Search

Nefazodone, a derivative of triazolones, belongs to a group of heterocyclic aromatic compounds. It is used as an antidepressant for treating depression, including major depressive disorder. Unlike other antidepressant groups such as selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors, Nefazodone does not share chemical similarities. Recent research has focused on studying the reactivity and chemical structure influenced by Nefazodone's medicinal features in the drug's adsorption process on single-wall Carbon Nanotube (CNT) as an adsorbent in the gas phase using density functional theory (DFT), Becke, 3-parameter, Lee–Yang–Parr (B3LYP) 6-311+G(d,p) basis set (DFT/B3LYP/6-311+G(d,p)). The effect of electronegative atoms and phenyl groups on the adsorption of Nefazodone on CNT has been studied by calculating the adsorption energy for all active sites. On the other hand, thermodynamic values, such as Gibbs free energy (−4873.09 kJ), Enthalpy (−4872.83 kJ), and Entropy (903.09 J/mol.kelvin), as well as thermodynamic capacity (497.45 J/mol.kelvin), were calculated to show the reactivity of Nefazodone. The stability and reactivity were examined through the energies of the highest occupied molecular orbital (HOMO) (−5.53 eV) and lowest unoccupied molecular orbital (LUMO) (−0.58 eV) of Nefazodone, highlighting ten regions with chemical activity, all of which are thermodynamically stable. Some Electronic parameters such as chemical potential (µ), electronegativity (χ), softness (σ), hardness (η), and electrophilicity index (ω) were calculated. The comparison of chemical potential values between Nefazodone(−3.05 eV) and the more stable complex (−3.81 eV) illustrates the more reactivity for the complex. This suggests that Nefazodone can be transferred to biological systems through such an adsorption mechanism.

Background and Objective: Cadmium is a potential environmental contaminant that causes adverse effects on the environment and the health of living organisms. Therefore, designing a simple and economic technique for its determination is very important. In this respect, a potentiometric sensor based on nefazodone as the ionophore and [BMIM]PF6 as the ionic additive were developed for the determination of ultra-trace amounts of cadmium (II),. Materials and Methods: In this study, a new membrane ion selective electrode was constructed with a composition entailed of 10% nefazodone, 2% [BMIM]PF6, 30% PVC and 58% dioctyl phthalate (DOP).The created potential discrepancy between the membrane and reference electrodes was used as a signal which demonstrates a direct relationship with the logarithmic concentration of cadmium (II) for its determination. Results: The constructed sensor showed an appropriate Nernstian slope (30.5 mV. Decade-1) in a wide concentration range (1×10-9 - 8×10-2 M) with the detection limit of 6×10-9 M. The electrode potential was pH-independent in the range of 3.5-8.0. The response time and lifetime of the electrode obtained 5 s and 15 weeks, respectively. Conclusion: The constructed sensor independent of sample preparation was employed successively for the measurement of low concentrations of cadmium (II) in the environmental samples .Moreover, the obtained findings were in a good agreement with the results of flame atomic absorption spectroscopy. Therefore, the designed electrode established pinpoint accuracy and it can be used for the determination of cadmium (II) in aqueous samples.

The article presents a case study of a patient with chronic neuropathic pain after hemipelvectomy who received intraganglionic lidocaine injections under CT guidance, demonstrating a transient but significant reduction in pain. Topics include the challenges of managing post-amputation and phantom limb pain, the potential benefits of targeting dorsal root ganglion (DRG) neurons for pain relief, and the use of image-guided intraganglionic injection techniques for precise drug delivery to DRGs.

What is known and objective: Statins, also known as 3‐hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors, and antidepressant drugs are frequently used in combination due to the high and growing incidence of cardiovascular diseases and psychiatric disorders worldwide. Several aspects on management, the risk of adverse events (AEs) occurrence and the potential clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) drug‐drug interactions (DDIs) between these two classes have not been well investigated. The aim of the present review was to describe the PK and PD interactions, of clinical relevance, between statins and antidepressant drugs and provide a comprehensive overview of their pharmacological features for appropriate multiple drug regimens. Methods: Relevant studies were identified through a literature search of PubMed and the Cochrane databases focusing on clinically relevant DDIs between statins and antidepressants. Only papers in English were included in the search. Results and discussion: Pharmacodynamic (PD) drug‐drug interactions (DDIs) are unlikely to occur as statins are highly selective inhibitors of HMG‐CoA reductase with no relevant effect on other enzymes or receptor systems. Despite the numerous PK studies on individual drugs belonging to statins and antidepressant agents, only a few case reports regarding specific DDIs are present in the literature and no clinical studies have been performed. PK data allow to speculate on potential DDIs, comparing the metabolic pathways, intestinal and liver transporters and elimination routes. Overall, second‐generation antidepressants, in particular citalopram, escitalopram, mirtazapine, reboxetine and venlafaxine, have weak inhibitory effects on various cytochrome (CYP) isozymes and seem to have a more advantageous DDIs profile in vivo. Conversely, nefazodone, fluoxetine, paroxetine and fluvoxamine influence considerably CYPs activity with potential effects on statins plasma levels, although pravastatin, pitavastatin and rosuvastatin are not susceptible to inhibition by any CYP. Albeit no studies have been performed on P‐glycoprotein (P‐gp), interactions of clinical relevance are unlikely. What is new and conclusion: Although DDIs with antidepressants are potentially, but rarely clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. An evaluation on DDIs between these drugs can be useful for future PK/PD studies on drug‐drug interaction to provide clinicians with more data for appropriate multiple drug regimens. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 -4  M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 -6 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC 50 value being 4.57 ± 0.02. The pIC 50 values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 -6  M (sertraline and buspirone), ≥10 -5  M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 -5  M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.

Introduction We have recently compared all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Here we present a protocol for a network meta-analysis aimed at extending these results, updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of specific adverse events and tolerability in the acute treatment of major depression in adults. Methods and analysis We will include all double-blind randomised controlled trials comparing one active drug with another or with placebo in the acute treatment major depression in adults. We will compare the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will include the total number of patients experiencing specific adverse events; experiencing serious adverse events; and experiencing at least one adverse event. Published and unpublished studies will be retrieved through relevant database searches, trial registries and websites; reference selection and data extraction will be completed by at least two independent reviewers. For each outcome we will undertake a network meta-analysis to synthesise all evidence. We will use local and global methods to evaluate consistency. We will perform all analyses in R. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application. Discussion This work will provide an in- depth analysis and an insight into the specific adverse events of individual antidepressants. Ethics and dissemination This review does not require ethical approval. PROSPERO registration number CRD42019128141. [ABSTRACT FROM AUTHOR]

Copyright of Al-Mustansiriyah Journal for Pharmaceutical Sciences is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nefazodone is an anti-depressant that interacts with a wealth of pharmacological targets, including some that may exert anti-dyskinetic and anti-psychotic effects in Parkinson’s disease (PD), notably serotonin 1A and 2A receptors. In this study, we sought to determine the effect of nefazodone on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Six common marmosets developed parkinsonism following administration of MPTP, after which they were treated chronically with L-DOPA to induce stable dyskinesia and PLBs. In behavioural experiments, nefazodone (0.01, 0.1 and 1 mg/kg) or vehicle was administered in combination with L-DOPA and its effects on dyskinesia, PLBs and parkinsonian disability were assessed. The addition of nefazodone 0.01, 0.1 and 1 mg/kg to L-DOPA reduced the severity of peak dose dyskinesia by ≈ 21%, ≈ 39% and ≈ 42% (all P < 0.05), while it did not have any significant effect on PLBs, when compared to L-DOPA/vehicle. Parkinsonian disability was not affected by any dose of nefazodone. Our results suggest that nefazodone may be effective to alleviate L-DOPA-induced dyskinesia in PD, while it may not exert any beneficial effect on dopaminergic psychosis. [ABSTRACT FROM AUTHOR]

This study examined the ability of several human pharmaceuticals to modulate hepatic piscine CYP-mediated monooxygenase activities. Effects of six pharmaceuticals: diclofenac, sulfamethoxazole, tramadol, carbamazepine, venlafaxine and nefazodone, were investigated in vitro in rainbow trout hepatic microsomes. The reactions of 7-ethoxyresorufin-O-deethylase (EROD) and benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylase (BFCOD), were used as markers for hepatic CYP1A and CYP3A-like activities, respectively. Our results showed that EROD and BFCOD activities were both affected by nefazodone. Nefazodone inhibited EROD in a dose dependent manner and was found to be a potent non-competitive inhibitor of EROD with a K i value of 6.6 μM. BFCOD activity was inhibited non-competitively in the presence of nefazadone with K i value of 30.7 μM. BFCOD activity was slightly reduced only by the highest concentration of carbamazepine. Diclofenac, sulfamethoxazole, tramadol, and venlafaxine did not affect the activity of either EROD or BFCOD. We further exposed microsomal fraction to mixtures of six pharmaceuticals to investigate potential inhibition. The results showed that EROD and BFCOD activity was inhibited on 94% and 80%, respectively at higher tested concentration. To our knowledge, this is the first report to demonstrate an inhibitory effect of nefazodone on hepatic CYP1A and CYP3A-like proteins in rainbow trout. [ABSTRACT FROM AUTHOR]

Formation of reactive metabolites that are capable to react with macromolecules could contribute to drug-induced toxicity. As part of early drug screening strategy to support small molecule structure-activity relationship analysis, glutathione (GSH) trapping is commonly used for the detection of reactive metabolites. When trapped, the GSH conjugates can be characterized using mass spectrometry (MS)-based methods. In the present study, an efficient method was developed for rapid identification and characterization of GSH-trapped metabolites with a single run using a quadrupole orbitrap high-resolution mass spectrometer. The selective ion monitoring of m/z 272.0888, a characteristic product ion corresponding to deprotonated γ-glutamic-dehydroalanyl-glycine in the negative ionization mode, was applied as a survey scan leveraging all ion fragmentation mode using in-source collision-induced dissociation. Detection of the extracted product ions within 5.0 Δppm mass accuracy indicated the presence of putative GSH conjugates. Incorporation of fast polarity switching option and multiple data-dependent acquisition scans in a single cycle allowed the determination of accurate mass and multiple MS/MS spectra of GSH conjugates in both negative and positive ionization modes, which featured rich fragments for structural characterization. The effectiveness of this method was evaluated with four model compounds including acetaminophen, clozapine, diclofenac, and nefazodone in both liver microsome and cryopreserved hepatocyte incubations. Successful characterization of multiple GSH conjugates in each case validated this method. Overall, this approach provided a sensitive tool for rapid detection and characterization of GSH conjugates in vitro. Notably, this method could be suitable for high-throughput screening of reactive metabolites in the early drug discovery process.Sensitive detection and characterization of glutatione conjugates using a high-resolution quadrupole orbitrap mass spectrometer [ABSTRACT FROM AUTHOR]

Objective: The Predictors of Remission in Depression to Individual and Combined Treatments [PReDICT] study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive disorder among treatment-naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes.Method: Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment.Results: A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission.Conclusions: Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes. [ABSTRACT FROM AUTHOR]

Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodoneinduced liver toxicity are not well defined. In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2α, was significantly increased, and splicing of XBP1 was observed. Nefazodone-suppressed protein secretion was evaluated using a Gaussia luciferase reporter assay that measures ER stress. The ER stress inhibitors (4-phenylbutyrate and salubrinal) and knockdown of ATF-4 gene attenuated nefazodone-induced ER stress and cytotoxicity. Nefazodone activated the MAPK signaling pathway, as indicated by increased phosphorylation of JNK, ERK1/2, and p38. Inhibition of ERK1/2 reduced ER stress caused by nefazodone. Taken together, our findings suggest that ER stress contributes to nefazodone-induced toxicity in HepG2 cells and that the MAPK signaling pathway plays an important role in ER stress. [ABSTRACT FROM AUTHOR]

Nefazodone (NEF) is an antidepressive agent that was widely used in the treatment of depression until its withdrawal from the market, due to reports of liver injury and failure. NEF hepatotoxicity has been associated with mitochondrial impairment due to interference with the OXPHOS enzymatic activities, increased ROS generation and decreased antioxidant defenses. However, the mechanisms by which NEF induces mitochondrial dysfunction in hepatocytes are not completely understood. Here, we investigated the mitochondrial mechanisms affected upon NEF exposure and whether these might be linked to drug hepatotoxicity, in order to infer liabilities of future drug candidates. Two moderately hepatotoxic NEF concentrations (20 and 50 μM) were selected from dose-response growth curves performed in HepG2 cells. Cell viability, caspase activity, nuclear morphology, mitochondrial transmembrane potential, mitochondrial superoxide levels, and the expression of genes associated with different cellular pathways were evaluated at different time points. NEF treatment led to an increase in the expression of genes associated with DNA-damage response, antioxidant defense and apoptosis and a decreased expression of genes encoding proteins involved in oxidative phosphorylation, DNA repair, cell proliferation and cell cycle progression, which seem to constitute mechanisms underlying the observed mitochondrial and cell function impairment. [ABSTRACT FROM AUTHOR]

A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS. [ABSTRACT FROM AUTHOR]

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD 90 ) and 50% (APD 50 ) repolarization, reduced the maximum upstroke velocity (dV/dt max ) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including I Kr , I Ks , I Na , and I Ca . Among them, I Kr and I Na showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K + channels. [ABSTRACT FROM AUTHOR]

Chimeric mice with humanized livers (PXB mice) are used to investigate the metabolism and pharmacokinetics of drugs in humans. However, residual murine enzymatic activities derived from the liver and the presence of mouse small intestinal metabolism can hamper the prediction of human drug metabolism. Recently murine Cytochrome P450 3a gene knockout chimeric mice with humanized livers ( Cyp3a KO CM) were developed. To evaluate the prediction of drug metabolism, nefazodone (NEF) was administered orally at 10 mg/kg to the following mouse strains: Cyp3a KO CM, murine Cyp3a gene knockout ( Cyp3a KO), PXB and severe combined immunodeficiency (SCID) mice. Liquid chromatography-mass spectrometry was used for metabolic profiling of plasma, urine and bile. The prediction of human metabolite levels such as hydroxy nefazodone (OH-NEF), triazoledione form (TD), m-chlorophenylpiperazine and dealkyl metabolites in Cyp3a KO CM was superior to that in Cyp3a KO, PXB or SCID mice. Further, clinical exposure levels of NEF, OH-NEF and TD were reproduced in Cyp3a KO CM. In contrast, NEF was rapidly metabolized to TD in both PXB and SCID mice but not in Cyp3a KO mice, suggesting that murine CYP3A is involved in the elimination of NEF in these mice. These findings demonstrate that the metabolic profile of NEF in Cyp3a KO CM differs qualitatively and quantitatively from that in PXB mice due to the higher metabolic rate of NEF and its metabolites via murine CYP3A. Therefore Cyp3a KO CM might be useful in predicting the metabolic profiles of drug candidates in humans. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Rationale: This paper describes a strategy for the profiling and identification of metabolites based on chemical group classification using high-resolution accurate mass (HR/AM) full scan mass spectrometry (MS) and All-Ion fragmentation (AIF) MS² data. Methods: The proposed strategy uses a hybrid quadrupole Orbitrap (Q-Exactive) employing stepped normalised collision energy (NCE) at 35% and 80% to produce key chemically diagnostic product ions from full coverage of the product ion spectrum. This approach allows filtering of high-resolution AIF MS² data in order to identify parent-related compounds produced following incubation in rat liver microsomes (RLMs). Results: An antidepressant drug, nefazodone (NEF), was selected as the model test compound to demonstrate the proposed workflow for metabolite profiling. This resulted in the identification of three indicative chemical groups within NEF: triazolone, phenoxy and chlorophenylpiperazine. High-resolution mass spectrometry provides increased specificity to distinguish between two characteristic product ion masses m/z 154.0975 (C7H12N3O) and 154.0419 (C8H9NCl), which are not fully resolved by spectrometers operating at nominal mass resolution, indicative of compounds containing the triazolone and chlorophenylpiperazine moieties, respectively. Conclusions: This post-acquisition processing strategy provides comprehensive detection and identification of high- and low-level metabolites from an 'all-in-one' analysis. This enables functional groups to be systematically traced across a wide range of metabolites, leading to the successful identification of 28 in vitro NEF-related metabolites. In our hands this approach has been applied to agrochemical environmental fate and dietary metabolism studies, as well as metabolomics and biomarker analysis. [ABSTRACT FROM AUTHOR]

Abstract: Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC50 of 45.3nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding. [Copyright &y& Elsevier]

Based upon a variety of neurobiological conceptualizations, a limited number of studies have been performed to assess the response of hypersexual behavior to psychopharmacologic therapy. In the present article, we conducted a review of empirical studies that evaluated a psychopharmacologic treatment for hypersexual behavior. Study characteristics reviewed include the participants, research designs, pharmacologic agent(s) examined and dosage(s), medication side effects, comorbid psychiatric illness, assessment of hypersexual behavior, and outcomes. Several studies report significant attenuation of hypersexual symptoms with pharmacologic treatment. However, significant methodological limitations narrow the rigor of these findings. Considerations for comorbidity and recommendations for enhancement of future outcome research are provided. [ABSTRACT FROM AUTHOR]

Drugs can be metabolically activated to soft and hard electrophiles, which are readily trapped by glutathione (GSH) and cyanide (CN), respectively. These adducts are often detected and structurally characterized using separate tandem mass spectrometry methods. We describe a new method for simultaneous screening of GSH and CN adducts using precursor ion (PI) and neutral loss (NL) scans-dependent product ion spectral acquisition and data mining tools on an triple quadrupole linear ion trap mass spectrometry. GSH, potassium cyanide, and their stable isotope labeled analogues were incubated with liver microsomes and a test compound. Negative PI scan of m/z 272 for detection of GSH adducts and positive NL scans of 27 and 29 Da for detection of CN adducts were conducted as survey scans to trigger acquisition of enhanced resolution (ER) spectrum and subsequent enhanced product ion (EPI) spectrum. Post-acquisition data mining of EPI data set using NL filters of 129 and 27 Da was then performed to reveal the GSH adducts and CN adducts, respectively. Isotope patterns and EPI spectra of the detected adducts were utilized for identification of their molecular weights and structures. The effectiveness of this method was evaluated by analyzing reactive metabolites of nefazodone formed from rat liver microsomes. In addition to known GSH- and CN-trapped reactive metabolites, several new CN adducts of nefazodone were identified. The results suggested that current approach is highly effective in the analysis of both soft and hard reactive metabolites and can be used as a high-throughput method in drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Tamoxifen, a medication used in the treatment of breast cancer, often induces menopausal symptoms. Certain medications and natural supplements taken or prescribed to alleviate tamoxifen-induced hot flashes and depressive states in women with breast cancer interact with tamoxifen. This paper reviews potentially problematic interactions and offers treatment recommendations. Methods: Medline (1950-June 1, 2010), Embase Classic+Embase (1947-June 1, 2010) and PsycINFO (1967-June 1, 2010) were searched through Ovid. The word “tamoxifen” was searched with “depression” and then with “menopaus*” and “symptoms”, with “treatment” as a limit. “Tamoxifen” was later searched with the MeSH terms “drug interaction” or “drug incompatibility”. Results: Venlafaxine is efficacious for the treatment of hot flashes and depression and safe to use in combination with tamoxifen. Gabapentin is also efficacious in treating tamoxifen-induced hot flashes and, since it does not interact with cytochrome P450 system, is likely safe to use in patients using tamoxifen. Desvenlafaxine and pregabalin may be alternatives to venlafaxine and gabapentin, respectively, although desvenlafaxine has not yet been studied in this population. Paroxetine, fluoxetine and bupropion are strong CYP2D6 inhibitors which should be avoided in tamoxifen users. Fluvoxamine and nefazodone both inhibit CYP3A, which could potentially affect the metabolism of tamoxifen. Clonidine can be an alternative agent but may carry significant side effects. Evidence of medicinal products for the treatment of tamoxifen-induced hot flashes is equivocal at best. Conclusions: Clinicians should remain cautious about using strong inhibitors and/or inducers of cytochrome 2D6 and 3A4 concomitantly with tamoxifen. Use of natural menopausal supplements and diets rich in isoflavones should not be encouraged in tamoxifen users until more data is available. There are however safe treatments for hot flashes and depression in tamoxifen users. [Copyright &y& Elsevier]

The present study aimed to evaluate the effect of the serotonin antagonists and reuptake inhibitors trazodone and nefazodone on liver injury induced by treatment with carbon tetrachloride (CCl4) in rats. Liver damage was induced in rats by oral administration of CCl4 (2.8 mL/kg in olive oil). Nefazodone (5, 10, or 20 mg/kg), trazodone (5, 10, or 20 mg/kg), silymarin (25 mg/kg), or saline (control) was orally administered once daily in association with CCl4 and for one week thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl4- treated rats, treatment with trazodone (5, 10, 20 mg/ kg), reduced serum alanine aminotransferase (ALT) levels by 24, 38.6, and 49.3%. Serum aspartate aminotransferase (AST) levels were decreased by 18.1, 37.9, and 42.2%, and alkaline phosphatase (ALP) levels decreased by 25.7, 32.6, and 39.7%, respectively. Nefazodone (5, 10, 20 mg/kg) in a dosedependent manner reduced the elevation of ALT levels by 15.6, 36.5, and 45.9%, AST levels by 16.7, 17.3, and 43%, and ALP by 30.5, 37.5, and 42.9%, respectively. Silymarin treatment reduced the levels of ALT, AST, and ALP by 56.1-62.8, 56.0-64.0, and 50.1-58.2%, respectively. The administration of CCl4 decreased levels of reduced glutathione in blood compared to the vehicle-treated group. In CCl4- treated rats, reduced glutathione levels increased after trazodone in a dose-dependent manner. Reduced glutathione was increased by nefazodone at concentrations of 5 and 10 mg/kg, but not after 20 mg/kg nefazodone. Reduced glutathione levels were increased by the administration of silymarin to near normal values. The administration of CCl4 resulted in a marked increase in nitric oxide levels in serum (the concentrations of nitrite/nitrate) as compared to the control group. Treatment with trazodone or nefazodone caused a dose-dependent decrease in serum nitric oxide levels compared with the CCl4 control group. Histopathological and histomorphometric examinations also indicated that CCl4-induced liver injury was less severe in trazodone and nefazodone-treated groups than in the CCl4 control groups. Metabolic perturbations caused by CCl4 in the form of decreased intracellular protein and mucopolysaccharide content in hepatocytes were improved by treatment with trazodone and nefazodone. It is concluded that administration of serotonin antagonists and reuptake inhibitors trazodone and nefazodone is associated with a reduction in experimental liver injury induced by CCl4. [ABSTRACT FROM AUTHOR]

Objective. This case report seeks to promote physician awareness of the potential drug interaction between corticosteroid medications and cytochrome P450 3A4 (CYP3A4) inhibitors. Setting. Tertiary care multispecialty referral center. Discussion. Corticosteroid injections are commonly used as effective treatments for a variety of pain disorders. Recently, there has been a greater appreciation of the potential drug interactions between CYP3A4 inhibitors and corticosteroid medications including topical steroid preparations. We report a case of triamcinolone acetonide induced secondary adrenal insufficiency related to impaired CYP3A4 metabolism by coadministration of nefazodone. Conclusion. Physicians should recognize the potential effects of CYP3A4 inhibitors particularly when administering or prescribing systemic corticosteroid medications. [ABSTRACT FROM AUTHOR]

Objective: Psychotherapy-pharmacotherapy combinations are frequently recommended for the treatment of chronic depressive disorders. Our aim in this novel reanalysis of archival data was to identify patient subgroups on the basis of symptom trajectories and examine the clinical significance of the resultant classification on basis of differential treatment effects to psychotherapy (cognitive behavioral analysis system of psychotherapy), pharmacotherapy (nefazodone), and their combination. Method: We selected data for 504 patients diagnosed with chronic depression from archival data of a clinical trial (N = 681) and analyzed treatment courses (as assessed by the Hamilton Rating Scale for Depression) using growth mixture models, a contemporary exploratory analysis technique. Results: Three patient subgroups were identified from the typical patterns of change of depression severity during 12-week acute-phase treatment. Within these patient subgroups, differential treatment effects were evident: combination treatment clearly outperformed the 2 monotherapies in the largest patient subgroup, characterized by moderate depression severity, but not in the remaining 2 subgroups, characterized by low and severe depression at baseline. Patient characteristics prior to initiation of treatment enabled allocation of 61% of patients to these subgroups. Conclusions: Research on patient subgroups with different change patterns may support classifications of patients that indicate which treatment is most effective for which type of patient. [ABSTRACT FROM AUTHOR]

1. The utility of multivariate analysis in in vitro metabolite identification studies was examined with nefazodone, an antidepressant drug with a well-established metabolic profile. 2. The chromatographic conditions were purposefully chosen to reflect those utilized in high-throughput screening for microsomal stability of new chemical entities. 3. Molecular ion, retention time information on groups of human liver microsomal samples with/without nefazodone was evaluated by principal component analysis (PCA). Resultant scores and loadings plots from the PCA revealed the segregation and the ions of interest that designated the drug and its corresponding metabolites. Subsequent acquisition of tandem mass spectrometry (MS/MS) spectra for targeted ions permitted the interrogation and interpretation of spectra to identify nefazodone and its metabolites. 4. A comparison of nefazodone metabolites identified by PCA versus those found by traditional metabolite identification approaches resulted in very good correlation when utilizing similar analytical methods. Fifteen metabolites of nefazodone were identified in β-nicotinamide adenine dinucleotide phosphate (NADPH)-supplemented human liver microsomal incubations, representing nearly all primary metabolites previously reported. 5. Of the 15 metabolites, eight were derived from the N-dealkylation and N-dephenylation of the N-substituted 3-chlorophenylpiperazine motif in nefazodone, six were derived from mono- and bishydroxylation, and one was derived from the Baeyer Villiger oxidation of the ethyltriazolone moiety in nefazodone. [ABSTRACT FROM AUTHOR]

Abstract: Background: Individuals with chronic depression respond poorly to both medication and psychotherapy. The reasons for the poorer response, however, remain unclear. One potential factor is the presence of comorbid Axis II personality disorders (PDs), which occur at high rates among these patients. Methods: This study examines the moderating influence of co-occurring PDs, primarily in cluster C, among 681 chronically depressed adult outpatients who were randomly assigned to 12 weeks of treatment with nefazodone, a specialized psychotherapy for chronic depression, or their combination. Results: At baseline, 50.4% (n =343) of patients met criteria for one or more Axis II disorders. Following 12 weeks of treatment, patients with comorbid PDs had statistically lower depression scores (M =12.2, SD=+9.2) than patients without comorbid PDs (M =13.5, SD=+8.7). There was no differential impact of a comorbid PD on responsiveness to medication versus psychotherapy. The results did not change when the data were analyzed using an intent-to-treat sample or when individual personality disorders were examined separately. Limitations: Patients with severe borderline, antisocial, and schizotypal PDs were excluded from study entry; therefore, these data primarily apply to patients with cluster C PDs and may not generalize to other Axis II conditions. Conclusions: Comorbid Axis II disorders did not negatively affect treatment outcome and did not differentially affect response to psychotherapy versus medication. Treatment formulations for chronically depressed patients with certain PDs may not need to differ from treatment formulations of chronically depressed patients without co-occurring PDs. [Copyright &y& Elsevier]

It has been suggested that increase in delta sleep ratio (DSR), a marker for the relative distribution of slow wave activity (SWA) over night time, is associated with clinical response to antidepressant treatment. We examined this index and its relationship to rapid eye movement (REM) suppression before and during long-term treatment with nefazodone, which does not suppress REM sleep, and paroxetine which does. The effect of serotonin (5-HT2A) receptor blockade on the evolution of SWA during treatment was also investigated. In a double-blind, randomised, parallel group, 8-week study in 29 depressed patients, sleep electroencephalograms were performed at home at baseline, on night 3 and 10, and at 8 weeks of treatment with either paroxetine or nefazodone. SWA was automatically analysed and a modified DSR (mDSR) was derived, being the ratio of amount of SWA in the first 90 min of sleep to that in the second plus third 90-min periods. At baseline, the pattern of SWA over night time was similar to other reports of depressed patients. mDSR improved over the course of treatment; there was no difference between remitters and non-remitters but there was a significant drug effect and a significant drug × time effect with paroxetine patients having a much higher mDSR after treatment, regardless of clinical status. SWA and REM during antidepressant treatment appear to be interdependent and neither of them alone is likely to predict response to treatment. Higher mDSR did not predict therapeutic response. 5-HT2A blockade by nefazodone does not increase SWA above normal levels. [ABSTRACT FROM AUTHOR]