Genotoxic and oxidative effect of duloxetine on mouse brain and liver tissues.

We evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide oxidative potential in the same cells. A kinetic time/dose strategy showed the effect of 2, 20, and 200 mg/kg of the drug administered intraperitoneally once in comparison with a control and a methyl methanesulfonate group. Each parameter was evaluated at 3, 9, 15, and 21 h postadministration in five mice per group, except for the DNA oxidation that was examined only at 9 h postadministration. Results showed a significant DNA damage mainly at 9 h postexposure in both organs. In the brain, with 20 and 200 mg/kg we found 50 and 80% increase over the control group (p ≤ 0.05), in the liver, the increase of 2, 20, and 200 mg/kg of duloxetine was 50, 80, and 135% in comparison with the control level (p ≤ 0.05). DNA, lipid, protein and nitric oxide oxidation increase was also observed in both organs. Our data established the DNA damaging capacity of duloxetine even with a dose from the therapeutic range (2 mg/kg), and suggest that this effect can be related with its oxidative potential.

TNFα enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy.

Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress.

DUOX2, a common modulator in preventive effects of monoamine-based antidepressants on water immersion restraint stress- and indomethacin- induced gastric mucosal damage.

Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation.

Cytogenotoxic effects of venlafaxine hydrochloride on cultured human peripheral blood lymphocytes.

The potential genotoxic effect of venlafaxine hydrochloride (venlafaxine), an antidepressant drug-active ingredient, was investigated by using in vitro chromosome aberrations (CAs) and cytokinesis-block micronucleus (CBMN) assays in human peripheral blood lymphocytes (PBLs). Mitotic index (MI) and cytokinesis-block proliferation index (CBPI) were also calculated to determine the cytotoxicity of this active drug. For this aim, the human PBLs were treated with 25, 50, and 100 µg/ml venlafaxine for 24 h and 48 h. The results of this study showed that venlafaxine significantly induced the formation of structural CA and MN for all concentrations (25, 50, and 100 µg/ml) and treatment periods (24 h and 48 h) when compared with the negative and the solvent control (except 25 µg/ml at 48 h for MN). In addition, the increases in the percentage of structural CA and MN were concentration-dependent for both treatment times. With regard to cell cycle kinetics, venlafaxine significantly decreased the MI at all concentrations, and also CBPI at the higher concentrations for both treatment times as compared to the control groups. The present results indicate for the first time that venlafaxine had significant clastogenic and cytotoxic effects at the tested concentrations (25, 50, and 100 µg/ml) in the human PBLs, in vitro; therefore, its excessive and careless use may pose a potential risk to human health.

Levomilnacipran: More of the Same?

OBJECTIVE: The primary objective of this narrative review is to provide clinicians an in-depth analysis of the mechanism of action, pharmacokinetics, toxicology, and efficacy of levomilnacipran. We propose that unlike selective serotonin reuptake inhibitors (SSRIs), or even their precursor serotonin-norepinephrine reuptake inhibitors (SNRIs), levomilnacipran demonstrates a potentially unique ability to alleviate the fatigue symptom cluster of major depressive disorder (MDD). DATA SOURCES: A literature review was completed in PubMed using the MeSH term levomilnacipran. STUDY SELECTION: Inclusion criteria were English-language only, randomized controlled trials and systematic reviews published through March 2019. Analyses using product labels and anecdotal or uncontrolled reports of clinical applications were excluded. Only published data from short-term and long-term trials were analyzed. The search resulted in 73 articles. The evidence-based review comprises a total of 31 articles. DATA SYNTHESIS: The data analyzed suggest that levomilnacipran has evidence in the treatment of MDD. More specifically, data suggest that levomilnacipran may be unique among SSRI and SNRI antidepressants in its ability to improve the fatigue symptom cluster in MDD. CONCLUSIONS: Further investigations are warranted into levomilnacipran's potentially unique ability to alleviate the fatigue symptom cluster of MDD. Future head-to-head studies and studies that assess for clinically relevant improvements in fatigue are needed.

Toxicological Assessment of Venlafaxine: Acute and Subchronic Toxicity Study in Rats.

Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most popular options. Venlafaxine is a nontricyclic dual-acting serotonin-norepinephrine reuptake inhibitor. Although an increased incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then assayed: alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological examination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug may be addictive.

Differential behavioural responses to venlafaxine exposure route, warming and acidification in juvenile fish (Argyrosomus regius).

Antidepressants, such as venlafaxine (VFX), which are considered emerging environmental pollutants, are increasingly more present in the marine environment, and recent evidence suggest that they might have adverse effects on fish behaviour. Furthermore, altered environmental conditions associated to climate change (e.g. warming and acidification) can also have a determinant role on fish behaviour, fitness and survival. Yet, the underlying interactions between these environmental stressors (pharmaceuticals exposure and climate change) are still far from being fully understood. The aim of this study was to assess behavioural responses (in juvenile meagre (Argyrosomus regius) exposed to VFX via water ([VFX] ~20µgL-1) and via dietary sources ([VFX] ~160µgkg-1 dry weight), as well as to increased temperature (ΔT°C=+5°C) and high CO2 levels (ΔpCO2 ~1000µatm; equivalent to ΔpH=-0.4units). Overall, VFX bioaccumulation in fish plasma was enhanced under the combination of warming and acidification. VFX triggered fish exploration, whereas fish activity and shoal cohesion were reduced. Acidification alone decreased fish exploration and shoal cohesion, and reversed fish preference to turn leftwards compared to control conditions. Such alterations were further enhanced by VFX exposure. The combination of warming and acidification also reduced shoal cohesion and loss of lateralization, regardless of VFX exposure. The distinct behaviour observed when VFX contamination, acidification and warming acted alone or in combination highlighted the need to consider the likely interactive effects of seawater warming and acidification in future research regarding the toxicological aspects of chemical contaminants.

Exposure to SSRI-type antidepressants increases righting time in the marine snail Ilyanassa obsoleta.

Exposure to human antidepressants has been shown to disrupt locomotion and other foot-mediated mechanisms in aquatic snails. We tested the effect of three selective serotonin reuptake inhibitor (SSRI)- and one selective serotonin-norepinephrine reuptake inhibitor (SNRI)-type antidepressants on the righting response in the marine snail, Ilyanassa obsoleta. All four antidepressants (fluoxetine, sertraline, paroxetine, venlafaxine) significantly increased righting time compared with controls with an exposure time as short as 1 h. Dose responses were nonmonotonic with effects seen mainly at the lowest exposure concentrations and shortest duration. The lowest concentration to show an effect was 3.45 µg/L fluoxetine with a 2-h exposure period and is about 3.71 times higher than environmental concentrations. Our results highlight rapid disruption of another foot-mediated behavior in aquatic snails by SSRI-type antidepressants. We discuss these and other reported nonmonotonic dose responses caused by antidepressants in terms of the various possible physiological mechanisms of action in nontarget aquatic species.

An 11-year retrospective review of venlafaxine ingestion in children from the California Poison Control System.

Venlafaxine is commonly used in the United States for approved and non-Food and Drug Administration-approved indications in adults. It is used off-label to treat children for psychiatric diagnoses. The aim of the study was to describe venlafaxine toxicities in children and to identify the venlafaxine dose per weight that correlates with toxicities. An 11-year retrospective study of venlafaxine ingestion in children was performed using the California Poison Control System (CPCS) database. Data was extracted from phone calls received by CPCS clinicians and follow-up phone calls made to assess the patient's progress in a health-care setting. Inclusion criteria were venlafaxine ingestion cases reported to CPCS between January 2001 and December 2011, children aged 20 years and under, venlafaxine as the only ingested substance, managed in a health-care facility, and followed to a known outcome. Two hundred sixty-two cases met the study criteria. Common presentations included gastrointestinal (14.9%), altered mental status (13.7%), and tachycardia (13.4%). The majority of the cases resulted in no effect (51.5%) or minor effect (19.9%). The average estimated dose per weight was 18.3 mg/kg in all patients and 64.5 mg/kg in those experiencing moderate-to-severe adverse effects. Seizures occurred in only 4 of the 262 cases at doses ranging from 1500 to 7500 mg. Although the estimated dose per weight exceeded 10 mg/kg for the majority of the cases, only 12 cases resulted in moderate or severe outcomes. The majority of venlafaxine ingestion cases in children resulted in either no clinical effects or minor clinical effects.

Negative effect of serotonin-norepinephrine reuptake inhibitor therapy on rat bone tissue after orchidectomy.

Our goal was to determine if venlafaxine has a negative effect on bone metabolism. Rats were divided into three groups. The sham-operated control group (SHAM), the control group after orchidectomy (ORX), and the experimental group after orchidectomy received venlafaxine (VEN ORX) in standard laboratory diet (SLD) for 12 weeks. Bone mineral content (BMC) was measured by dual energy X-ray absorptiometry (DXA). Bone marker concentrations of carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), amino-terminal propeptide of procollagen type I (P1NP), bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 (BMP-2) were examined in bone homogenate. The femurs were used for biomechanical testing. Compared to the ORX group we found lower BMD in the diaphysis area of the femur in the VEN ORX group, suggesting a preferential effect on cortical bone. Of the bone metabolism markers, there was significant decrease (ORX control group versus VEN ORX experimental group) in BALP levels and increase in sclerostin and CTX-I levels, suggesting a decrease in osteoid synthesis and increased bone resorption. The results suggest that the prolonged use of venlafaxine may have a negative effect on bone metabolism. Further studies are warranted to establish whether venlafaxine may have a clinically significant adverse effect on bone.