- Semi-automated set-up for exhaustive micro-electromembrane extractions of basic drugs from biological fluids. [Journal Article]
- ACAnal Chim Acta 2018 Apr 16; 1005:34-42
- Manual handling of microliter volumes of samples and reagents is usually prone to errors and may have direct consequence on the overall performance of microextraction process. Direct connection of a ...
Manual handling of microliter volumes of samples and reagents is usually prone to errors and may have direct consequence on the overall performance of microextraction process. Direct connection of a syringe pump and a disposable microextraction unit using flexible polymeric tubing was employed for semi-automated liquid handling in micro-electromembrane extraction (μ-EME). A three-phase μ-EME system was formed by consecutive withdrawal of microliter volumes of donor solution, free liquid membrane (FLM) and acceptor solution into the unit. Excellent repeatability and accuracy of the withdrawal sequence was achieved for solution volumes typically used in μ-EME (1-5 μL) as well as excellent correlation between the initially withdrawn and the finally collected solution volumes. μ-EMEs were initiated by application of d.c. electric potential to the terminal aqueous solutions and specific μ-EME parameters were optimized in order to ensure complete transfer of model analytes from donor to acceptor solution. Exhaustive μ-EMEs of three basic drugs, nortriptyline, papaverine and haloperidol, were achieved from 1.3 μL of acidified donor solution (10 mM HCl) across 2.5 μL of FLM (1-ethyl-2-nitrobenzene) into 1.3 μL of acidified acceptor solution (25 mM HCl) in 10 min at 150 V. The three drugs were also exhaustively extracted from salt- and protein-containing standard solutions, human urine and human plasma with extraction recoveries ranging from 79 to 102%. Resulting acceptor solutions were analysed by capillary electrophoresis with ultraviolet detection (CE-UV) and the μ-EME-CE-UV method was characterized by good linearity (coefficients of determination ≥ 0.992), high repeatability (RSD values ≤ 6.5%) and limits of detection ≤ 0.15 mg/L.
- Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages. [Journal Article]
- JLJ Leukoc Biol 2018 Jan 26
- Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas...
Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.
- Pharmacokinetic determination and analysis of nortriptyline based on GC-MS coupled with hollow-fiber drop-to-drop solvent microextraction technique. [Journal Article]
- BBioanalysis 2018; 10(3):143-152
- 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...
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.
- Fast and easy extraction of antidepressants from whole blood using ionic liquids as extraction solvent. [Journal Article]
- TTalanta 2018 Apr 01; 180:292-299
- This study aims to prove that ionic liquids (ILs) can be used as extraction solvents in a liquid-liquid microextraction, coupled to LC-MS/MS, for the quantification of a large group of antidepressant...
This study aims to prove that ionic liquids (ILs) can be used as extraction solvents in a liquid-liquid microextraction, coupled to LC-MS/MS, for the quantification of a large group of antidepressants in whole blood samples. The sample preparation procedure consisted of adding 1.0mL aqueous buffer pH 3.0 and 60µL of IL (1-butyl-3-methylimidazolium hexafluorophosphate) to 1.0mL whole blood. Subsequently, a 5-min rotary mixing step was performed followed by centrifugation. The lower IL phase was collected, diluted 1:10 in methanol and 10µL was injected into the LC-MS/MS. The following analytes were included in the full-quantitative method: agomelatine, amitriptyline, bupropion, clomipramine, dosulepin, doxepin, duloxetine, escitalopram, fluoxetine, imipramine, maprotiline, mianserin, mirtazapine, nortriptyline, paroxetine, reboxetine, trazodone and venlafaxine. Selectivity was checked for 10 different whole blood matrices. Additionally, possible interferences of deuterated standards or other antidepressants were evaluated. Overall, no interferences were found. For each analyte a matrix-matched calibration curve was constructed (7 levels, n = 6), covering therapeutic and low toxic concentrations. Accuracy and precision were evaluated over eight days, at three concentration levels (n = 2). Bias, repeatability and intermediate precision results met with the proposed validation criteria, except for fluvoxamine, which was therefore only included in the semi-quantitative method. LOQs were set at the lowest calibrator concentration and LOD values were - for most analytes - within a range of 1-2ng/mL. Recoveries (RE) and matrix effects (ME) were evaluated for five types of donor whole blood, at two concentration levels. RE values were within a range of 53.11-132.98%. ME values were within a range of 61.92-123.24%. In conclusion, this study proves the applicability of ILs as extraction solvents for a large group of antidepressants in complex whole blood matrices.
- Sex-dependent metabolism of nevirapine in rats: impact on plasma levels, pharmacokinetics and interaction with nortriptyline. [Journal Article]
- IJInt J Antimicrob Agents 2018 Jan 05
- Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and it is the first choice NNRTI during pregna...
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and it 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 the NVP metabolism and in the 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 analyzed. NVP plasma levels were higher in female than in male rats, and pharmacokinetic parameters such as tmax, Cmax,t1/2and AUClastshowed about 4-, 5-, 7- and 20-fold higher values in female rats. In vitro experiments carried out with hepatic microsomes confirmed a slower NVP metabolism in female rats, with a Vmaxvalue 2-fold lower than in male hepatic microsomes. The major metabolite in both sexes was 12-OH-NVP, being the Vmaxvalue for this metabolite 15-fold lower in female than in male rat hepatic microsomes. The inhibition of the NVP metabolism by NT was similar in both sexes with statistically non-significant differences in the IC50values. In summary, NVP is metabolized extremely slower in female than in male rats, but the inhibitory effect of NT is similar in both sexes.
- Differential change on depressive symptom factors with antidepressant medication and cognitive behavior therapy for major depressive disorder. [Journal Article]
- JAJ Affect Disord 2018 Mar 15; 229:111-119
- CONCLUSIONS: The scales contained differing numbers of items pertaining to specific depressive symptoms.The heterogeneity of MDD can be parsed into a consistent factor structure, with the factors showing differential rapidity, but ultimately similar, improvement across treatments.
- Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking. [Review]
- PPharmacotherapy 2018; 38(2):235-258
- Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventabl...
Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies-NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first-line treatment of smoking cessation)-and novel therapies: cytisine, N-acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second-line treatments used when first-line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N-acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high-quality randomized double-blind placebo-controlled trials with long-term follow-up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids.
- Systematic assessment of different solvents for the extraction of drugs of abuse and pharmaceuticals from an authentic hair pool. [Journal Article]
- FSForensic Sci Int 2018; 282:137-143
- Hair analysis has been established as a prevalent tool for retrospective drug monitoring. In this study, different extraction solvents for the determination of drugs of abuse and pharmaceuticals in h...
Hair analysis has been established as a prevalent tool for retrospective drug monitoring. In this study, different extraction solvents for the determination of drugs of abuse and pharmaceuticals in hair were evaluated for their efficiency. A pool of authentic hair from drug users was used for extraction experiments. Hair was pulverized and extracted in triplicate with seven different solvents in a one- or two-step extraction. Three one- (methanol, acetonitrile, and acetonitrile/water) and four two-step extractions (methanol two-fold, methanol and methanol/acetonitrile/formate buffer, methanol and methanol/formate buffer, and methanol and methanol/hydrochloric acid) were tested under accurately equal experimental conditions. The extracts were directly analyzed by liquid chromatography-tandem mass spectrometry for opiates/opioids, stimulants, ketamine, selected benzodiazepines, antidepressants, antipsychotics, and antihistamines using deuterated internal standards. For most analytes, a two-step extraction with methanol did not significantly improve the yield compared to a one-step extraction with methanol. Extraction with acetonitrile alone was least efficient for most analytes. Extraction yields of acetonitrile/water, methanol and methanol/acetonitrile/formate buffer, and methanol and methanol/formate buffer were significantly higher compared to methanol. Highest efficiencies were obtained by a two-step extraction with methanol and methanol/hydrochloric acid, particularly for morphine, 6-monoacetylmorphine, codeine, 6-acetylcodeine, MDMA, zopiclone, zolpidem, amitriptyline, nortriptyline, citalopram, and doxylamine. For some analytes (e.g., tramadol, fluoxetine, sertraline), all extraction solvents, except for acetonitrile, were comparably efficient. There was no significant correlation between extraction efficiency with an acidic solvent and the pka or log P of the analyte. However, there was a significant trend for the extraction efficiency with acetonitrile to the log P of the analyte. The study demonstrates that the choice of extraction solvent has a strong impact on hair analysis outcomes. Therefore, validation protocols should include the evaluation of extraction efficiency of drugs by using authentic rather than spiked hair. Different extraction procedures may contribute to the scatter of quantitative results in inter-laboratory comparisons. Harmonization of extraction protocols is recommended, when interpretation is based on same cut-off levels.
- Mechanistic Physiologically Based Pharmacokinetic (PBPK) Model of the Heart Accounting for Inter-individual Variability: Development and Performance Verification. [Journal Article]
- JPJ Pharm Sci 2017 Nov 23
- Modern model-based approaches to cardiac safety and efficacy assessment require accurate drug concentration-effect relationship establishment. Thus, knowledge of the active concentration of drugs in ...
Modern model-based approaches to cardiac safety and efficacy assessment require accurate drug concentration-effect relationship establishment. Thus, knowledge of the active concentration of drugs in heart tissue is desirable along with inter-subject variability influence estimation. To that end, we developed a mechanistic physiologically based pharmacokinetic model of the heart. The models were described with literature-derived parameters and written in R, v.3.4.0. Five parameters were estimated. The model was fitted to amitriptyline and nortriptyline concentrations after an intravenous infusion of amitriptyline. The cardiac model consisted of 5 compartments representing the pericardial fluid, heart extracellular water, and epicardial intracellular, midmyocardial intracellular, and endocardial intracellular fluids. Drug cardiac metabolism, passive diffusion, active efflux, and uptake were included in the model as mechanisms involved in the drug disposition within the heart. The model accounted for inter-individual variability. The estimates of optimized parameters were within physiological ranges. The model performance was verified by simulating 5 clinical studies of amitriptyline intravenous infusion, and the simulated pharmacokinetic profiles agreed with clinical data. The results support the model feasibility. The proposed structure can be tested with the goal of improving the patient-specific model-based cardiac safety assessment and offers a framework for predicting cardiac concentrations of various xenobiotics.
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- Is Venlafaxine More Effective than Escitalopram and Nortriptyline in the Management of Painful Symptoms in Patients with Major Depression? [Journal Article]
- PPharmacopsychiatry 2017 Nov 15
- BackgroundConflicting data regarding the efficacy of antidepressants of different mechanism of action on unexplained painful physical symptoms (UPPS) in depression have been publi...
BackgroundConflicting data regarding the efficacy of antidepressants of different mechanism of action on unexplained painful physical symptoms (UPPS) in depression have been published so far.ObjectiveThe aim of this study was to compare the impact of escitalopram (ESC), nortriptyline (NOR), and venlafaxine (VEN) on UPPS in patients with major depression.Materials and methodsSixty patients, participants in the GENDEP study, with a diagnosis of depression according to the ICD-10 criteria were randomly assigned to treatment with ESC (10-30 mg, mean dose 15.2, standard deviation [SD]±9.2) or NOR (50-150 mg, mean dose 106.2, SD±8.2). Additionally, 30 patients who were treated with VEN (75-225 mg, mean dose 181.3, SD±8.8) were included. Before inclusion (day 0) and throughout the study (days 14, 28, 42, 56), the severity of pain was monitored using the visual analog scale.ResultsThe patients treated with ESC, NOR, and VEN did not differ in the intensity of pain at days 0, 14, 28, 42, and 56.ConclusionOur results do not support the hypothesis suggesting the superiority of VEN over ESC and NOR in the management of UPPS in major depression.