, which requires future studies. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to determine the confidence level of mental health practitioners in Oman regarding the use of antidepressants during pregnancy and breastfeeding, assess their knowledge and need for further training in this area, and examine their current prescribing patterns and preferences. Methods: A questionnaire-based survey was conducted from May to June 2017 among all practitioners in the psychiatry specialty, including medical officers authorized to prescribe medications, at the Behavioral Medicine Department of Sultan Qaboos University Hospital and Al Masarra Hospital. Results: Forty-two practitioners (response rate = 89.4%) responded to the questionnaire. Of them, 10 (23.8%) had no experience, while 30 (71.4%) had experience in prescribing antidepressants during both pregnancy and breastfeeding periods. Twenty-seven (64.3%) respondents felt that they were confident in prescribing antidepressants for women during their perinatal period, while 30.0% were neutral. Moreover, 35 (83.3%) participants expressed the need for more training in this area. Furthermore, 34 (81.0%) believed that more training in perinatal psychiatry should be included in the psychiatry curriculum. There was no consistent prescribing pattern (either prescribing or avoiding) among our participating practitioners during the first trimester of pregnancy and breastfeeding periods. The drug of choice in the first trimester of pregnancy was fluoxetine preferred by approximately 85.0% of the practitioners, but avoided by 10.0% of practitioners in the same period. This was followed by amitriptyline (50.0% vs. 23.0%), sertraline (50.0% vs. 9.0%), imipramine (28.0% vs. 84.0%). During breastfeeding, the drug of choice for approximately 74.0% of the practitioners was paroxetine, but avoided by 15.0% of practitioners. This was followed by sertraline (50.0% vs. 8.0%). The most common reasons for prescription during pregnancy were safety, evidence-based practice, and low teratogenicity. For breastfeeding, the main reasons for prescription were low levels of the drug in breast milk, safety, and evidence-based practice. On the other hand, high teratogenicity, neonatal side effects, limited data, and lack of evidence were among the most common reasons behind avoiding prescribing during pregnancy, while high levels of breast milk, neonatal side effects, limited evidence, and safety concerns were the most common reasons during the breastfeeding period. Conclusions: There was inconsistency among mental health practitioners in making prescription decisions and in their prescribing patterns. [ABSTRACT FROM AUTHOR]

This study introduces a reliable and inexpensive magnetic dispersive solid phase extraction to extract imipramine and its primary metabolite (desipramine) from urine samples. To accomplish this aim, Fe3O4 magnetic nanoparticles were synthesized by sonication, subsequently, polycarbonate was precipitated gradually onto the surface of them to form the adsorbent. Extraction recoveries of 85% and 76%, enrichment factors of 57 and 51, limits of detection of 2.5 and 2.8 μg/L, and limits of quantification of 8.3 and 9.3 μg/L were obtained for imipramine and desipramine under the optimal conditions, respectively. In addition, relative standard deviations for intra‐ (n = 6) and inter‐day (n = 5) precisions at two concentrations (50 and 100 μg/L of each analyte) were less than or equal to 4%. Short extraction time, good repeatability, high enrichment factors, and simplicity are the main advantages of the proposed method. [ABSTRACT FROM AUTHOR]

Knowledge of gender-specific drug distributions in different organs are of great importance for personalized medicine and reducing toxicity. However, such drug distributions have not been well studied. In this study, we investigated potential differences in the distribution of imipramine and chloroquine, as well as their metabolites, between male and female kidneys. Kidneys were collected from mice treated with imipramine or chloroquine and then subjected to atmospheric pressure matrix-assisted laser desorption ionization-mass spectrometry imaging (AP-MALDI-MSI). We observed differential distributions of the drugs and their metabolites between male and female kidneys. Imipramine showed prominent distributions in the cortex and medulla in male and female kidneys, respectively. Desipramine, one of the metabolites of imipramine, showed significantly higher (*** p < 0.001) distributions in the medulla of the male kidney compared to that of the female kidney. Chloroquine and its metabolites were accumulated in the pelvis of both male and female kidneys. Interestingly, they showed a characteristic distribution in the medulla of the female kidney, while almost no distributions were observed in the same areas of the male kidney. For the first time, our study revealed that the distributions of imipramine, chloroquine, and their metabolites were different in male and female kidneys.