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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.

Objective: We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect., Methods: The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs., Results: The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect., Conclusion: To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Stepwise covariate modeling (SCM) has a high computational burden and can select the wrong covariates. Machine learning (ML) has been proposed as a screening tool to improve the efficiency of covariate selection, but little is known about how to apply ML on actual clinical data. First, we simulated datasets based on clinical data to compare the performance of various ML and traditional pharmacometrics (PMX) techniques with and without accounting for highly-correlated covariates. This simulation step identified the ML algorithm and the number of top covariates to select when using the actual clinical data. A previously developed desipramine population-pharmacokinetic model was used to simulate virtual subjects. Fifteen covariates were considered with four having an effect included. Based on the F1 score (an accuracy measure), ridge regression was the most accurate ML technique on 200 simulated datasets (F1 score = 0.475 ± 0.231), a performance which almost doubled when highly-correlated covariates were accounted for (F1 score = 0.860 ± 0.158). These performances were better than forwards selection with SCM (F1 score = 0.251 ± 0.274 and 0.499 ± 0.381 without/with correlations respectively). In terms of computational cost, ridge regression (0.42 ± 0.07 seconds/simulated dataset, 1 thread) was ~20,000 times faster than SCM (2.30 ± 2.29 hours, 15 threads). On the clinical dataset, prescreening with the selected ML algorithm reduced SCM runtime by 42.86% (from 1.75 to 1.00 days) and produced the same final model as SCM only. In conclusion, we have demonstrated that accounting for highly-correlated covariates improves ML prescreening accuracy. The choice of ML method and the proportion of important covariates (unknown a priori) can be guided by simulations., (© 2024. The Author(s).)

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUC last ), and extrapolated to infinity (AUC inf ), and the maximum plasma concentration (C max ) were determined. For both dextromethorphan and desipramine, AUC inf and C max were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUC inf , C max , and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings., (© 2023, The American College of Clinical Pharmacology.)

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated., (© 2020 John Wiley & Sons Ltd.)

The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (C max ) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (T max ) 1-2 hr, elimination half-life (t 1/2 ) 17.2 hr, area under plasma concentration-time curve (AUC) 487.4 ng ml -1  hr -1 , apparent clearance (Cl/F) 2.6 L hr -1  kg -1 , and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations., (© 2020 John Wiley & Sons Ltd.)

Tricyclic Antidepressants (TCAs) are a group of the main category of antidepressant drugs, which are commonly prescribed to treat major depressive disorder. Determination of TCA drugs is very important for clinical and forensic toxicology, especially for therapeutic drug monitoring in various biofluids. High Performance Liquid Chromatography (HPLC) is a well-established technique for this purpose. A lot of progress has been made in this field since the past 10 years. Novel extraction techniques, and novel materials for sample preparation, novel columns and novel applications of analysis of various biofluids for the determination of TCAs in combination with other drugs are some typical examples. Moreover, advances have been performed in terms of Green Analytical Chemistry principles. Herein, we aim to discuss the developed HPLC methods that were reported in the literature for the time span of 2008-2018., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was -80.73 J/K·mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.

Amitriptyline poisoning (AT) is a common poisoning, and AT possess the ability to promote life-threatening complications by its main action on the central nervous and cardiovascular systems. The pharmacokinetic properties might be altered at toxic levels compared to therapeutic levels. The effect of coated activated charcoal hemoperfusion (CAC-HP) on the accumulation of AT and its active metabolite nortriptyline (NT) in various tissues was studied in a non-blinded randomized controlled animal trial including 14 female Danish Land Race piglets. All piglets were poisoned with amitriptyline 7.5 mg/kg infused in 20 min, followed by orally instilled activated charcoal at 30 min after infusion cessation. The intervention group received 4 h of CAC-HP followed by a 1-h redistribution phase. At study cessation, the piglets were euthanized, and within 20 min, vitreous fluid, liver tissue, ventricle and septum of the heart, diaphragm and lipoic and brain tissues were collected. AT and NT tissue concentrations were quantified by UHPLC-MS/MS. A 4-h treatment with CAC-HP did not affect the tissue accumulation of AT in the selected organs when tested by Mann-Whitney U test (p values between 0.44 and 0.73). For NT concentrations, p values were between 0.13 and 1.00. Although not significant, an interesting finding was that data showed a tendency of increased tissue accumulation of AT and NT in the CAC-HP group compared with the control group. Coated activated charcoal hemoperfusion does not significantly alter the tissue concentration of AT and NT in the AT-poisoned piglet.

The wide spread use of central nervous system (CNS) drugs has caused thousands of deaths in clinical practice while there are few antidotes or effective treatments to decrease their accumulation in CNS. In this study, we used amitriptyline (AMI) and dexamethasone (DEX) as the corresponding poisoning and pre-protecting drugs, respectively, to study whether DEX has the potential to reduce AMI accumulation in brain. By measuring the pharmacokinetic data of AMI and its main metabolite nortriptyline (NOR), we found that DEX possibly accelerated the metabolism and elimination of AMI with minimal effects on the concentrations of NOR in blood. Nevertheless, the results indicated that DEX reduced the brain/plasma concentration ratio of AMI and NOR, even if the plasma concentration of NOR had an upward trend. Western blot results showed the overexpression of cyp3a2 and P-gp in rat liver and brain capillaries tissues. We propose that cyp3a2 and P-gp could be upregulated in the liver and blood-brain barrier (BBB) when using DEX. Further experiments suggest that DEX may serve as the ligand of PXR to induce P-gp expression., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline., (© 2018, The American College of Clinical Pharmacology.)

The objectives are to review the role of pharmacogenomics in drug metabolism of medications typically used in patients with irritable bowel syndrome (IBS) focusing predominantly on cytochrome P450 metabolism. Other aims are to provide examples of genetic variation of receptors or intermediary pathways that are targets for IBS drugs and to critically appraise the situations where precision medicine is impacting health in IBS. Pharmacogenomics impacts both pharmacokinetics and pharmacodynamics. Although large clinical trials have not incorporated testing for genetic variations that could impact the efficacy of medications in IBS, there are therapeutic advantages to inclusion of pharmacogenomics testing for individual patients, as has been demonstrated particularly in the treatment with central neuromodulators in psychiatry practice. Clinical practice in IBS is moving in the same direction with the aid of commercially available tests focused on drug metabolism. Specific mechanisms leading to pathophysiology of IBS are still poorly characterized, relative to diseases such as cancer and inflammatory bowel disease, and, therefore, pharmacogenomics related to drug pharmacodynamics is still in its infancy and requires extensive future research. With increased attention to pharmacogenomics affecting drug metabolism, it is anticipated that pharmacogenomics will impact care of IBS., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Gastric pharmacobezoars are a rare entity that can induce mechanical gastric outlet obstructions and sometimes prolong toxic pharmacological effects. Certain medications, such as sustained-release forms, contain cellulose derivatives that may contribute to the adhesion between pills and lead to the creation of an aggregate resulting in a pharmacobezoar. Case reports are rare, and official guidelines are needed to help medical teams choose proper treatment options., Case Presentation: Our patient was a 40-year-old Caucasian woman with borderline personality disorder and active suicidal thoughts who was found unconscious after a massive drug consumption of slow-release clomipramine, lorazepam, and domperidone. On her arrival in the emergency room, endotracheal intubation was preformed to protect her airway, and a chest x-ray revealed multiple coffee grain-sized opaque masses in the stomach. She was treated with activated charcoal followed by two endoscopic gastric decontaminations 12 h apart in order to extract a massive gastric pharmacobezoar by manual removal of the tablets., Conclusion: This case demonstrates that in the case of a massive drug consumption, a pharmacobezoar should be suspected, particularly when cellulose-coated pills are ingested. Severe poisoning due to delayed drug release from the gastric aggregate is a potential complication. Detection by x-ray is crucial, and treatment is centered on removal of the aggregate. The technique of decontamination varies among experts, and no formal recommendations exist to date. It seems reasonable that endoscopic evaluation should be performed in order to determine the appropriate technique of decontamination. Care should be patient-oriented and take into account the clinical presentation and any organ failure, and it should not be determined solely by the suspected medication ingested. Thus, serum levels are not sufficient to guide management of tricyclic antidepressant intoxication.

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-NVP) where competitively inhibited with similar inhibitory constant values (K i  = 4.01, 3.97 and 4.40 μM, respectively). Time-dependent inhibition of the NVP metabolism was also detected, with a 2.5-fold reduction in the IC 50 values of NT for 2-, 3-, and 12-OH-NVP formation when NT was preincubated with the microsomal suspension in the presence of an NADPH-generating system. A concentration-dependent inhibition of the formation of NVP metabolites by the main NT metabolite (10-OH-NT) was also observed, however, the inhibitory potency of 10-OH-NT was much lower than that of the parent drug. The apparent hepatic intrinsic clearance of NVP determined in these in vitro experiments was used to predict the in vivo clearance of NVP using the "well-stirred" and the "parallel-tube" models, resulting in values close to those previously observed in vivo clearance. Finally, a good prediction of the increase in the plasma concentrations of NVP when co-administered with NT was obtained employing the inhibitory constant of NT determined in vitro and the estimated plasma concentration of NT entering the liver., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit ® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study., Materials and Methods: Coacervation technique using Eudragit ® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined., Results and Discussion: The disintegration time of the SGF were found as A1 < A2 < A3 < A5 < A4 (8% Eudragit ® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab., Conclusions: According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit ® E-100) formulations could be promising alternatives to Remeron SolTab.

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and is the first-choice NNRTI during pregnancy. NVP shows a sex dimorphic profile in humans with sex differences in bioavailability, biotransformation and toxicity. In this study, sex differences in NVP metabolism and inhibition of NVP metabolism by the antidepressant nortriptyline (NT) were evaluated using rats as experimental animals. NVP was administered orally to male and female rats and sex differences in plasma levels and pharmacokinetic parameters were analysed. NVP plasma levels were higher in female compared with male rats, and pharmacokinetic parameters such as maximum plasma concentration (C max ), time to C max (T max ), half-life (t 1/2 ) and area under the plasma concentration-time curve from the time of dosing to the last measurable concentration (AUC last ) showed ca. 4-, 5-, 7- and 22-fold higher values in female rats. In vitro experiments carried out with hepatic microsomes confirmed slower NVP metabolism in female rats, with a maximum velocity (V max ) 2-fold lower than in male hepatic microsomes. The major metabolite in both sexes was 12-hydroxynevirapine (12-OH-NVP), with the V max for this metabolite being 15-fold lower in female compared with male rat hepatic microsomes. Inhibition of NVP metabolism by NT was similar in both sexes, with statistically non-significant differences in 50% inhibitory concentration (IC 50 ) values. In summary, NVP is metabolised more slowly in female compared with male rats, but the inhibitory effect of NT is similar in both sexes., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

Tianeptine is an atypical antidepressant with a unique mechanism of action and recently it has been also reported that its major metabolite, compound MC5, possesses pharmacological activity similar to that of the parent drug. The current study aims to investigate the pharmacokinetics (PK) of both tianeptine and MC5 after intravenous or intraperitoneal administration of the parent drug as well as the metabolic ratio of MC5 in rats. To achieve these goals an LC-MS/MS method using the small sample volume for the quantitation of tianeptine and its active metabolite MC5 in rat plasma and liver perfusate has been developed and validated. Following an intravenous administration of tianeptine pharmacokinetic parameters were calculated by non-compartmental analysis. The average tianeptine volume of distribution at steady state was 2.03 L/kg and the systemic clearance equaled 1.84 L/h/kg. The mean elimination half-lives of tianeptine and MC5 metabolite were 1.16 and 7.53 h, respectively. The hepatic clearance of tianeptine determined in the isolated rat liver perfusion studies was similar to the perfusate flow rate despite the low metabolic ratio of MC5. Mass spectrometric analysis of rat bile indicated that tianeptine and MC5 metabolite are eliminated with bile as glucuronide and glutamine conjugates. Bioavailability of tianeptine after its intraperitoneal administration was 69%. The PK model with a metabolite compartment developed in this study for both tianeptine and MC5 metabolite after two routes of administration may facilitate tianeptine dosage selection for the prospective pharmacological experiments.

Aim: A simple, sensitive and robust technique of hollow-fiber drop-to-drop solvent microextraction coupled with GC-MS has been successfully developed for the detection of antidepressant drug nortriptyline in human blood and urine samples. The recoveries of the drug from the spiked samples are found to be well within the range and appropriate to support the method., Results: The LOD for the drug was obtained to be 0.007, 0.009 and 0.021 μg ml -1 in deionized water, urine and blood samples of human subjects, respectively. Linearity was obtained over the concentration range of 0.5-5.0 mg l -1 in deionized water with correlation coefficient 0.99672.

Mirtazapine is one of antidepression which is used mainly in the treatment of depression, moreover, it is sometimes used in the treatment of anxiety disorders, insomnia, nausea, and vomiting, and to produce weight gain when desirable. The action of mirtazapine is an antagonist of certain adrenergic and serotonin receptors, and, furthermore, the drug is used strong as antihistamine, and it is occasionally defined as a noradrenergic and specific serotonergic antidepressant (NaSSA). The comprehensive profile of mirtazapine gives more detailed information about nomenclature, formulae, elemental analysis, and appearance. In addition, the numerous methods of drug synthesis are summarized. Also the profile covers the physicochemical properties as: the value of pK a , drug solubility, melting point, X-ray powder diffraction, and analysis methods for example: (compendial, electrochemical, spectroscopic, and method of chromatographic). Besides that, the profile covered pharmacological profile and clinical pharmacokinetics in subtitle's (absorption, distribution, metabolism, and elimination). About 100 references were given as a proof of the above-mentioned studies., (© 2018 Elsevier Inc. All rights reserved.)

The increasing death rate caused by drug overdose points to an urgent demand for the development of novel detoxification therapy. In an attempt to detoxify tricyclic antidepressant overdose, we prepared a lipid nanoemulsion, called squarticles, as the nanoantidote. Squalene was the major lipid matrix of the squarticles. Here, we present the animal study to investigate both the pharmacokinetic and pharmacodynamic effects of squarticles on amitriptyline intoxication. The anionic and cationic squarticles had average diameters of 97 and 122 nm, respectively. Through the entrapment study, squarticles could intercept 40%-50% of the amitriptyline during 2 h with low leakage after loading into the nanoparticles. The results of isothermal titration calorimetry demonstrated greater interaction of amitriptyline with the surface of anionic squarticles ( K a =28,700) than with cationic ones ( K a =5,010). Real-time imaging showed that intravenous administration of anionic squarticles resulted in a prolonged retention in the circulation. In a rat model of amitriptyline poisoning, anionic squarticles increased the plasma drug concentration by 2.5-fold. The drug uptake in the highly perfused organs was diminished after squarticle infusion, indicating the lipid sink effect of bringing the entrapped overdosed drug in the tissues back into circulation. In addition, the anionic nanosystems restored the mean arterial pressure to near normal after amitriptyline injection. The survival rate of overdosed amitriptyline increased from 25% to 75% by treatment with squarticles. Our results show that the adverse effects of amitriptyline intoxication could be mitigated by administering anionic squarticles. This lipid nanoemulsion is a potent antidote to extract amitriptyline and eliminate it., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR. Interestingly, while tianeptine also produces many opiate-like behavioral effects such as analgesia and reward, it does not lead to tolerance or withdrawal. Furthermore, the primary metabolite of tianeptine (MC5), which has a longer half-life, mimics the behavioral effects of tianeptine in a MOR-dependent fashion. These results point to the possibility that MOR and its downstream signaling cascades may be novel targets for antidepressant drug development.

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping. Once developed and qualified in adults, we characterized the dynamic changes in metabolism and pharmacokinetics of desipramine after birth by scaling the system-specific parameters of the model from adults to pediatrics. The developed modeling strategy provides a prototypical workflow that can also be applied to other drugs with similar properties and a high volume of distribution., (© 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Coated activated charcoal haemoperfusion (CAC-HP) is a well-known treatment modality. Case reports have revealed conflicting results about the efficacy of CAC-HP in the treatment of amitriptyline (AT) poisoning, and no randomized clinical trials have been identified in the literature. This study aimed at quantifying the efficacy of modern CAC-HP as an adjunctive treatment of AT intoxication compared with standard care alone. Fourteen female Danish landrace pigs were randomized to either standard care or standard care plus 4 hr of CAC-HP. The pigs were anaesthetized, and vital parameters were continuously recorded. Amitriptyline infusion (7.5 mg/kg) was completed in 20 min. Thirty minutes after AT infusion, activated charcoal was instilled orally in both groups. In the intervention group, CAC-HP was initiated 60 min. after AT infusion. Blood and urine samples were collected as were vital parameters at specific time intervals. The protocol was approved by the Danish Experimental Animal Expectorate and complied with the NIH guide for care and use of laboratory animals. Data were managed according to the ARRIVE guidelines. No statistical significant differences between intervention and control groups were found when analysing for differences in AT levels in plasma at any time-point. Furthermore, significant differences between the control and intervention groups in regard to vital parameters could not be found either. In our animal model, the addition of CAC-HP did not improve the clearance of AT compared with standard treatment alone. We suggest that the effect of modern CAC-HP as a treatment modality in AT-poisoned human patients may be inadequate., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endo-lysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 μM, 5 μM). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 μM) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 μM), while changes in CD63 pattern already occurred at intermediate concentrations (5 μM). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs.

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound K i values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound K i values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

Major circulating drug metabolites can be as important as the drugs themselves in efficacy and safety, so establishing methods whereby exposure to major metabolites following administration of parent drug can be predicted is important. In this study, imipramine, a tricyclic antidepressant, and its major metabolite desipramine were selected as a model system to develop metabolite prediction methods. Imipramine undergoes N-demethylation to form the active metabolite desipramine, and both imipramine and desipramine are converted to hydroxylated metabolites by the polymorphic enzyme CYP2D6. The objective of the present study is to determine whether the human pharmacokinetics of desipramine following dosing of imipramine can be predicted using static and dynamic physiologically-based pharmacokinetic (PBPK) models from in vitro input data for CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) populations. The intrinsic metabolic clearances of parent drug and metabolite were estimated using human liver microsomes (CYP2D6 PM and EM) and hepatocytes. Passive diffusion clearance of desipramine, used in the estimation of availability of the metabolite, was predicted from passive permeability and hepatocyte surface area. The predicted area under the curve (AUCm/AUCp) of desipramine/imipramine was 12- to 20-fold higher in PM compared with EM subjects following i.v. or oral doses of imipramine using the static model. Moreover, the PBPK model was able to recover simultaneously plasma profiles of imipramine and desipramine in populations with different phenotypes of CYP2D6. This example suggested that mechanistic PBPK modeling combined with information obtained from in vitro studies can provide quantitative solutions to predict in vivo pharmacokinetics of drugs and major metabolites in a target human population., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Drugs used in the treatment of migraine have been reported to be highly associated with the occurrence of clinically significant drug-drug interactions (DDIs). Multiple drug therapy regimens are used for migraine treatment, particularly for chronic migraine. In fact, additional pharmacological agents are usually administered during an acute migraine attack in patients chronically treated with the prophylactic therapy. The variety of drugs available for migraine prophylactic and acute treatment, and consequently their pharmacological interactions, might complicate the choice of a safe combination therapy., Areas Covered: This study discusses the prophylactic-acute DDIs from a pharmacokinetic and pharmacodynamic perspective, particularly interactions between antiepileptic drugs, tricyclic antidepressants, β-blockers, calcium channel blockers, triptans, nonsteroidal anti-inflammatory drugs and ergot derivatives. The available online tools have been used to evaluate the clinically significant DDIs., Expert Opinion: The interactions between different drugs might be accurately predicted by the huge and detailed knowledge about the molecular pathways involved in pharmacodynamics and pharmacokinetics. Pharmacogenomic research has shed further light onto the mechanisms involved in the inter-individual variation in drug response and DDIs. Based on this knowledge, this paper will provide suggestions to improve the appropriateness of the drug choice in the prescription of preventative and acute migraine medications.

Purpose: Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their ratios during pregnancy. Second, we describe Center for Epidemiologic Studies Depression scale (CES-D) scores during pregnancy., Methods: During 13 pregnancies, every trimester and 3 months after pregnancy, the clomipramine and desmethylclomipramine concentrations were measured with LC-MSMS and the severity of depression was assessed by taking the CES-D score. All concentrations used in our calculations were in fact the ratio between actual plasma concentration (μg/l) and the actual dose (mg). We compared differences in ratios between trimesters by using the Friedman test., Results: Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy., Conclusions: The mean concentrations of the pharmacologically active metabolite of clomipramine and desmethylclomipramine changes during pregnancy, where a decrease in mean concentrations was found during pregnancy. In case of recurrent disease, we recommend to control clomipramine and its metabolite concentrations, while both are active.

Fibromyalgia is characterized by chronic generalized pain accompanied by a wide range of clinical manifestations. Most clinical practice guidelines recommend multidisciplinary treatment using a combination of pharmacological and non-pharmacological therapies. The tricyclic antidepressant amitriptyline has been most thoroughly studied in fibromyalgia. Amitriptyline has been evaluated in placebo-controlled studies, and it has served as an active comparator to other therapeutic interventions in the treatment of fibromyalgia. In addition, several systematic reviews and meta-analyses have evaluated its efficacy and safety for the treatment of fibromyalgia. Data from individual studies as well as from systematic reviews indicate that low doses (10-75 mg/day) of amitriptyline are effective for the treatment of fibromyalgia and, despite the limited quality of the data, they do not seem to be associated with relevant tolerability or safety issues. Consistent with some clinical guidelines, we believe amitriptyline in low doses should be considered a first-line drug for the treatment of fibromyalgia.

Rationale: Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive., Objectives: We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline., Methods: Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation., Results: P450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea., Conclusions: In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.

Introduction: Antidepressants (ADs) are widely used among elderly persons, making AD-related safety an important issue., Areas Covered: This review highlights safety considerations related to AD use including risks associated with inappropriate and off-label use. The age-related pharmacokinetic and pharmacodynamic changes underlying safety concerns connected to ADs are outlined. Drug-drug interactions as a cause of AD-related adverse drug reactions (ADRs) are also discussed. We reviewed scientific evidence concerning three important safety outcomes related to ADs in elderly persons: cardiac arrhythmias, hyponatraemia and falls/fractures., Expert Opinion: Several AD-related ADRs in elderly people are likely to be preventable. Current evidence suggests that selective serotonin re-uptake inhibitors (SSRIs) are best avoided particularly in persons with kidney disease due to the risk of hyponatraemia. The use of tricyclic antidepressants (TCAs) should be limited in the elderly due to anticholinergic adverse effects. TCAs should also be avoided in elderly persons at high risk of cardiovascular events due to a risk of cardiac arrhythmia. Emerging evidence suggests that SSRIs also have arrhythmogenic potential. Both TCAs and SSRIs should be used cautiously in elderly persons at risk of falls. Future research in this area should aim to investigate the lowest effective dose of AD possible, the relationship between AD dose and adverse effects, and which elderly subgroups are most prone to develop severe ADRs.

Purpose: Amitriptyline is the most widely used tricyclic antidepressant (TCA). Although amitriptyline hydrochloride 10 and 25 mg has been marketed in Korea, no data on the dose proportionality of amitriptyline in Korean subjects are available. This clinical trial was designed to evaluate and compare the relative bioavailability with regard to dose proportionality between the two marketed strengths of amitriptyline hydrochloride tablets after a single-dose, oral administration under fasting conditions in healthy, male, Korean volunteers., Methods: This single-dose, randomized, open-label, 2-way crossover study was conducted in healthy male Korean subjects. Subjects were randomly assigned to 1 of 2 dose groups and received a single dose of 10 or 25 mg amitriptyline hydrochloride under fasting conditions, followed by the alternate dose in the subsequent study period. High performance liquid chromatography (HPLC)-mass spectrometry (MS)/MS detection was applied to determine plasma concentrations. Pharmacokinetic parameters were calculated, C(max), AUC(last), AUC(0-∞), t(½), and T(max). Statistical analysis was performed for the assessment of dose proportionality. Tolerability was assessed for up to 96 hours after administration., Findings: Twelve healthy Korean subjects completed this trial (mean [SD] age, 21.7 [1.9] years; height, 174.5 [5.0] cm; and weight, 66.7 [9.4] kg). Although 4 subjects experienced a total 5 adverse events (AEs), no serious AEs were reported during the study. The mean values of C(max) and AUC were proportional to the doses of 10 and 25 mg. The C(max), AUC(last), and AUC(0-∞) of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng·h/mL and 109.74 ng·h/mL, respectively. The C(max), AUC(last), and AUC(0-∞) of amitriptyline hydrochloride 25 mg were 17.69 ng/mL, 260.68 ng·h/mL, and 296.87 ng·h/mL, respectively., Implications: Our results suggest that the 2 strengths of amitriptyline hydrochloride (10 and 25 mg) exhibited linear (dose-dependent) pharmacokinetics in these healthy, male, Korean subjects. Based on these results, a predictable and linear increase in systemic exposure can be expected. ClinicalTrials.gov identifier: NCT01367080., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

The aim of this study was to investigate the influence of demethylation rate on the outcome of obsessive-compulsive disorder patients treated with clomipramine. Eighteen patients meeting the DSM-IV criteria for obsessive-compulsive disorder received 150-300 mg of clomipramine daily in a single-blind design for 12 weeks. The patients were evaluated with the Clinical Global Impression scale and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Clinical assessment and serum measurements of clomipramine and desmethylclomipramine were carried out at baseline and after 3, 6, 8, 10, and 12 weeks. A greater improvement in Clinical Global Impression scale rating was associated with a lower desmethylclomipramine/daily dose and the total clomipramine and desmethylclomipramine/daily dose. Moreover, an improved response on the YBOCS-obsession score was associated with higher serum levels of clomipramine and the total clomipramine and desmethylclomipramine/daily dose. Patients with a greater reduction in baseline YBOCS rating had a lower desmethylclomipramine/clomipramine ratio. These data suggest that a lower demethylation rate correlates with better clinical outcome.

Objective: Our study aimed to investigate the effect of mirtazapine on bone metabolism in the orchidectomized rat model., Methods: Rats were divided into three groups. A sham-operated control group (SHAM group) and a control group after orchidectomy (ORX group) received the standard laboratory diet (SLD). An experimental group after orchidectomy (ORX MIRTA group) received SLD enriched with mirtazapine for 12 weeks. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone marker concentrations of osteoprotegerin (OPG), amino-terminal propeptide of procollagen type I, bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 were examined in bone homogenate. The femurs were used for biomechanical testing., Results: Compared with the control ORX group, we found a lower BMD in the ORX MIRTA group. The differences were statistically significant, although not in the lumbar vertebrae. BMD was lower in the MIRTA group, suggesting a preferential effect on cortical bone. However, although the thickness of the diaphyseal cortical bone was not different, the fragility in the femoral neck area was statistically significantly different between the groups in biomechanical testing. Regarding the bone metabolism markers, there was a significant decrease in OPG and BALP levels, suggesting a reduction in osteoid synthesis., Conclusions: The results suggest that prolonged use of mirtazapine may have a negative effect on the synthesis of bone and on its mechanical strength, especially in the femoral neck. Further studies are warranted to establish whether mirtazapine may have a clinically significant adverse effect on bone exclusively in the model of gonadectomized rats, or whether the effect occurs also in the model of gonadally intact animals and in respective human models., (© 2015 S. Karger AG, Basel)

One of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found. In vitro studies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT. In vivo human studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Dispersive liquid-liquid microextraction (DLLME) coupled with high performance liquid chromatography by ultraviolet detection (HPLC-UV) as a fast and inexpensive technique was applied to the determination of imipramine and trimipramine in urine samples. Response surface methodology (RSM) was used for multivariate optimization of the effects of seven different parameters influencing the extraction efficiency of the proposed method. Under optimized experimental conditions, the enrichment factors and extraction recoveries were between 161.7-186.7 and 97-112%, respectively. The linear range and limit of detection for both analytes found to be 5-100ng mL(-1) and 0.6ng mL(-1), respectively. The relative standard deviations for 5ng mL(-1) of the drugs in urine samples were in the range of 5.1-6.1 (n=5). The developed method was successfully applied to real urine sample analyses., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to evaluate the patients with acute amitriptyline poisoning and investigate predictive factors for the development of life-threatening complications., Methods: Demographics, clinical, laboratory, and electrocardiographic (ECG) findings of 250 patients were evaluated retrospectively. Predictive parameters for the development of serious complications were studied., Results: Median age of patients was 14.6 years, of which, 70% of patients were female and 66% were in pediatric age group. The most common pathological clinical finding and laboratory abnormality were alteration of consciousness and hyponatremia. The rate of convulsive seizure, arrhythmia, and respiratory depression were 17 (6.8%), 16 (6.4%), and 11 (4.4%), respectively. These complications were more seen in pediatric patients than adults (15.8% and 1.2%). The incidence of hyponatremia was more in pediatric patients and severe poisoning groups (38.8 and 53.4%, respectively). The levels of amitriptyline and nortriptyline were significantly higher in the group with complications than the group without complications (p < 0.05). All adult patients were discharged with good prognosis. In pediatric age group, one patient was discharged with severe neurological sequelae and one patient died. QRS duration >100 ms, long corrected QT duration interval, and low Glasgow Coma Score (GCS) at admission were identified as independent risk factors for the development of life-threatening complications (odds ratio: 69.4, 1.9, and 1383, respectively; p < 0.05)., Conclusion: Amitriptyline poisoning may be associated with life-threatening complications, especially in pediatric age group and in patients with hyponatremia. Low GCS, presence of hyponatremia, high serum drug levels, and pathological ECG findings on admission may be helpful in predicting the development of complications and poor prognosis., (© The Author(s) 2014.)

Background: Tianeptine is widely used for controlling depressive symptoms., Objective: The aim of this study was to evaluate the bioequivalence between the generic (test) formulation containing tianeptine sodium 12.5 mg and the branded (reference) formulation Stablon® with regard to their pharmacokinetic profiles., Methods: A randomized, two-sequence, two-treatment crossover study was conducted in healthy male Korean volunteers. All of the enrolled subjects were allocated to one of two sequence groups. They were administered a tablet of the test or reference formulation and then administered the alternative formulation after a 7-day washout period. The blood samples were taken before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 10 hours after dosing. The plasma concentrations of tianeptine were analyzed using high-performance liquid chromatography with tandem mass spectrometer. Tolerability was assessed throughout the study., Results: The pharmacokinetic parameters were assessed in the 40 subjects who completed the study. The tianeptine C(max) for the test formulation was 283.13 ± 57.58 ng/mL (mean ± SD) and that for the reference formulation was 272.50 ± 59.00 ng/mL. The AUC(last) of tianeptine was 803.24 ± 180.94 ng×h/mL for the test formulation and 792.27 ± 180.93 ng×h/mL for the reference formulation. The geometric mean ratio (%) of the test to reference formulation was 104.04 (90% CI, 99.66 - 108.61) for C(max) and 101.30 (98.01 - 104.71) for AUC(last). Clinically significant adverse events were not reported during the study., Conclusion: The test and reference formulations of tianeptine were bioequivalent with regard to the pharmacokinetic parameters of Cmax and AUC(last). Both formulations were tolerated by all of the participants.

Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time., Areas Covered: This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013., Expert Opinion: The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach.

A simple, rapid and sensitive chiral capillary zone electrophoresis coupled with acetonitrile-field-amplified sample stacking method was developed that allows the simultaneous enantioselective separation of the mirtazapine, N-demethylmirtazapine, 8-hydroxymirtazapine and mirtazapine-N-oxide. The separation was achieved on an uncoated 40.2 cm×75 μM fused silica capillary with an applied voltage of 16 kV. The electrophoretic analyses were carried out in 6.25 mM borate-25 mM phosphate solution at pH 2.8 containing 5.5 mg/mL carboxymethyl-β-cyclodextrin. The detection wavelength was 200 nm. Under these optimized conditions, satisfactory chiral separations of four pair enantiomers were achieved in less than 7 min in vitro. After one step clean-up liquid-liquid extraction using 96-well format, sample was introduced capillary zone electrophoresis with acetonitrile-field-amplified sample stacking to enhance the sensitivity of enantiomers. The method was validated with respect to specificity, linearity, lower limit of quantitation, accuracy, precision, extraction recovery and stability. The lower limit of quantification was 0.5 ng/mL with linear response over the 0.5-50 ng/mL concentration range for each mirtazapine, N-demethylmirtazapine and 8-hydroxymirtazapine enantiomer. The developed and validated method has been successfully applied to the enantioselective pharmacokinetic studies in 12 healthy volunteers after oral administration of rac- mirtazapine.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Thermoreversible biogels can serve as effective systems for delivery of drugs through nose with increased nasal residence time. The objective of this study was to use chitosan and glycerophosphate based thermoreversible systems for delivery of doxepin to brain through intranasal administration. Formulations were prepared by admixture of suitable dilutions of chitosan and glycerophosphate with or without polyethylene glycol, followed by addition of the antidepressant doxepin hydrochloride. Both systems were evaluated for gelling characteristics, rheology, mucoadhesion, in vitro release, and ex vivo permeation through sheep nasal mucosa. In vivo efficacy was evaluated in Swiss albino mice through the forced swim test. Nasal tissues of mice subjected to repeated exposure to formulation were evaluated histopathologically. Both formulations gelled rapidly at 37°C, returned to sol state on cooling, and exhibited thixotropy. Addition of polyethylene glycol decreased the glycerophosphate content required for gelation and rendered the formulation isotonic. Both gels showed good mucoadhesion, enhanced drug permeation, and provided prolonged in vitro release at 37°C. Efficacy of the formulation in treated groups was inferred from the measured pharmacodynamic parameter and histopathological reports of formulation treated groups showed no significant local toxicity. The biogels could be potential systems for effective drug delivery to brain via nose.

In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrollment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and ≥ 2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products.

Neuropathic pain represents a diagnostic challenge and is difficult to treat. In recent years, clinical trials have led to the development of a number of new treatment guidelines. The guidelines recommend drugs for the most important types of neuropathic pain and suggest alternatives in the event of lack of effect or intolerable adverse effects. Patients with this condition often suffer from anxiety, depression and insomnia, which influences the choice of drug. This article presents the most important drugs on which these guidelines concur.

Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.