Search

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]

Abstract: The synthesis of a diverse library of compounds structurally related to maprotiline, a norepinephrine reuptake transporter (NET) selective antidepressant which has recently been identified as a novel in vitro antiproliferative agent against Burkitt's lymphoma (BL) cell lines is reported. A series of 9,10-dihydro-9,10-ethanoanthracenes were synthesised with modifications to the bridge of the dihydroethanoanthracene structure and with alterations to the basic side chain. A number of compounds were found to reduce cell viability to a greater extent than maprotiline in BL cell lines. In addition a related series of novel 9-substituted anthracene compounds were investigated as intermediates in the synthesis of 9,10-dihydro-9,10-ethanoanthracenes. These compounds proved the most active from the screen and were found to exert a potent caspase-dependant apoptotic effect in the BL cell lines, while having minimal effect on the viability of peripheral blood mononuclear cells (PBMCs). Compounds also displayed activity in multi-drug resistant (MDR) cells. [Copyright &y& Elsevier]

Background. Anti-inflammatory and immunomodulatory activities have been reported for maprotiline, a strong norepinephrine reuptake inhibitor. In addition, some other antidepressant drugs have shown beneficial effects in experimental colitis. Methods. All the animals were divided into normal and depressed groups. In normal rats colitis was induced by instillation of 2mL of 4% acetic acid and after 2 hours, maprotiline (10, 20, and 40 mg/kg, i.p.) was administered. In reserpinised depressed rats, depression was induced by injection of reserpine (6 mg/kg, i.p.), 1 h prior to colitis induction, and then treated with maprotiline (10, 20, and 40 mg/kg). Treatment continued daily for four days. Dexamethasone (1mg/kg, i.p.) was given as a reference drug. On day five following colitis induction, animals were euthanized and distal colons were assessed macroscopically, histologically, and biochemically (assessment of myeloperoxidase activity). Results. Maprotiline significantly improved macroscopic and histologic scores and diminished myeloperoxidase activity in both normal and depressed ratswhile reserpine exacerbated the colonic damage. Conclusion. Our data suggests that the salutary effects of maprotiline on acetic acid colitis are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug. [ABSTRACT FROM AUTHOR]

The effect of LC mobile phase composition and flow rate (2-50 µL/min) on mobility behavior in vacuum differential mobility spectrometry (vDMS) was investigated for electrosprayed isobaric antidepressant drugs (AD); amitriptyline, maprotiline, venlafaxine; and structurally related antidepressants nortriptyline, imipramine, and desipramine. While at 2 µL/min, no difference in compensation voltage was observed with methanol and acetonitrile, at 50 µL/min, acetonitrile used for LC elution of analytes enabled the selectivity of the mobility separation to be improved. An accurate and sensitive method could be developed for the quantification of six AD drugs in human plasma using trap/elute micro-LC setup hyphenated to vDMS with mass spectrometric detection in the selected ion monitoring mode. The assay was found to be linear over three orders of magnitude, and the limit of quantification was of 25 ng/mL for all analytes. The LC-vDMS-SIM/MS method was compared to a LC-MRM/MS method, and in both cases, inter-assay precisions were lower than 12.5 and accuracies were in the range 91.5-110%, but with a four times reduced analysis time (2 min) for the LC-vDMS-SIM/MS method. This work illustrates that with vDMS, the LC mobile phase composition can be used to tune the ion mobility separation and to improve assay selectivity without additional hardware., (© 2022. The Author(s).)

Abstract: Antidepressant drugs are commonly used for treatment of different medical disorders besides of psychiatric diseases. Accumulating evidence suggests that antidepressants exhibit anti-inflammatory activity in vivo and in vitro conditions, but the mechanisms of this property are not clear very well. In our earlier work, we demonstrated that i.c.v. and i.p. injection of maprotiline, as an antidepressant, decreased paw edema at the fourth hour after subplantar injection of carrageenan. Therefore, this work was undertaken to investigate anti-inflammatory effects of maprotiline in more details. Our results verified that i.p. (25 and 50mg/kg) and i.c.v. (100μg/rat) application of maprotiline significantly reduced paw edema at 1, 2, 3 and 4h intervals after carrageenan challenge. Pathological examinations and MPO activity also showed that both i.p. and i.c.v. maprotiline considerably inhibited infiltration of PMN leucocytes into the inflamed paws. Additionally, i.p. and i.c.v. maprotiline at all applied doses noticeably declined levels of IL-1β into the site of inflammation, while only i.p. maprotiline at a dose of 50mg/kg significantly decreased TNF-α levels in the carrageenan-injected paws. These results confirmed anti-edematogenic activity of i.p. and i.c.v. maprotiline in the carrageenan induced paw edema model and showed that these properties of maprotiline might be mediated through inhibition of PMN infiltration and release of IL-1β and TNF-α. [Copyright &y& Elsevier]

Abstract: Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reuptake ability. We found that maprotiline decreased cell viability in a concentration- and time-dependent manner in Neuro-2a cells. Maprotiline induced apoptosis and increased caspase-3 activation. The activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. Maprotiline also induced [Ca2+]i increases which involved the mobilization of intracellular Ca2+ stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca2+ chelator, suppressed maprotiline-induced ERK phosphorylation, enhanced caspase-3 activation and increased maprotiline-induced apoptosis. In conclusion, maprotiline induced apoptosis in Neuro-2a cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca2+- and ERK-dependent. [Copyright &y& Elsevier]

There is increasing interest in the pathophysiology and neurochemistry of the prefrontal cortex (PFC) in depression. Blood flow and metabolism are decreased in the PFC of patients with depression compared to controls. Changes in long-chain polyunsaturated fatty acids (PUFAs) are also associated with depression. This study was conducted to elucidate a possible role of PFC activity of an enzyme involved in the release of docosahexaenoic acid (DHA), i.e. calcium-independent phospholipase A2 (iPLA2), in the effects of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline, in mice. Treatment of Balb/C mice with maprotiline for 4 wk resulted in reduction in the level of behavioural despair, as determined by decreased immobility and increased climbing during the forced swim test. In contrast, mice treated with maprotiline plus bilateral prefrontal cortical injections of antisense oligonucleotide to iPLA2, showed significantly increased immobility and decreased climbing, to levels comparable to saline-treated controls, indicating abolishment of the antidepressant-like effect of maprotiline. Lipidomic analyses showed significant decreases in phosphatidylcholine species containing long-chain PUFAs and increases in lysophosphatidylcholine after maprotiline treatment, indicating increased PLA2 activity and endogenous release of eicosapentaenoic acid (EPA) or DHA after maprotiline treatment. These changes in lipid profiles were absent in mice that received maprotiline and PFC injections of antisense oligonucleotide to iPLA2. Together, the results indicate that PFC iPLA2 activity plays an important role in the antidepressant-like effect of maprotiline, possibly through endogenous release of long-chain PUFAs. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Although several adverse effects of antidepressants on the gastrointestinal tract have been described (bleeding, constipation, dolichocolon), their influence on gallbladder motility was not investigated.The aim of our study was to investigate the effects of selected antidepressants on gallbladder emptying in patients with major depression. METHODS: The study was set up as an open clinical trial, with the same intervention (ingestion of test meal provoking gallbladder emptying) undertaken in 112 patients with major depression. There were 30 patients not taking antidepressants (the control group), 25 patients taking amitriptyline, 30 patients taking maprotiline, and 27 patients taking fluoxetine. The volume of gallbladder in the study patients was measured by ultrasonography before the test meal, and 15, 30, 45 and 60?min after the meal. RESULTS: 1?h after ingestion of the study meal, the amitriptyline group showed incomplete gallbladder emptying (F=10.829, df=3, p=0.000; mean residual volume 11.0?6.1?mL), while in the control, maprotiline and fluoxetine groups emptying of gallbladder was complete (mean residual volumes 5.0?3.3?mL, 5.6?3.7?mL and 5.7?2.3?mL, respectively). DISCUSSION: In patients with cholecystitis, it would be wise to use antidepressants which do not impair gallbladder emptying, like maprotiline or fluoxetine, and to avoid amitriptyline. [ABSTRACT FROM AUTHOR]

Objective: To explore the site of action of maprotiline, as an atypical antidepressant, on carrageenan-induced paw edema. Subjects: Male Wistar rats were used. Methods: Firstly, the anti-inflammatory effect of systemic maprotiline (12.5, 25 and 50 mg kg) was assessed using a paw edema model. Secondly, different doses of maprotiline were administrated intracerebroventricularly, intrathecally and locally before carrageenan challenge. Finally, we tried to reverse the anti-inflammatory effect of maprotiline by propranolol (10 mg kg), prazosin (4 mg kg), yohimbine (10 mg kg), naloxone (4 mg kg) and mifepristone (5 mg kg). Results: Systemic, intracerebroventricular and subplantar application of maprotiline significantly inhibited peripheral edema, but intrathecal maprotiline did not alter the degree of paw swelling. The applied antagonists failed to change the anti-inflammatory activity of maprotiline. Conclusion: These results demonstrate that maprotiline has a potent anti-inflammatory effect and this effect is linked to the peripheral and supraspinal actions of the drug. [ABSTRACT FROM AUTHOR]

A method for separation of three antidepressants, maprotiline, desipramine, and moclobemide, by reversed-phase high-performance liquid chromatography (RP-HPLC) was developed and validated. To find optimal conditions and estimate the impact of individual parameters on the separation, a complete set of 23 interdependent relationships of the mobile phase composition, temperature, and the volume flow rate were examined. Full separation of the investigated components from a laboratory mixture was achieved on a Supelcosil LC-18 (120 mm × 4.6 mm, 5 µm) column, using two solvent systems, 3% ammonium ion in water/ethanol and acetonitrile, and alternating isocratic gradient-isocratic elution modes. Relevance of the proposed method for therapeutic drug monitoring is anticipated. [ABSTRACT FROM AUTHOR]

Abstract: Maprotiline (N-methyl-9,10-ethanoanthracene-9(10H)-propanamine) is a tetra cyclic antidepressant. It is a highly selective inhibitor of norepinephrine reuptake. The solid and solution in CCl4 and methanol infrared spectra of maprotiline were recorded. The fully optimized equilibrium structure of maprotiline was obtained from DFT calculations by using the B3LYP functional in combination with 6-31G and 6-311G(d,p) basis sets. The results of harmonic and anharmonic frequency calculations on maprotiline were presented. The vibrational spectra were interpreted, with the aid of normal coordinate analysis based on a scaled quantum mechanical (SQM) force field. Vibrational assignment of all the fundamentals was made using the total energy distribution (TED). The possible interaction between maprotiline and neurotransmitter serotonin (5-HT) were investigated. [Copyright &y& Elsevier]

Abstract: There have been few comparisons of strains and antidepressants in the unpredictable chronic mild stress (UCMS) paradigm in mice. This study was undertaken to determine the influence of such factors using four antidepressants drugs including the tricyclics imipramine (20mg/(kgday)) and desipramine (10mg/(kgday)), the tetracyclic maprotiline (20mg/(kgday)) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mg/(kgday)) in both Swiss and BALB/c mice. A 6-week UCMS regimen induced deterioration of the coat state and decreased grooming behaviours in the splash test in BALB/c mice but not Swiss mice. The four antidepressants reversed the UCMS-induced effects in BALB/c mice in both measures. However, imipramine and fluoxetine reached significance in the splash test while desipramine and maprotiline displayed only a trend. In conclusion, these results emphasize that BALB/c mice are more sensitive than Swiss mice for studying the effects of the UCMS model as well as for testing antidepressant-like properties. [Copyright &y& Elsevier]

Abstract: Alterations of antioxidant enzyme activities have been described in a number of psychiatric disorders including major depression. Subsequently, the present study examined the effects of different types of antidepressants (desipramine, imipramine, maprotiline and mirtazapine) in different concentrations (10−5, 10−6 and 10−7 M) on the mRNA levels of various enzymes of the antioxidant system, including both intracellular superoxide dismutase isoforms, glutathione peroxidase and catalase as well as several enzymes of the glutathione metabolism in monocytic U-937 cells after short- and long-term treatment (2.5 and 24 h) via RT-PCR. Results indicated mainly short-term decreases in the mRNA levels of antioxidant enzymes after treatment with these substances in all the concentrations used. In addition, after long-term treatment, significant increases in the mRNA levels were seen in the cases of Cu, Zn superoxide dismutase, γ-glutamyl-cysteine synthetase, glutathione-S-transferase and glutathione reductase, including the impacts of all the antidepressants used in concentrations of 10−6 M and 10−7 M. Based on the large number of significant effects of all types of antidepressants tested on various antioxidant enzymes, we suggest that antioxidant enzymes may represent important targets in the course of antidepressive treatment. [Copyright &y& Elsevier]

Four tetracyclic antidepressants, maprotiline, mianserin, mirtazapine, and setiptiline, were extracted from human whole blood and plasma samples by disk solid-phase extraction with Empore C18 cartridges. They were determined by gas chromatography (GC) with nitrogen-phosphorus detection. Recoveries of maprotiline, mianserin, mirtazapine, and setiptiline spiked into whole blood or plasma were more than 83%. Regression equations for the four drugs showed excellent linearity in the range of 25–1000 ng in 0.2 ml whole blood and in 0.5 ml plasma. The limits of detection for the drugs were 4.1–18.2 ng per 0.2 ml for whole blood and 3.4–13.5 ng per 0.5 ml for plasma. The limits of quantification for the four drugs were 25 ng in 0.2 ml whole blood and in 0.5 ml plasma. Intraday and interday coefficients of variation for the antidepressants in both human specimens were below 15%. The above data show that relatively hydrophobic and basic drugs in crude biological samples such as whole blood can be extracted by disk solid-phase extraction very efficiently and with good reproducibility, and suggest that the extraction method is also useful as pretreatments before more sophisticated detection methods such as GC-mass spectrometry (MS) and liquid chromatography-MS(-MS). [ABSTRACT FROM AUTHOR]

Abstract: Agents such as clozapine, olanzapine and mirtazapine frequently trigger an increase in body weight. Though the mechanisms have not been thoroughly clarified, recent studies indicate a role for ghrelin in regulation of appetite and weight gain. We investigated the relation of maprotiline induced weight gain to serum ghrelin and adiponectin levels, as well as insulin resistance in lean subjects with depressive disorder. A total of 40 male lean subjects with depressive disorder were treated with maprotiline (150 mg/day) for 30-days. Clinical data, fasting plasma glucose, lipids, insulin levels, serum ghrelin and adiponectin concentrations were determined before and after treatment. Insulin resistance was estimated using the homeostasis model assessment (HOMA) formula. After 30 days of treatment with maprotiline, mean body mass index increased significantly. Blood ghrelin and insulin levels and HOMA indexes increased, and adiponectin concentration decreased (p <0.001, for all) after the treatment period. Changes in ghrelin levels correlated neither of the parameters tested; whereas decrease in plasma adiponectin was associated with an increase in BMI (r =−0.671, p <0.001). In conclusion, the results indicate that treatment of lean patients with depressive disorder with maprotiline results in an increase in serum ghrelin and reduction in adiponectin levels. Weight gain due to maprotiline treatment may be related to its negative effects on the metabolic variables. [Copyright &y& Elsevier]

Abstract: Background: To investigate the effects of antidepressants on glucose–insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization. Methods: Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n =11, fluoxetine n =12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (S I), glucose effectiveness (S G), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method. Results: The HAM-D scores were reduced significantly (P <0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P =0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239±682 vs. 4698±597 pmol; P =0.04) during the FSIGT. Limitations: The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course. Conclusions: The results suggest that the β-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity. [Copyright &y& Elsevier]

Maprotiline, an atypical antidepressant, can induce prolonged QT and torsades de pointes. We studied the effects of maprotiline on human ether- a- go- go-related gene (HERG) channels expressed in Xenopus oocytes and HEK293 cells. Maprotiline induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and tail currents of HERG. The V1/2 values in the absence and presence of 1–20 μM maprotiline were not significantly different, while the values decreased according to the concentrations of the drug at 50–300 μM. The IC50 for a maprotiline block of HERG current in Xenopus oocytes did not change according to depolarization; 39.5 ± 3.2 (μM at -40 mV and 43.6 ± 2.8 μM at +40 mV. The block of HERG by maprotiline was examined after treatment of trinitrobenzene sulfonic acid (TNBS), an amino-group reagent that neutralizes the positively charged amino-groups of peptide N-terminal and lysine residues. TNBS inhibited the change of V1/2 values induced by 50–300 mM maprotiline, and aggravated the drug-induced gmax decrease. The IC50 for the maprotiline-induced blockade of HERG currents in HEK293 cells at 36°C was 0.13 nM at +20 mV. Our findings suggest that the arrhythmogenic side effects of maprotiline are caused by a blockade of HERG and possibly by a blockade of delayed rectifier K+ channel. [ABSTRACT FROM AUTHOR]

Abstract: The acidic dissociation constants of several hydrophobic drugs, amiodarone and a series of antidepressants that show a secondary or tertiary amino group, were determined in a 50% methanol/water mixture by capillary zone electrophoresis. The electrophoretic behavior of buffers prepared from sodium acetate, tris(hydroxymethyl) aminomethane hydrochloride, sodium hydrogenphosphate, ammonium chloride, ethanolamine, butilammonium chloride, and sodium borate in the hydroalcoholic solution was tested. Thus, all of them follow the Ohm''s law until about 25kV and, therefore, they can be used without significant Joule heat dissipation at 20kV. For the studied drugs, buffers prepared with phosphate or borate give effective mobility measurements lower than those from other buffers. The wide pK a range of the studied drugs provides a wide pH range where the protonated forms of the amino compounds coexist with hydrogenphosphate ions and where the neutral amines coexist with boric acid. The decrease of the experimental effective mobilities in these instances can be explained through the interactions between coexisting species. Therefore, phosphate and borate buffers should be avoided to determine the mobility of amines with aqueous pK a higher than 8, at least in solutions with high methanol content. Independent measurements of acidic dissociation constants of drugs validate this statement. [Copyright &y& Elsevier]

Potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function has been proposed as being useful in the treatment of depression, but thus far, little is known about the possible changes in AMPA receptor expression in the brain, after antidepressant treatment. The present study was carried out to study the expression of AMPA receptor subunits in different brain regions of mice that had been chronically injected with maprotiline. The latter is a modified tricyclic antidepressant that functions as a noradrenaline uptake inhibitor. Daily intraperitoneal injection with 10 mg/kg maprotiline for 30 days resulted in significantly increased GluR1 and GluR2/3 subunit expression in the nucleus accumbens and dorsal striatum as detected by immunohistochemistry; and significantly increased GluR1 and GluR2/3 expression in the hippocampus, as demonstrated by Western blot analysis. No change, or a decrease in GluR2 expression was detected in all the brain regions by both immunohistochemistry and Western blots. The increase in GluR1 and GluR2/3, but no increase in GluR2 subunits suggests that there could be an increase in calcium permeability of AMPA receptors in limbic/striatal brain regions after maprotiline treatment. This could lead to increased synaptic activity or plasticity in the hippocampus and striatum, and may underlie the therapeutic effect of maprotline, and possibly, other antidepressant drugs. [ABSTRACT FROM AUTHOR]

Abstract: Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 μM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site. [Copyright &y& Elsevier]

Abstract: State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30mg/kg), maprotiline (25mg/kg), and fluoxetine (15mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2×2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning. [Copyright &y& Elsevier]

In Madin-Darby canine kidney (MDCK) cells, the effect of maprotiline, an antidepressant, on intracellular Ca2+ concentration ([Ca2+]i) was measured using fura-2. Maprotiline (>2.5 µM) caused a rapid rise of [Ca2+]i in a concentration-dependent manner (EC50 200 µM). Maprotiline-induced [Ca2+]i rise was reduced by removal of extracellular Ca2+ or by addition of La3+, but was not altered by voltage-gated Ca2+-channel blockers. Maprotiline-induced Mn2+ influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca2+ influx. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of maprotiline on [Ca2+]i was nearly abolished; also, pretreatment with maprotiline reduced a portion of thapsigargin-induced [Ca2+]i rise. U73122, an inhibitor of phospholipase C, abolished [Ca2+]i rise induced by ATP (but not by maprotiline). Overnight incubation with 1–10 µM maprotiline enhanced cell viability, but 20–50 µM maprotiline decreased it. These findings suggest that maprotiline rapidly increases [Ca2+]i in renal tubular cells by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release, and may modulate cell proliferation in a concentration-dependent manner. [ABSTRACT FROM AUTHOR]