Abstract We used a meta‐dynamics/semi‐empirical quantum mechanics/continuum solvent model (MTD/SQM/CSM) implemented in the CREST software (P. Pracht, F. Bohle, and S. Grimme, Physical Chemistry Chemical Physics , 2020, 22 , 7169–7192) to explore the binding mechanism of cucurbit[7]uril (CB[7]) with three drug molecules with similar structures: trazodone (TZ), m ‐chlorophenyl piperazine, and trimethoprim. Our computation well reproduced the measured binding trend and suggested the preferred protonation state of each drug in the complex and the extent the conformation of the drug molecule was changed upon binding. We found the overall binding affinity to be determined by a subtle balance among various interactions, including nonbonding interactions, desolvation penalty, and conformational change. The best binder to CB[7], TZ, achieved strong binding affinity by adopting the boat conformation of the piperazine ring that allowed it to form two strong intermolecular H─bonds in the doubly protonated state without causing too unfavorable desolvation penalty upon binding.

Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation participates in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. Antidepressant drugs have been reported to reduce neuroinflammation by acting also on glial cells. Herein, the potential anti-inflammatory and neuroprotective effects of trazodone (TRZ) on the microglial human microglial clone 3 (HMC3) cell line were investigated. HMC3 cells were activated by a double inflammatory stimulus (lipopolysaccharide [LPS] and tumour necrosis factor-alpha [TNF-α], 24 h each), and the induction of inflammation was demonstrated by (i) the increased expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and ionized calcium-binding adapter molecule 1 (IBA-1), and (ii) the increased release of interleukin 6 (IL-6) and transforming growth factor-beta (TGF-β). TRZ effects were evaluated by treating HMC3 cells for 24 h before (pre-treatment) and after (post-treatment) the double inflammatory stimulus. Notably, TRZ treatments significantly decreased the expression of NF-kB and IBA-1 and the release of the cytokines IL-6 and TGF-β. Moreover, TRZ prevented and reduced the release of quinolinic acid (QUIN), a known neurotoxic kynurenine metabolite. Finally, cellular supernatants collected from microglial cells pre-treated LPS-TNF-α with TRZ were able to improve neuronal-like cell viability, demonstrating a potential neuroprotective effect. Overall, this study suggests the anti-inflammatory effects of TRZ on human microglia and strives for its neuroprotective properties.

Interaction between antidepressant drug trazodone with double-stranded DNA: Multi-spectroscopic and computational analysis

Development and characterization of a non-enzymatic electrochemical biosensor for rapid determination of sorbent-based extracted trazodone and doxepin in complicated samples

Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study

The antidepressant drug trazodone (TRZ) is commonly used for treating depression, anxiety, and insomnia, however, it causes cardiotoxicity, which is one of its limitations. The objective of this work was to investigate the impact of sage (Salvia officinalis) in rats against cardiotoxicity induced by TRZ and to investigate the mechanisms involved in its cardio-protective properties through autophagy and oxidative stress. Fifty male albino rats were split randomly into five experimental groups: control group, sage oil group (100 mg/kg), TRZ group (20 mg/kg), protective group, and curative group. Cardiac function biomarkers (aspartate aminotransferase [AST], creatine kinase-MB [CK-MB], and cardiac troponin T [cTnI]) were assessed in serum. Oxidative stress and inflammatory biomarkers in cardiac tissue (total antioxidant capacity, malondialdehyde, and tumor necrosis factor-α) were evaluated. Heart tissues were subjected to histological, immunohistochemical, and ultrastructural evaluations. DNA damage also evaluated. Significant rise in the levels of AST, CK-MB, and cTnI were observed with enhanced autophagy along with marked histopathological changes in the form of interrupted muscle fibers with wide interstitial spaces with areas of hemorrhage and extravasated blood and interstitial mononuclear cellular infiltration in TRZ group. DNA damage was also significantly increased in TRZ group. However, administration of sage in both protective and curative groups show marked improvement of the cardiac alterations. In conclusion, sage ameliorated the alterations in the heart induced by trazadone through modulation of autophagy and oxidative stress.

Drug interactions are significant considerations for intradermal testing (IDT). Trazodone (TRZ) is an anxiolytic and selective histaminergic (H1 ) antagonist with no interaction in human prick tests; however, interaction in canine IDT is unknown. Trazodone will not adversely affect intradermal histamine reactions in dogs. Fourteen nonanxious, nonatopic, healthy client-owned dogs were enrolled in this randomised, blinded, cross-over study. Dogs were randomised to receive low-dose TRZ (4 mg/kg) (Teva Pharmaceuticals), high-dose TRZ (8 mg/kg) or no TRZ per os two hours before intravenous sedation with dexmedetomidine (5 mcg/kg) (Dexdomitor; Zoetis). Intradermal testing was performed with five quadrupling dilutions of histamine (1:100,000 to 1:25,600,000 w/v; Greer) and 0.9% saline (Hospira), observing a minimum two weeks washout period between treatments. Two observers, who were blinded to treatment and the identity of the injections, evaluated each test using previously established subjective and objective methods. The mean wheal diameter of histamine 1:1,600,000 w/v was significantly smaller with low-dose TRZ (4 mg/kg) compared to the control group (p = 0.048; repeated measures ANOVA with post hoc Tukey's test). For all other histamine dilutions and saline, mean wheal diameter was not significantly different among groups. There were no significant differences in the subjective scores of all histamine dilutions and saline (p > 0.05; Friedman test). A single oral dose of TRZ does not adversely affect intradermal histamine reactions in dogs.

The concurrent use of several medications is a common practice in the treatment of complex psychiatric conditions. One such commonly used combination is aripiprazole (ARI), an antipsychotic, and trazodone (TRZ), an antidepressant. In addition to their effects on dopamine and serotonin systems, both of these compounds are inhibitors of the 7-dehydrocholesterol reductase (DHCR7) enzyme. To evaluate the systemic and nervous system distribution of ARI and TRZ and their effects on cholesterol biosynthesis, adult mice were treated with both ARI and TRZ for 21 days. The parent drugs, their metabolites, and sterols were analyzed in the brain and various organs of mice using LC-MS/MS. The analyses revealed that ARI, TRZ, and their metabolites were readily detectable in the brain and organs, leading to changes in the sterol profile. The levels of medications, their metabolites, and sterols differed across tissues with notable sex differences. Female mice showed higher turnover of ARI and more cholesterol clearance in the brain, with several post-lanosterol intermediates significantly altered. In addition to interfering with sterol biosynthesis, ARI and TRZ exposure led to decreased ionized calcium-binding adaptor molecule 1 (IBA1) and increased DHCR7 protein expression in the cortex. Changes in sterol profile have been also identified in the spleen, liver, and serum, underscoring the systemic effect of ARI and TRZ on sterol biosynthesis. Long-term use of concurrent ARI and TRZ warrants further studies to fully evaluate the lasting consequences of altered sterol biosynthesis on the whole body.

Polypharmacy is commonly used to treat psychiatric disorders. These combinations often include drugs with sterol biosynthesis inhibiting side effects, including the antipsychotic aripiprazole (ARI), and antidepressant trazodone (TRZ). As the effects of psychotropic medications are poorly understood across the various tissue types to date, we investigated the effects of ARI, TRZ, and ARI + TRZ polypharmacy on the post-lanosterol biosynthesis in three cell lines (Neuro2a, HepG2, and human dermal fibroblasts) and seven peripheral tissues of an adult mouse model. We found that both ARI and TRZ strongly interfere with the function of 7-dehydrocholesterol reductase enzyme (DHCR7) and lead to robust elevation in 7-dehydrocholesterol levels (7-DHC) and reduction in desmosterol (DES) across all cell lines and somatic tissues. ARI + TRZ co-administration resulted in summative or synergistic effects across the utilized in vitro and in vivo models. These findings suggest that at least some of the side effects of ARI and TRZ are not receptor mediated but arise from inhibiting DHCR7 enzyme activity. We propose that interference with sterol biosynthesis, particularly in the case of simultaneous utilization of medications with such side effects, can potentially interfere with functioning or development of multiple organ systems, warranting further investigation.

Individual and simultaneous treatment with antipsychotic aripiprazole and antidepressant trazodone inhibit sterol biosynthesis in the adult brain

Trazodone (TRZ) is an antidepressant drug which widely used to treat insomnia, but it has a cardiotoxic effect which considered one of the TRZ limitations. The aim of this study was to investigate the protective role of l-carnitine in rats against TRZ-induced cardiotoxicity, as well as to look into the molecular mechanisms underlying its cardioprotective effects via autophagy-mediated cell death and oxidative stress. Male albino rats were randomized into four experimental groups (n = 8): normal control, TRZ group (TRZ, 20 mg/kg/day), l-carnitine group (LC, 200 mg/kg/day), and Co-treated group (l-carnitine and TRZ). All treatments were administered via oral gavage for 4 weeks. Cardiac enzymes (AST & CK-MB) and serum cardiac troponin T(cTnI) were assessed. Oxidative stress biomarkers in heart tissue (malondialdehyde; MDA, total thiol, and catalase activity) were measured. Autophagy related-genes (ATG-5 and Beclin-1), P62, and TNF-α were quantified. AST and CK-MB and cTnI significantly (p < 0.001) were increased with enhanced autophagy as well as severe histopathological changes which were manifested as scattered chronic inflammatory cells with focal fragmentation of myocardial fibers and loss of nuclei in TRZ-treated group. However, daily administration of l-carnitine (200 mg/kg) for 28 days completely reversed TRZ-induced the increased cardiac enzymes, autophagy, and myocardial inflammatory processes to the normal values. TRZ administration might have the potential to cause cardiotoxic effects that can be treated with l-carnitine administration.

Trazodone (TZD) is a tetracyclic serotonin antagonist and reuptake inhibitor that is used as a second-generation phenylpiperazine antidepressant. However, the plasma concentrations of TZD have shown individual variations in clinical practice. Quantification of TZD plasma concentrations may be an effective and valuable method to balance the clinical efficacy and adverse reactions. This study aimed to establish a novel liquid chromatography coupled with mass spectrometry (LC-MS) assay for measuring TZD concentrations in human plasma for therapeutic drug monitoring (TDM). After protein precipitation with acetonitrile, LC-MS quantification of TZD was performed in the multiple reaction monitoring mode with chromatographic separation using a mobile phase of MeOH and 0.1% formic acid in water. This method validation intends to investigate specificity, sensitivity, linearity, precision, accuracy, recovery, matrix effect, and stability according to United states food and drug administration guidelines. This method showed good selectivity because no interfering peaks were observed in the plasma samples during the 2-minute run time. The range of the calibration curve was 1-3000 ng/mL. The detection and quantification limits were 0.3 and 1 ng/mL, respectively. The intraday and interday accuracies were 96.5%-103.4%, with precision relative SD% values of <5%, except for the limit of quality. The mean TZD recovery from human plasma was 95.4%-104.5%. Finally, this method was successfully applied to TDM in 20 patients. The TZD plasma concentrations of the patients ranged between 21.5 and 2267.3 ng/mL. A novel analytical method was established to measure TZD by LC-MS coupled with an automatic 2-dimensional liquid chromatograph mass spectrometer coupler 9500 (LC-MS/MS-Mate 9500), which is superior to the ordinary LC-MS system in separation, transport, anti-interference, sensitivity, and quantitative analysis stability.

In recent years, analytical chemistry has been facing new challenges, particularly in developing low-cost, green, and easy-to-reproduce methods. In this work, a simple, reproducible, and low-cost electrochemical (voltammetric) molecularly imprinted polymer (MIP) sensor was designed specifically for the detection of trazodone (TZD). Trazodone (TZD) is an antidepressant drug consumed worldwide since the 1970s. By combining electropolymerization (surface imprinting) with screen-printed electrodes (SPCEs), the sensor is easy to prepare, is environmentally friendly (uses small amounts of reagents), and can be used for in situ analysis through integration with small, portable devices. The MIP was obtained using cyclic voltammetry (CV), using 4-aminobenzoic acid (4-ABA) as the functional monomer in the presence of TZF molecules in 0.1 M HCl. Non-imprinted control was also constructed in the absence of TZD. Both polymers were characterized using CV, and TZD detection was performed with DPV using the oxidation of TZD. The polymerization conditions were studied and optimized. Comparing the TZD signal for MIP/SPCE and NIP/SPCE, an imprinting factor of 71 was estimated, indicating successful imprinting of the TZD molecules within the polymeric matrix. The analytical response was linear in the range of 5–80 µM, and an LOD of 1.6 µM was estimated. Selectivity was evaluated by testing the sensor for molecules with a similar structure to TZD, and the ability of MIP/SPCE to selectively bind to TZD was proven. The sensor was applied to spiked tap water samples and human serum with good recoveries and allowed for a fast analysis (around 30 min).

Continuous adsorption studies of pharmaceuticals in multicomponent mixtures by agroforestry biochar

Risk of falls and fractures similar with zopiclone and trazodone

Barré-Lièou syndrome (BLS) is a manifestation of various autonomic and secondary symptoms including muscle stiffness, tinnitus, dizziness, and pain in various body parts. Although considered to be caused by hyperactivation of the autonomic nervous system due to trauma, there is currently no firmly established etiology or evidence on the treatment and clinical features of BLS. We retrospectively examined the clinical features of BLS and evaluated the efficacy of trazodone (TZD) for its treatment. We conducted a retrospective analysis of the data of 20 consecutive cases with suspected BLS who were treated in our hospital between 2016 and 2019. BLS symptoms were rated on a 10-point scale, and two groups were defined, that is, a mild-BLS group (BLS scores, 1-5) and a severe-BLS group (BLS scores, 6-10). Univariate analysis of patient factors was performed. The BLS score was 6.0 ± 1.7, and the maximum TZD dose was 80 ± 34 mg/day; nine patients (45%) were TZD free, and no TZD side effects were observed, while all patients had a good clinical outcome. There were significant differences between the mild-BLS and severe-BLS groups in the period from injury to diagnosis (p = 0.015), chest/back pain (p < 0.001), constipation (p = 0.001), and maximum TZD dose (p = 0.008). BLS involves posttraumatic autonomic symptoms accompanied by depression and insomnia. The sympathetic hypersensitivity theory could explain its etiology. TZD could effectively and safely treat BLS, and early diagnosis and treatment can contribute toward good clinical outcomes. Enhanced recognition and understanding of this disease are warranted.

Trazodone (TRZ) is a commonly prescribed antidepressant with significant off-label use for insomnia. A recent drug screening revealed that TRZ interferes with sterol biosynthesis, causing elevated levels of sterol precursor 7-dehydrocholesterol (7-DHC). Recognizing the well-documented, disruptive effect of 7-DHC on brain development, we designed a study to analyze TRZ effects during pregnancy. Utilizing an in vivo model and human biomaterial, our studies were designed to also account for drug interactions with maternal or offspring Dhcr7 genotype. In a maternal exposure model, we found that TRZ treatment increased 7-DHC and decreased desmosterol levels in brain tissue in newborn pups. We also observed interactions between Dhcr7 mutations and maternal TRZ exposure, giving rise to the most elevated toxic oxysterols in brains of Dhcr7+/− pups with maternal TRZ exposure, independently of the maternal Dhcr7 genotype. Therefore, TRZ use during pregnancy might be a risk factor for in utero development of a neurodevelopmental disorder, especially when the unborn child is of DHCR7+/− genotype. The effects of TRZ on 7-DHC was corroborated in human serum samples. We analyzed sterols and TRZ levels in individuals with TRZ prescriptions and found that circulating TRZ levels correlated highly with 7-DHC. The abundance of off-label use and high prescription rates of TRZ might represent a risk for the development of DHCR7 heterozygous fetuses. Thus, TRZ use during pregnancy is potentially a serious public health concern.

Depresioa gaixotasun psikiatriko ohikoenen artean dago, eta haren intzidentziaren gorakada etengabea da. Depresioaren jatorria eta mekanismo etiologikoak azaltzen dituzten hainbat teoria garatu diren arren, gaixotasunaren oinarri neurobiologikoaren alderdi asko ezezagunak dira oraindik. Hipotesi esanguratsuenak depresioaren teoria monoaminergikoa, neurotrofikoa eta neuroinflamatorioa dira, eta horien eta beste batzuen jatorria, ebidentziak eta xehetasunak aditzera ematen dira berrikuspen honetan. Iraganean depresioa tratatzeko farmakoen aurkikuntza zorizkoa izan da, eta haien ekintza-mekanismoen ikerketak gaixotasunean ageri diren nahasmendu neurobiologikoei buruzko ezagutza eman digu. Azken hamarkadetan, aldiz, paradigma aldatu da, eta tratamendu berriak depresioaren etiopatogeniaren ituetan oinarritzen hasi dira. Patologiaren tratamendu farmakologikoaren oinarrian antidepresibo klasikoak daude. Duela hamarkada ugari aurkitu ziren, eta geroztik erabili dira: monoaminooxidasaren inhibitzaileak, antidepresibo triziklikoak eta monoaminen birxurgapenaren inhibitzaileak. Trazodona eta mirtazapina antidepresiboak, profil farmakodinamiko konplexuagokoak, urte batzuk geroago garatu ziren. Farmako talde horien eragin desiragaitz ohikoak ekiditeko eta tratamenduaren eraginkortasuna hobetzeko xedez ekintza-mekanismo alternatiboak esploratu dira, eta ikerketa horietatik sortu dira, esate baterako, agomelatina, tianeptina eta bortioxetina. Horien eraginkortasuna eta erabilera oso mugatuak dira, dena den. Ketamina, aldiz, denbora laburrean depresioaren tratamenduaren iraultza abian jarri duen substantzia izan da, sintomen hobekuntza nabarmena eta azkarra erakutsi duelako entsegu anitzetan, segurtasun eta tolerantzia egokiarekin batera. Azkenik, nabarmentzekoak dira substantzia haluzinogenoak, depresioaren eta beste gaixotasun psikiatrikoen tratamendurako erakutsi duten potentzial izugarriari esker. Depresioari dagokionez, psilozibina da psikodelikoen artean azpimarragarriena: paziente deprimituen hobekuntza azkarra eta iraunkorra eragiten badu ere, haren mekanismo antidepresiboak ezezagunak dira, eta horiek argitzeko entseguak ikerketaren gailurrean daude egun.

Anticholinergic drugs can be used as a treatment for many diseases. However, anticholinergic drugs are also known for their cognition-related side effects. Recently, there has been an increasing number of reports indicating a positive association between exposure to anticholinergic drugs and Alzheimer's disease (AD). Our novel study provides evidence of interactions between two representative anticholinergic drugs [Chlorpheniramine (CPM), a common antihistamine, and Trazodone (TRD), an antidepressant] with neuroprotective amyloid-beta (Aβ) chaperone, lipocalin-type prostaglandin D synthase (L-PGDS) and the amyloid beta-peptide (1–40). Here, we demonstrate that CPM and TRD bind to L-PGDS with high affinity where chlorpheniramine exhibited higher inhibitory effects on L-PGDS as compared to Trazodone. We also show that the interactions between the drug molecules and Aβ(1–40) peptides result in a higher fibrillar content of Aβ(1–40) fibrils with altered fibril morphology. These altered fibrils possess higher cytotoxicity compared to Aβ(1–40) fibrils formed in the absence of the drugs. Overall, our data suggest a mechanistic link between exposure to anticholinergic drugs and increased risk of Alzheimer's disease via inhibition of the neuroprotective chaperone L-PGDS and direct modification of Aβ amyloid morphology and cytotoxicity.

Abstract Introduction With steadily growing numbers of patients with a depressive disorder, the effect of antidepressants on sleep architecture is of increasing concern. One major oral antidepressant medication is trazadone, which has also been prescribed in low doses for sleep insomnia treatment. Here, we investigate the effect of trazadone on NREM sleep instability also known as cyclic alternating pattern (CAP) in community-dwelling older men. Methods CAP was scored in overnight EEG recordings from 41 older men on trazadone (TRZ) and 50 age-matched men who did not use trazadone (NTRZ), participating in the Osteoporotic Fractures in Men Sleep Study. A high performance automated detection system determined the ratio between CAP time and NREM sleep time (CAP rate), the number of A1-phases per hour of NREM sleep (A1 index), and the number of A2+A3-phases per hour of NREM sleep (A2+A3 index). The effect of TRZ on CAP parameters was determined using the Mann-Whitney U test. Results CAP rate was significantly decreased in men using trazadone (NTRZ: 58.2±19.7%, TRZ: 47.9±15.9%) as compared to non-trazadone user (p &amp;lt; 0.01). Subtype indices did not show any significant difference between both groups but to some extent less frequent A2-A3 phases for TRZ user (A1-phases: NTRZ 13.0±18.7 no./h vs. TRZ 10.8±20.4 no./h, p = 0.35; A2+A3-phases: NTRZ 51.5±33.7 no./h vs. TRZ 44.7±23.3 no./h, p = 0.068). Conclusion CAP rate was significantly decreased in older men on trazadone as compared to older men who did not use trazadone, suggesting that trazadone usage has a stabilising effect on sleep micro-structure. Support The National Heart, Lung, and Blood Institute (NHLBI) provides funding for the MrOS Sleep ancillary study “Outcomes of Sleep Disorders in Older Men” under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839.