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Depression is a mental illness that affects patients' behavior, and it impacts approximately 264 million people globally. Tetracyclic antidepressants (TeCAs) are one class of medication that is available for the treatment of depression. These medications work by modifying hormones such as serotonin, norepinephrine, and dopamine. TeCAs, such as setiptiline, amoxapine, mianserin, maprotiline, and mirtazapine, are four ring‐based compounds that assist in preventing the brain from reabsorbing the neurotransmitters norepinephrine and serotonin. Each of these medications interacts with adrenergic (α1 and α2) and serotonin (5HT1 and 5HT2) receptors independently. Using biological samples (plasma, blood, and urine) and pharmaceutical formulations, this review focuses on providing a complete overview of the various analytical conditions maintained for the medications in the above class and their metabolites. Major analytical methods such as mass spectrometry, gas chromatography, and high‐performance liquid chromatography are used to quantify and determine the drugs. This review provides a thorough understanding of impurity identification, pharmacokinetic and stability evaluations, and structural degradation quantification. It provides valuable and reliable information for research, enhancing their understanding of the subject matter. [ABSTRACT FROM AUTHOR]

Dermatofibrosarcoma protuberans is a soft tissue tumor that arises from the dermis. This relatively rare, low-grade tumor has a high propensity for local recurrence unless it is completely excised. Dermatofibrosarcoma protuberans classically progresses slowly as a plaque on the trunk of young adults. It often resembles a scar that is slowly growing overmonths to years. Because of its rarity and subtle progression, this form of skin cancer will often go undiagnosed for years. Over time, dermatofibrosarcoma protuberans can become invasive into the subcutaneous fat, muscle, fascia, and chestwall. Diagnosis of dermatofibrosarcoma protuberans is made by a core needle or incisional biopsy. Once diagnosed, cure rates approach 100%. The purpose of this article is to review the epidemiology, pathophysiology, clinical features, differential diagnosis, diagnosis, staging, and treatment of dermatofibrosarcoma protuberans. Increasing healthcare providers' awareness about this rare form of skin cancer and its recognition may improve patient outcomes. [ABSTRACT FROM AUTHOR]

Potentiometry with membrane selective electrodes is preferable for measuring the various constituents of pharmaceuticals. In this work, carbon paste electrodes (CPE) were prepared, modified, and tested for the determination of maprotiline hydrochloride, which acts as an antidepressant. The proposed CPE was based on an ionic association complex of maprotiline-tetraphenylborate, 2-nitrophenyloctyl as a binder, and sodium tetraphenylborate as an ionic lipophilic additive. The optimized composition improved potentiometric properties up to theoretical Nernst response values of −59.5 ± 0.8 mV dec−1, in the concentration range of maprotiline from 1.6 × 10−7 to 1.0 × 10−2 mol L−1, and a detection limit of 1.1 × 10−7 mol L−1. The CPE provides excellent reversibility and reproducibility, exhibits a fast response time, and is applicable over a wide pH range. No significant effect was observed in several interfering species tested. The proposed electrode was used for the precise determination of maprotiline in pure solutions, urine samples, and a real sample—the drug Ludiomil. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc finger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Maprotiline is an antidepressant that has been found to cause hypoglycemia. However, the effect of maprotiline on diabetic nephropathy (DN) has not been investigated. Here, we explored the effect of maprotiline on human renal glomerular endothelial cells (HRGECs) in response to high glucose (HG) stimulation. We found that maprotiline attenuated HG-induced oxidative stress in HRGECs with decreased reactive oxygen species production and increased superoxide dismutase activity. Maprotiline repressed the HG-induced expression of cyclooxygenases 2 at both mRNA and protein levels in HRGECs. The increased thromboxane B2 level and decreased 6-keto-prostaglandin F1α level induced by HG were significantly attenuated by maprotiline treatment. Maprotiline also prevented the HG-induced increase in the permeability of HRGECs and the decrease in the zonula occludens-1 expression and downregulated HG-induced increase in the expression of protein kinase C-α (PKC-α) in HRGECs. This protective effect of maprotiline on HG-induced HRGECs dysfunction was abolished by overexpression of PKC-α. In conclusion, maprotiline displayed a protective effect on HG-challenged HRGECs, which was mediated by the regulation of PKC-α. These findings provide further evidence for the potential use of maprotiline for the treatment of DN. [ABSTRACT FROM AUTHOR]

Maprotiline (MAP), is an active ingredient of some antidepressants which has been broadly used for the therapy of depression. The overdose of MAP in the treatment of patients with depression can lead to significant side effects, even lethal intoxication. Therefore, it is very important to develop simple, inexpensive, fast and reliable detection methods for MAP in interested samples. In our present study, we have offered a novel poly(vinylchloride) (PVC) membrane maprotiline‐selective potentiometric sensor based on a type of MOFs, known as MIL‐53(Al), as electroactive ionophore substance. The sensor prepared at the optimum membrane composition exhibited a linear response for maprotiline hydrochloride in the concentration range of 1,0×10−9 M−1,0×10−2 M with a slope of 59,1 mV/decade and detection limit of 9,0×10−10 M. The pH working range of the sensor was determined as 2,0–9,5. The response time of the sensor was very fast and less than 5 s. With these performance features, it has been shown that the current sensor has quite superior features compared to the potentiometric MAP‐selective sensor available in the literature. The potentiometric application of the sensor was successfully carried out with the detection of MAP in pharmaceutical tablets containing MAP‐HCl. [ABSTRACT FROM AUTHOR]

Potentiometry with membrane selective electrodes is preferable for measuring the various constituents of pharmaceuticals. In this work, carbon paste electrodes (CPE) were prepared, modified, and tested for the determination of maprotiline hydrochloride, which acts as an antidepressant. The proposed CPE was based on an ionic association complex of maprotiline-tetraphenylborate, 2-nitrophenyloctyl as a binder, and sodium tetraphenylborate as an ionic lipophilic additive. The optimized composition improved potentiometric properties up to theoretical Nernst response values of −59.5 ± 0.8 mV dec−1, in the concentration range of maprotiline from 1.6 × 10−7 to 1.0 × 10−2 mol L−1, and a detection limit of 1.1 × 10−7 mol L−1. The CPE provides excellent reversibility and reproducibility, exhibits a fast response time, and is applicable over a wide pH range. No significant effect was observed in several interfering species tested. The proposed electrode was used for the precise determination of maprotiline in pure solutions, urine samples, and a real sample—the drug Ludiomil.

Maprotiline, a tetracyclic antidepressant, is used for the management of mental disorders and various types of chronic pain. In our previous work, we found the inhibitory effect of maprotiline on inflammatory mediator’s expression like tumor necrosis factor  (TNF-) and interleukin 1β (IL-1β). As part of that study, we sought to evaluate the effect of maprotiline on the expression of some inflammatory mediators such as cyclooxygenases 2 (COX2) and inducible nitric oxide synthase (iNOS). For this reason we used an in vitro model system of lipopolysaccharide (LPS)-stimulated human U937 macrophages and also an in vivo model of carrageenan-induced paw edema in rats. We measured the expression of these genes by quantitative RT-real time PCR. The expression of COX2 and iNOS significantly decreased by maprotiline in U937 macrophages and carrageenan-induced paw inflammation in rats. Our finding also confirmed that intraperitoneal (i.p.) injection of maprotiline inhibited carrageenan-induced paw edema. Moreover, maprotiline significantly decreased the migration of polymorphonuclear (PMN) leukocytes to the site of inflammation. The results of the present study provide further evidence for the anti-inflammatory effect of maprotiline. This effect appears to be mediated by down regulation of inflammatory genes. Further studies are needed to evaluate the complex cellular and molecular mechanisms of maprotiline.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC. [ABSTRACT FROM AUTHOR]

Objective: To reveal the effect and mechanism of Jiaotai Pill (交泰丸, JTP) on insomniac rats. Methods: The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). In behavioral experiments, rats were divided into control, insomniac model, JTP [3.3 g/(kg•d)], and diazepam [4 mg/(kg•d)] groups. The treatment effect of JTP was evaluated by weight measurement (increasement of body weight), open field test (number of crossings) and forced swimming test (immobility time). A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal, model, JTP, citalopram [30 mg/(kg•d)], maprotiline [40 mg/(kg•d)] and bupropion [40 mg/(kg•d)] groups. Expressions of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) were analyzed by quantitative polymerase chain reaction (qPCR) and Western blot in normal, model and JTP groups. A high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method was established to determine the pharmacokinetics, urine cumulative excretion of metformin in vivo, and tissue slice uptake in vitro, which were applied to assess the activity of organic cation transporters (OCTs) in hypothalamus and peripheral organs. Results: Compared with the insomniac model group, the body weight and spontaneous locomotor were increased, and the immobility time was decreased after treatment with JTP (P<0.01). Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased (P<0.01). The norepinephrine content was increased in peripheral organs and decreased in hypothalamus (P<0.05 or P<0.01). At the same time, SERT, DAT, OCT1, OCT2, and OCT3 were down-regulated in hypothalamus and peripheral organs (P<0.05). NET was down-regulated in peripheral organs and up-regulated in hypothalamus (P<0.05 or P<0.01). Moreover, the activity of OCTs in hypothalamus and peripheral organs was inhibited (P<0.05). Conclusion: JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs. [ABSTRACT FROM AUTHOR]

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2–CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery.

Background: Research has revealed that the expression of PD-L1 is significantly upregulated in tumour cells and that the binding of programmed cell death protein 1 (PD-1) to programmed cell death 1 ligand 1 (PD-L1) inhibits the response of T cells, thereby suppressing tumour immunity. Therefore, blocking PD-L1/PD-1 signalling has become an important target in clinical immunotherapy. Some old drugs, namely, non-anticancer drugs, have also been found to have antitumour effects, and maprotiline is one of them. Maprotiline is a tetracyclic antidepressant that has been widely used to treat depression. However, it has not yet been reported whether maprotiline can exert an antitumour effect on melanoma., Objective: This study aimed to investigate the antitumour efficacy of maprotiline in mice with melanoma., Methods: In this study, female C57BL/6 mice were used to establish a tumour-bearing animal model. After treatment with maprotiline, the survival rate of mice was recorded daily. The expression of relevant proteins was detected by Western blotting, the proportion of immune cells was detected by flow cytometry, and the infiltration of immune cells in tumour tissue was detected by immunofluorescence staining., Results: Maprotiline was found to inhibit the proliferation and migration of B16 cells while increasing cell apoptosis. Importantly, treatment with maprotiline decreased the expression of PD-L1 and increased the proportion of CD4+ T cells, CD8+ T cells, and NK cells in the spleen. It also increased the infiltration of CD4+ and CD8+ T cells in tumour tissue., Conclusion: Our research findings suggest that maprotiline enhances the antitumour immune response in mouse melanoma by inhibiting PD-L1 expression. This study may discover a new PD-L1 inhibitor, providing a novel therapeutic option for the clinical treatment of tumours., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This current study aimed to develop a simple, fast, and reproducible isocratic reverse-phase ultra-fast liquid chromatographic (RP-UFLC) method to detect and quantify maprotiline hydrochloride (MAP) in bulk drug and pharmaceutical formulations. Chromatographic separation was accomplished on a C18 column (100 × 4mm, 3 µm) under isocratic elution with the use of a binary solution of acetonitrile and phosphate buffer at a pH of 7 (75 : 25, v/v) and a flow rate of 0.4 mL per minute at 215 nm. The linearity was excellent in the concentration range of MAP from 0.1 to 1.5 µg/mL with a regression coefficient of 0.9996. The proposed method was validated with the respective ICH guidelines. The drug was subjected to hydrolytic, acidic, basic, thermal, photolytic, and oxidative stress conditions as required by the ICH regulation. The method was found to be suitable for use in routine practice to analyze MAP in the pharmaceutical dosage form. [ABSTRACT FROM AUTHOR]

Summary: We investigated the potential augmenting effects of 19 clinically available antidepressants on noradrenaline (NA)‐induced contractions in guinea pig urethra smooth muscle (USM). Concentration‐response curves for NA‐induced contractions in guinea pig USM strips were obtained in the absence or presence of selected antidepressants. Desipramine, an active metabolite of imipramine, produced a contraction and potentiated NA‐induced contraction at the distal urethra without affecting the proximal urethra. Further, nortriptyline and amoxapine, tricyclic antidepressants, produced a contraction and potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected or reduced by imipramine, clomipramine, trimipramine, and amitriptyline at the proximal and distal urethra. Maprotiline, a tetracyclic antidepressant, potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected by mianserin at the proximal and distal urethra. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), potentiated NA‐induced contraction at the distal urethra, while NA‐induced contraction was unaffected by fluvoxamine, sertraline, and escitalopram at the proximal and distal urethra. Milnacipran, a serotonin‐noradrenaline reuptake inhibitor (SNRI), potentiated NA‐induced contraction at the proximal and distal urethra, whereas duloxetine potentiated it at the distal urethra. Mirtazapine slightly inhibited NA‐induced contraction at the distal urethra. Aripiprazole and sulpiride did not affect NA‐induced contractions at the proximal nor distal urethra. Trazodone inhibited NA‐induced contraction at both urethras. Desipramine, nortriptyline, amoxapine, maprotiline, paroxetine, milnacipran, and duloxetine likely induce urinary disturbance by increasing urethral resistance and augmenting NA‐induced contraction, which should be carefully considered when delivering guidance for drug administration to patients. [ABSTRACT FROM AUTHOR]

Maprotiline, a tetracyclic antidepressant, is used for the management of mental disorders and various types of chronic pain. In our previous work, we found the inhibitory effect of maprotiline on inflammatory mediator's expression like tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). As part of that study, we sought to evaluate the effect of maprotiline on the expression of some inflammatory mediators such as cyclooxygenases 2 (COX2) and inducible nitric oxide synthase (iNOS). For this reason we used an in vitro model system of lipopolysaccharide (LPS)-stimulated human U937 macrophages and also an in vivo model of carrageenan-induced paw edema in rats. We measured the expression of these genes by quantitative RT-real time PCR. The expression of COX2 and iNOS significantly decreased by maprotiline in U937 macrophages and carrageenan-induced paw inflammation in rats. Our finding also confirmed that intraperitoneal (i.p.) injection of maprotiline inhibited carrageenan-induced paw edema. Moreover, maprotiline significantly decreased the migration of polymorphonuclear (PMN) leukocytes to the site of inflammation. The results of the present study provide further evidence for the anti-inflammatory effect of maprotiline. This effect appears to be mediated by down regulation of inflammatory genes. Further studies are needed to evaluate the complex cellular and molecular mechanisms of maprotiline. [ABSTRACT FROM AUTHOR]

The synthesis of [9, 10-dihydro-9-(4-methylaminobutyl)-9, 10-propanoanthracene] (2) as a homolog of the antidepressant [9, 10-dihydro-9-(3-methylaminopropyl)-9, 10-ethanoanthracene] (1) is described in the present paper. The key intermediate [9, 10-dihydro (4-pentyl)-9, 10- propanoanthracene-12-one] (7) is successfully synthesized by using the reaction of α-bromoacrolein with 9-pent-4-enyl-anthracene (4) followed by ring expansion and samarium diiodide deoxygenation.

Regardless of the known anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. In our earlier work, maprotiline, a heterocyclic antidepressants, considerably inhibited infiltration of polymorphonuclear cell leucocytes into the inflamed paw . To understand the mechanism involved, we evaluated the effect of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1) expression in stimulated endothelial cells. Endothelial cells were stimulated with lipopolysaccharide (LPS) in the presence and absence of maprotiline (10 -8 to 10 -6 M) and ICAM-1 and VCAM-1 expression were measured using real-time quantitative reverse transcription polymerase chain reaction. Maprotiline significantly decreased the LPS-induced expression of VCAM-1 at all applied concentrations. The expression of ICAM-1 decreased in the presence of maprotiline at 10 -6 M concentration (P<0.05). Since maprotiline inhibits the expression of adhesion molecules, ICAM-1 and VCAM-1 in LPS-stimulated human endothelial cells , it can be a possible way through which maprotiline exerts its anti-inflammatory properties.

Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt’s lymphoma (BL) is a rare form of non-Hodgkin’s lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity of a library of 9,10-dihydro-9,10-ethanoanthracene based compounds structurally related to the antidepressant drug maprotiline against BL cell lines MUTU-1 and DG-75. Structural modifications were achieved by Diels-Alder reaction of the core 9-(2-nitrovinyl)anthracene with number of dienophiles including maleic anhydride, maleimides, acrylonitrile and benzyne. The antiproliferative activity of these compounds was evaluated in BL cell lines EBV− MUTU-1 and EBV+ DG-75 (chemoresistant). The most potent compounds 13j, 15, 16a, 16b, 16c, 16d and 19a displayed IC50 values in the range 0.17−0.38 μM against the BL cell line EBV− MUTU-1 and IC50 values in the range 0.45−0.78 μM against the chemoresistant BL cell line EBV+ DG-75. Compounds 15, 16b and 16c demonstrated potent ROS dependent apoptotic effects on the BL cell lines which were superior to the control drug taxol and showed minimal cytotoxicity to peripheral blood mononuclear cells (PBMCs). The results suggest that this class of compounds merits further investigation as antiproliferative agents for BL.

Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a tetracyclic antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

Objective(s): Neuropathic pain remains a clinical problem and is poorly relieved by conventional analgesics. This study was designed to determine whether maprotiline administration was effective in alleviating symptoms of neuropathic pain and whether the antinociceptive effect of maprotiline mediated through the opioid system. Materials and Methods: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats, which resulted in thermal hyperalgesia, and mechanical and cold allodynia. Maprotiline (10, 20 and 40 mg/kg, IP) was administered on the 7th and 14th days after surgery. To study the role of the opioid system in the antinociceptive effects of maprotiline, maprotiline (20 mg/kg, IP) was administered in combination with naloxone (1 mg/kg, SC) on the 7th post-surgery day. Behavioral tests were done at 45 min after drug injections on the 7th and 14th days after surgery. Results:Systemic administration of maprotiline blocked heat hyperalgesia, cold allodynia and reduced mechanical allodynia. Also antihyperalgesic effect of maprotiline was reversed by pretreatment with naloxone. Conclusion: Our results suggest that maprotiline can be considered a potential therapeutic for the treatment of neuropathic pain, and the opioid system may be involved in the antihyperalgesic effects of maprotiline.

Background: Maprotiline is a tricyclic antidepressant (sometimes classified as a tetracyclic antidepressant), which is predominantly a norepinephrine/noradrenaline reuptake inhibitor, commonly prescribed for depression. Aim: To present a female patient with depressive episode and occurrence of hyponatremia during the maprotiline treatment. Case Report: A 62-year-old female was diagnosed with depressive episode four years ago. She was treated ambulatory with maprotiline 50mg/day and bromazepam 6mg/ day, from local psychiatrist. The patients also used enalapril 2x10 mg/day, metoprolol 2x50 mg/day, nifedipine 5 mg/day and simvastatin 20 mg/day for treating hypertension and dyslipidemia. After about 12 months of maprotiline use she was hospitalized at the Endocrinology unit of a local hospital due to appearance of confusion, unstable walking, cramps, as well as an increase in blood pressure. Then diagnosed hyponatremia (serum sodium level-112 mmol/L), corrected (137 mmol/L) by using parenteral therapy. The patient continued to use maprotiline without consultation with her psychiatrist. After one year, the patient was hospitalized at the Endocrinology unit of tertiary level due to detailed re-examination because of recurrent hyponatramia (117 mmol/L), corrected (136 mmol/L) by ambulatory use of parenteral therapy at a local hospital. Water test load was used and the Syndrome of inappropriate antidiuretic hormone secretion was diagnosed. Insulin Tolerance Test showed preserved the integrity of the hypothalamic-pituitary-adrenal axis. Antidepressant mirtazapine (15 mg/ day) was introduced due to recurrence of depression. Gradual reduction of depressive symptoms was observed to mirtazapine. Antihypertensive therapy, restriction of fluid intake and dietary regimen were still applied. Serum sodium concentrations were in the normal ranges over the past 18 months. Conclusion: Serum sodium level should be measured before and during the therapy with any class of antidepressants, especially in those patients with increased risk of the hyponatremia occurrence.

Background: As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure.Methods: We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard-dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes.Results: Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (N [number of studies] = 2, n [number of patients] = 448), sertraline (N = 2, n = 272), paroxetine (N = 2, n = 146), duloxetine (N = 1, n = 255), and maprotiline (N = 1, n = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (N = 7, n = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; p = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes.Conclusions: According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression. [ABSTRACT FROM AUTHOR]

The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral components of heart rhythm variability were examined in outbred male and female rats treated with these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral components in male and female rats. Maprotiline elevated LF and VLF components in males at rest, increased HR and reduced all spectral components in resting females. Stress against the background of DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components (especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF and VLF components. Thus, the central noradrenergic system participates in the formation of LF and VLF spectral components of heart rate variability at rest and especially during stressful stimulation, which can determine the phasic character of changes in the heart rate variability observed in stressed organism. [ABSTRACT FROM AUTHOR]

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 μM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo. [ABSTRACT FROM AUTHOR]

The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A 2 (iPLA 2 ) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline. Intraperitoneal injections of maprotiline increased iPLA 2 mRNA and protein expression in the prefrontal cortex. This treatment also reduced grooming responses to von-Frey hair stimulation of the face after facial carrageenan injection, indicating decreased sensitivity to pain. The antinociceptive effect of maprotiline was abrogated by iPLA 2 antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA 2 antisense oligonucleotide to the somatosensory cortex did not reduce the antinociceptive effect of maprotiline. Lipidomic analysis of the prefrontal cortex showed decrease in phosphatidylcholine species, but increase in lysophosphatidylcholine species, indicating increased PLA2 activity, and release of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after maprotiline treatment. Differences in sphingomyelin/ceramide were also detected. These changes were not observed in maprotiline-treated mice that received iPLA 2 antisense oligonucleotide to the prefrontal cortex. Metabolites of DHA and EPA may help to strengthen a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate a role of prefrontal cortical iPLA 2 and its enzymatic products in the antinociceptive effect of maprotiline. [ABSTRACT FROM AUTHOR]

BackgroundThe aim of the study was to evaluate the comparative risk of self-harm associated with the use of different antidepressants.MethodA cohort study was conducted using data from Taiwan's National Health Insurance Research Database from 2001 to 2012. A total of 751 606 new antidepressant users with depressive disorders were included. The study outcome was hospitalization due to self-harm (International Classification of Diseases, Ninth Revision, Clinical Modification codes: E950–E958 and E980–E988). Cox proportional hazards models with stratification of the propensity score deciles were used to estimate the hazard ratios of self-harm hospitalization during the first year following the initiation of antidepressant treatment.ResultsThere were 1038 hospitalization episodes due to self-harm that occurred during the follow-up of 149 796 person-years, with an overall incidence rate of 6.9 [95% confidence interval (CI) 6.5–7.4] per 1000. Compared with fluoxetine, the risk of self-harm hospitalization was higher for maprotiline [adjusted hazard ratio (aHR) = 3.00, 95% CI 1.40–6.45], milnacipran (aHR = 2.34, 95% CI 1.24–4.43) and mirtazapine (aHR = 1.40, 95% CI 1.06–1.86), lower for bupropion (aHR = 0.51, 95% CI 0.30–0.86), and similar level of risk was found for other selective serotonin reuptake inhibitors (citalopram, escitalopram, fluvoxamine, paroxetine and sertraline).ConclusionsThe risk of self-harm may vary across different antidepressant drugs. It would be of importance to conduct further research to investigate the influence of antidepressant use on self-harm behaviors. [ABSTRACT FROM PUBLISHER]

The synthesis of [9, 10-dihydro-9-(4-methylaminobutyl)-9, 10-propanoanthracene] (2) as a homolog of the antidepressant [9, 10-dihydro-9-(3-methylaminopropyl)-9, 10-ethanoanthracene] (1) is described in the present paper. The key intermediate [9, 10-dihydro (4-pentyl)-9, 10- propanoanthracene-12-one] (7) is successfully synthesized by using the reaction of α-bromoacrolein with 9-pent-4-enyl-anthracene (4) followed by ring expansion and samarium diiodide deoxygenation. [ABSTRACT FROM AUTHOR]

Regardless of the known anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. In our earlier work, maprotiline, a heterocyclic antidepressants, considerably inhibited infiltration of polymorphonuclear cell leucocytes into the inflamed paw. To understand the mechanism involved, we evaluated the effect of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1) expression in stimulated endothelial cells. Endothelial cells were stimulated with lipopolysaccharide (LPS) in the presence and absence of maprotiline (10-8 to 10-6 M) and ICAM-1 and VCAM-1 expression were measured using real-time quantitative reverse transcription polymerase chain reaction. Maprotiline significantly decreased the LPS-induced expression of VCAM-1 at all applied concentrations. The expression of ICAM-1 decreased in the presence of maprotiline at 10-6 M concentration (P<0.05). Since maprotiline inhibits the expression of adhesion molecules, ICAM-1 and VCAM-1 in LPS-stimulated human endothelial cells, it can be a possible way through which maprotiline exerts its anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing μ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice.Methods: Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus.Results: Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p < 0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive.Conclusions: Overall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain. [ABSTRACT FROM AUTHOR]

In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, and sertraline, from various biological fluids. In this regard, poly(3,4-ethylenedioxythiophene)-graphene oxide (PEDOT-GO) was electrodeposited on an SPME fiber as a conductive coating, then the fiber played the acceptor-electrode role during the extraction. Thus, the immigration of the analytes under the influence of an electric field and their absorption onto the fiber coating were accomplished simultaneously. Under the optimized conditions, the limits of detection for the target analytes were acquired in the range of 0.005-0.025 µg L -1 using gas chromatography-mass spectrometry. The linearity of the method was 0.010-500 µg L -1 for the imipramine and sertraline, 0.025-500 µg L -1 for the amitriptyline, nortriptyline, and desipramine, and 1.000-250 µg L -1 for the maprotiline (R 2 ≥ 0.9984). Moreover, this method provided suitable precision and fiber-to-fiber reproducibility, with RSDs ≤ 8.4%. The applicability of the proposed setup was eventually investigated for extraction of the drugs from human bone marrow aspirate, urine, plasma, and well water samples, in which satisfactory relative recoveries, from 93-105%, were obtained.

Objective: To evaluate the prescription pattern of antidepressants in patients with medical co-morbidity from major psychiatric centres in Asia. Methods: The Research on Asian Psychotropic Prescription Pattern for Antidepressants (REAP-AD 2013) collected data from 42 psychiatric centres in 10 Asian countries and regions. Antidepressant prescriptions of 2320 patients with various psychiatric disorders were evaluated. Of these, 370 patients who had specified medical co-morbidities formed the study cohort. Results: Escitalopram (20%) and mirtazapine (20%) were the most commonly prescribed antidepressants in patients with medical co-morbidity followed by sertraline (16%), trazodone (15%), and paroxetine (12%). Overall, more than half (52%; 247/476) of prescriptions comprised selective serotonin reuptake inhibitors. Slightly less than two-thirds (63%; n = 233) of patients received at least 1 selective serotonin reuptake inhibitor. In addition, 79% of patients were prescribed only 1 antidepressant. The mean number of antidepressants used per patient was 1.25 (standard deviation, 0.56). There were subtle differences in the most preferred antidepressant across medical illnesses such as diabetes mellitus, liver dysfunction, acid peptic disease, and cerebrovascular disease. Differences were also seen in prescription patterns across different countries. Conclusion: Although selective serotonin reuptake inhibitors formed the bulk of antidepressant prescriptions in the presence of medical co-morbidity, mirtazapine was also commonly used in the presence of medical co-morbidities. Specified medical morbidities do influence the selection of antidepressants. [ABSTRACT FROM AUTHOR]

Objective(s): Neuropathic pain remains a clinical problem and is poorly relieved by conventional analgesics. This study was designed to determine whether maprotiline administration was effective in alleviating symptoms of neuropathic pain and whether the antinociceptive effect of maprotiline mediated through the opioid system. Materials and Methods: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats, which resulted in thermal hyperalgesia, and mechanical and cold allodynia. Maprotiline (10, 20 and 40 mg/kg, IP) was administered on the 7th and 14th days after surgery. To study the role of the opioid system in the antinociceptive effects of maprotiline, maprotiline (20 mg/kg, IP) was administered in combination with naloxone (1 mg/kg, SC) on the 7th post-surgery day. Behavioral tests were done at 45 min after drug injections on the 7th and 14th days after surgery. Results: Systemic administration of maprotiline blocked heat hyperalgesia, cold allodynia and reduced mechanical allodynia. Also antihyperalgesic effect of maprotiline was reversed by pretreatment with naloxone. Conclusion: Our results suggest that maprotiline can be considered a potential therapeutic for the treatment of neuropathic pain, and the opioid system may be involved in the antihyperalgesic effects of maprotiline. [ABSTRACT FROM AUTHOR]

Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia with multiple etiologies is a common in diabetic patients. The current study describes the probability of interaction between Maprotiline, Selective Serotonine Reuptake Inhibitors like Citalopram for induction of hypoglycemia. Case Presentation: A 47 year-old diabetic woman used Tablet Citalopram 20mg daily because of Generalized anxiety disorder from two years ago, but 1 week after prescription of Tablet Maprotiline 25mg at night, she had recurrent and symptomatic hypoglycemia episodes. After decline of dosage of Maprotiline, hypoglycemia was improved and follow discontinuation of it, was completely resolved. Conclusion: The use of Maprotiline with Citalopram simultaneously may alter glycaemic control and induce a recurrent hypoglycemia and it is mentioned in the "warnings and precautions for implication". Of course the clinically relevant adverse drug responses may not recognized in clinical practice. [ABSTRACT FROM AUTHOR]

A simple, sensitive and accurate HPLC method has been developed and validated for determination impurities in maprotiline solid dosage forms. Chromatographic separation was achieved on Lichrospher RP Select B column (250 mm × 4.6 mm i.d., particle size 5 μm, maintained at 40°C) by a mobile phase consisted of ammonium hydrogen carbonate (pH 8.1; 0.05 M)-acetonitrile-methanol-tetrahydrofuran (20: 80: 32: 4.5, v/v/v/v) and a flow rate of 1.0 mL/min. The detection wavelength was set at 215 nm and injection volume was 10 μL. The drugs were subjected to oxidation, hydrolysis, photolysis and heat to apply stress conditions. The degradation products, when any, were well resolved from the pure active substance with significantly different retention time values, thus proved the stability indicating power of the method. The method met the International Conference on Harmonisation ( ICH) regulatory requirements. The results demonstrated that the method would have a great value when applied in quality control and stability studies for maprotiline tablets. [ABSTRACT FROM AUTHOR]