Antidepressant Duloxetine Research Articles

First-principles study of the physical properties and Hirshfeld surface analysis of the antidepressants duloxetine and sertraline

First-principles study of the physical properties and Hirshfeld surface analysis of the antidepressants duloxetine and sertraline

FDA recalls thousands of bottles of antidepressants over toxic chemical

In late October, the Food and Drug Administration (FDA) recalled more than 7,000 bottles of the popular antidepressant duloxetine, sold under the brand name Cymbalta, Consumer Affairs reported on Oct. 24. The agency found that the affected bottles of the drug, which is used to treat depression, anxiety and mood disorders, contained toxic levels of the chemical nitrosamine. While the FDA says that the chemical isn't likely to cause harm in low levels and that consumers can handle low levels of the chemical for 70 years without health risks, it can increase the risk of cancer and become toxic to humans when ingested at higher‐than‐acceptable levels over an extended period of time. “FDA, in collaboration with regulatory counterparts around the world, has set internationally recognized acceptable daily intake limits for nitrosamines,” the agency said. “If drugs contain levels of nitrosamines above the acceptable daily intake limits, FDA recommends these drugs be recalled by the manufacturer as appropriate.” Currently, this recall is classified as a Class II recall, which the FDA defines as “a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.” Towa Pharmaceutical Europe manufactured the contaminated pills, which were distributed across the United States. In total, there are 7,107 bottles of duloxetine that have higher‐than‐normal levels of nitrosamines. The affected medications are 20 mg pills that come in bottles of 500 pills and have an expiration date of December 2024 with a lot number of 220128.

Bionic nanopore recognition receptors for single-molecule enantioselectivity studies of chiral drugs

BackgroundEnantiodiscrimination of chiral drugs is critical for understanding physiological phenomena and ensuring medical safety. Although enantiomers of these drugs share identical physicochemical properties, they exhibit significant differences in pharmacodynamic, pharmacokinetic, and toxicological properties due to the differences in their three-dimensional shapes. Therefore, the development of effective methods for chiral recognition is of great significance and has been a hot topic in chemo/biological studies. ResultsIn this study, we designed a recognition receptor comprising a α-hemolysin (α-HL) nanopore and sulfobutyl ether-β-cyclodextrin (SBEβCD) for identifying the enantiomers of the antidepressant duloxetine at the single-molecule level. Chiral molecules were discriminated based on the different current blockages within the recognition receptor. The results indicated a strong interaction between R-duloxetine and the recognition receptor. By combining the experimental data and molecular docking results, we explored the recognition mechanism of the designed nanopore recognition receptor for chiral drug molecules. It was found that hydrophobic and electrostatic interactions play key roles in chiral recognition. Additionally, by comparing the binding kinetics of enantiomers to cyclodextrins in confined nanospace and bulk solution, we found that enantiomeric identification was better facilitated in the confined nanospace. Finally, the enantiomeric excess (ee) of the enantiomeric duloxetine mixture was measured using this recognized receptor. SignificanceThis strategy has the advantages of low cost, high sensitivity, and no need for additional derivative modifications, providing a new perspective on the development of chiral recognition sensors with excellent enantioselectivity in drug design, pharmaceuticals, and biological applications.

Duloxetine protected indomethacin-induced gastric mucosal injury by increasing serotonin-dependent RANTES expression and activating PI3K-AKT-VEGF pathway

Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are the principal mediators of inflammation. Thus, by screening the differential expression of cytokines in the gastric mucosa using cytokine array at 3 h after indomethacin exposure, when the gastric ulcer began to format, we found that indomethacin increased cytokines which promoted inflammation responses, whereas duloxetine decreased pro-inflammatory cytokines increased by indomethacin and increased RANTES expression. RANTES was consistently increased by pretreated with both 5 mg/kg and 20 mg/kg duloxetine at 3 h and 6 h after indomethacin exposure in male rats. Selective blockade of RANTES-CCR5 axis by a functional antagonist Met-RANTES or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin (5-HT), norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased 5-HT levels in platelet-poor plasma, while treatment with 5-HT promoted expression of RANTES in the gastric mucosa and alleviated the indomethacin-induced gastric injury. Furthermore, duloxetine activated PI3K-AKT-VEGF signaling pathway, which was regulated by RANTES-CCR5, and selective inhibitor of VEGF receptor axitinib blocked the prophylactic effect of duloxetine. Furthermore, duloxetine also protected gastric mucosa from indomethacin in female rats, and RANTES was increased by duloxetine after 6 h after indomethacin exposure too. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in gastroprotective effect of duloxetine against indomethacin, which advanced our understanding in inflammatory modulation by monoamine-based antidepressants.

MALDI Imaging Mass Spectrometry Visualizes the Distribution of Antidepressant Duloxetine and Its Major Metabolites in Mouse Brain, Liver, Kidney, and Spleen Tissues.

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none of these tissues is duloxetine or its metabolites homogeneously distributed, which has implications for both efficacy and toxicity. We found duloxetine to be similarly distributed in spleen red pulp and white pulp but differentially distributed in different anatomic regions of the liver, kidney, and brain, with dose-dependent patterns. Comparison with hematoxylin and eosin staining of tissue sections reveals that the ion images of endogenous lipids help delineate anatomic regions in the brain and kidney, while heme ion images assist in differentiating regions within the spleen. These endogenous metabolites may serve as a valuable resource for examining the spatial distribution of other drugs in tissues when staining images are not available. These findings may facilitate future mechanistic studies of the therapeutic and adverse effects of duloxetine. In the current work, we did not perform absolute quantification of duloxetine, which will be reported in due course. SIGNIFICANCE STATEMENT: The study utilized imaging mass spectrometry to examine the spatial distribution of duloxetine and its primary metabolites in mouse brain, liver, kidney, and spleen. These results may pave the way for future investigations into the mechanisms behind duloxetine's therapeutic and adverse effects. Furthermore, the mass spectrometry images of specific endogenous metabolites such as heme could be valuable in analyzing the spatial distribution of other drugs within tissues in scenarios where histological staining images are unavailable.

Effects of Duloxetine on Oxidant-Antioxidant System in Rat Brain Tissues

Objective: After the relationship between depression and oxidative stress (OS) was demonstrated, the effect of antidepressant drugs on OS has become important. In this study, we aimed to determine the effects of the antidepressant duloxetine on the activities of the superoxide dismutase (SOD), catalase (CAT), adenosine deaminase (ADA), xanthine oxidase (XO) and glutathione peroxidase (GSH-Px) enzymes as well as the lipid peroxidation (LP) product malondialdehyde (MDA) and nitric oxide (NO) levels in rat brains. 
 Material and Method: Twenty male Sprague-Dawley rats were used for the study. The first group was the control group (n=10) and the second group was the duloxetine group (n=10). Duloxetine was administered intragastrically once a day at a dose of 10 mg/kg for two weeks in the second group. Water was administered intragastrically once a day for two weeks in the first group. Rats were sacrificed at the end of the fourteenth day. The brain tissues were collected and then analyzes were performed.
 Results: As a result of this study, we found that duloxetine increased the SOD (P=0.026) activity and decreased the ADA (P=0.041), XO (P=0.034) and CAT (P=0.006) activities significantly compared to the control group. We also found an increase in the GSH-Px enzyme activity and decrease in the NO and MDA levels at non-significant rates in the duloxetine group brain tissues.
 Conclusion: The significant increase in the activity of the antioxidant enzyme SOD, the significant decrease in the activities of the XO and ADA enzymes, which can cause the formation of reactive oxygen products in the organism, and the insignificant decrease in the LP indicator MDA suggest that duloxetine can positively change the antioxidant status in rat brain tissues.

Do Microplastics Affect the Photodegradation of Duloxetine and Its Phototoxicity to Protozoan Spirostomum ambiguum (Müller, 1786) Ehrenberg, 1835?

As contaminants are often present in aquatic environments as mixtures, they may interact with each other and affect living organisms differently than when tested individually. Emerging pollutants such as pharmaceuticals and microplastics can be influenced by various environmental factors, with UV/Vis radiation being among the most significant. This study aimed to evaluate the photodegradation of the antidepressant duloxetine in the presence of four types of microplastics. Acute toxicity was tested using the Spirotox assay, duloxetine concentration was determined using HPLC-DAD analysis, and the resulting photodegradation products were tested using HPLC-MS/MS. Following 1 and 2 h of exposure in a sunlight simulator, the concentrations of duloxetine decreased by nine and thirteen times, respectively, while its toxicity to protozoa decreased by only two and three times. The presence of microplastics in the samples did not affect either the photodegradation process or the toxicity of duloxetine. HPLC-MS/MS analysis revealed the presence of 34 duloxetine photodegradation products. In silico toxicity analysis using the T.E.S.T. program for the protozoan Tetrahymena pyriformis indicated that one-third of the photoproducts were as toxic, and two products were found to be much more toxic than duloxetine. The high toxicity of one of these compounds was confirmed using the Spirotox test.

Antidepressant duloxetine hydrochloride protects against ovariectomy-induced bone loss in mice by inhibiting osteoclast differentiation

BackgroundSeveral studies have reported the association between osteoporosis and major depressive disorder (MDD) as well as the use of antidepressants. However, it remains to be elucidated whether these associations are related to exposure to antidepressants, a consequence of a disease process, or a combination of both. MethodsThis study investigates the independent effect of the antidepressant duloxetine hydrochloride (DH) on ovariectomy-induced bone loss in mice. One week after ovariectomy, the treated mice received DH. To explore the mechanism underlying the rescue of bone loss, bone marrow cells were isolated from mouse femurs and tibias, and macrophages extracted from them were induced to become osteoclasts in vitro while being treated with DH. Subsequently, the osteoclasts underwent Bulk RNA-Seq to reveal the involved signaling pathways. The results of the bioinformatic analysis were then validated through in vitro experiments. ResultsThe in vivo experiments demonstrated that DH treatment compromised ovariectomy-induced bone loss after 7 weeks. The in vitro experiments suggested that DH treatment attenuated osteoclast differentiation via the MAPKs/NFATc1 signaling pathway. ConclusionThe findings from this study suggest that DH, instead of causing bone mass loss, may assist in alleviating postmenopausal osteoporosis. These results can serve as a reference for the clinical treatment of patients with perimenopausal or postmenopausal depression using antidepressants.

Specific coenzyme preference switching for an aldo-keto reductase that synthesizes the chiral intermediate of duloxetine

The synthesis of chiral intermediates for the traditional antidepressant duloxetine has gained significant attention as the number of depressed patients continues to grow. S-N, N-Dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamide (S-DHTP) is a critical intermediate in the synthesis of duloxetine, and the chemical synthesis process is complex and environmentally unfriendly. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a major cost driver in the biocatalytic production of S-DHTP from N, N-Dimethyl-3-keto-3-(2-thienyl)-1-propanamide (DKTP). Here, we successfully modified the coenzyme preference of an aldo-keto reductase (AKR7-2-1) to use the cheaper reduced nicotinamide adenine dinucleotide (NADH) through a coenzyme preference modification approach. We utilized protein engineering to create a superior mutant, Y53F, which increased the coenzyme specificity of AKR7-2-1 by 875-fold and improved its thermal stability, enhancing its potential for industrial applications. Molecular dynamics simulations were performed to demonstrate the effect of mutations at key sites on the protein, revealing the altered coenzyme preference and increased thermal stability from structural and energetic changes. This study validates the viability of the coenzyme preference modification strategy for aldo-keto reductase, offering valuable insights for fellow researchers and guiding future investigations.

Anti-RAGE targets in cachexia: HMGB1, S100B, S100A1

Cachexia, mediated by the multiligand receptor RAGE (receptor for advanced glycation end products) and its ligands HMGB1, S100B, and S100A1, is a formidable multifactorial complication of the severe course of a number of somatic and malignant diseases. One of the most visualized symptoms of cachexia is a significant decrease in body weight, but the main one is the systemic shutdown of a number of regulatory centers that control the maintenance of homeostasis. Activation of these markers contributes to the launch and intensification of the destructive processes of cachexia, and blocking, in some cases, can reduce their intensity. Among known drugs from various therapeutic groups, there are blockers of one or more markers. For example, Papaverine antispasmodic as well as the nootropic anxiolytic Tenoten, antibacterial Pentamidine and antidepressant Duloxetine. This review describes in detail the significance of the listed markers in the pathogenesis of cachexia, especially in malignant pathology. An assumption was made about the possible control of cachectic progression with the help of such blockers to improve the quality of life of patients.

Identification of Spinal Inhibitory Interneurons Required for Attenuating Effect of Duloxetine on Neuropathic Allodynia-like Signs in Rats.

Neuropathic pain is a chronic pain condition that occurs after nerve damage; allodynia, which refers to pain caused by generally innocuous stimuli, is a hallmark symptom. Although allodynia is often resistant to analgesics, the antidepressant duloxetine has been used as an effective therapeutic option. Duloxetine increases spinal noradrenaline (NA) levels by inhibiting its transporter at NAergic terminals in the spinal dorsal horn (SDH), which has been proposed to contribute to its pain-relieving effect. However, the mechanism through which duloxetine suppresses neuropathic allodynia remains unclear. Here, we identified an SDH inhibitory interneuron subset (captured by adeno-associated viral (AAV) vectors incorporating a rat neuropeptide Y promoter; AAV-NpyP+ neurons) that is mostly depolarized by NA. Furthermore, this excitatory effect was suppressed by pharmacological blockade or genetic knockdown of α1B-adrenoceptors (ARs) in AAV-NpyP+ SDH neurons. We found that duloxetine suppressed Aβ fiber-mediated allodynia-like behavioral responses after nerve injury and that this effect was not observed in AAV-NpyP+ SDH neuron-selective α1B-AR-knockdown. These results indicate that α1B-AR and AAV-NpyP+ neurons are critical targets for spinal NA and are necessary for the therapeutic effect of duloxetine on neuropathic pain, which can support the development of novel analgesics.

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis.

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.

Combined exposure to non-antibiotic pharmaceutics and antibiotics in the gut synergistically promote the development of multi-drug-resistance in Escherichia coli

ABSTRACT The gut microbiota represents an important reservoir of antibiotic-resistant bacteria (ARB), which poses a significant threat to public health. However, little is known about the emergence of ARB in the gut after the combined exposure to antibiotics and non-antibiotic pharmaceutics. Here, Escherichia coli, a common opportunistic pathogen in the gut microbiota, was exposed to the antidepressant duloxetine (2.5 µg/L–25 mg/L) and/or chloramphenicol (6 µg/L–4 mg/L). The resistant strains were isolated to determine the minimum inhibition concentration (MIC) of 29 antibiotics. Then, genome-wide DNA sequencing, global transcriptomic sequencing, and real-time quantitative polymerase chain reaction were performed to quantify the synergy between duloxetine and chloramphenicol. Combined exposure synergistically increased the mutation frequency of chloramphenicol resistance by 2.45–9.01 fold compared with the independent exposure. A combination index reaching 187.7 indicated strong duloxetine and chloramphenicol synergy. The resultant mutants presented heritable enhanced resistance to 12 antibiotics and became ARB to eight antibiotics. Furthermore, combined exposure significantly increased the transcriptomic expression of acrA, acrB, and marA in E. coli, and generated a more robust oxidative stress response. Together with the occurrence of DNA mutations in marR in the mutants, stronger triggers to the AcrAB-TolC transport system and the MlaFEDB ABC transporter via reactive oxygen species (ROS)-induced mutagenesis, verified by gene knockout, contributed to the synergistic enhancement of antibiotic resistance in the combined exposure group. Regardless of whether their formation was induced by duloxetine, chloramphenicol, or their combination, the E. coli mutants showed 1.1–1.7-fold increases in the expression levels of acrA, acrB, acrZ, mdtE, and mdtF. This pattern indicated that the mutants shared the same resistance mechanisms against chloramphenicol, involving the improved efflux pumps AcrAB-TolC and mdtEF. Our findings demonstrated that antibiotics and non-antibiotic pharmaceutics synergistically accelerate the evolution of ARB and may enhance their spread.

Peripheral Neuropathy in Diabetes: Burden, Lifestyle and Pharmacological Interventions for Prevention and Treatment

Diabetes mellitus (DM) is a very common comorbidity worldwide, and it is associated with a wide variety of complications. Diabetic peripheral neuropathy (DPN) is one of these complications that increases the morbidity and mortality of these patients. Multiple studies indicated that lifestyle modifications are very beneficial for these patients in terms of decreasing the symptoms or preventing the progression of the disease. Therefore, a thorough search was conducted to study and shed light on the effects of lifestyle interventions, such as physical exercise, and pharmacological treatment on DPN. A total of 100 studies were found and 32 were selected based on whether or not they support the aim of the study. It was concluded that lifestyle interventions such as regular exercise, healthy diet and weight loss, which will all in turn improve the patient’s glycemic control, play a major role in controlling the disease and preventing its complications. Moreover, the aim of pharmacological interventions is a 30% reduction in pain intensity, however pharmacological interventions are limited in DPN, up till now the FDA approved only three medications that help in the reduction of the pain intensity. These medications are antidepressant duloxetine, anticonvulsant pregabalin, and the opioid-like analgesic tapentadol.

Modern approaches to the treatment of fibromyalgia

Fibromyalgia (FM) occurs in 5–12% of patients but is relatively rarely diagnosed, so most patients do not receive adequate treatment. The review analyses pharmacological and non-pharmacological methods of FM treatment. Data suggests that antidepressants (duloxetine, milnacipran, amitriptyline) and antiepileptics (pregabalin, gabapentin) are most effective. Among non-pharmacological methods, the effectiveness of cognitive-behavioral and mindfulness therapy, kinesiotherapy, and biofeedback has been shown. In the management of patients with FM, a combination of non-pharmacological methods and medications can reduce pain and improve the quality of life.

Cisplatin-induced neurotoxicity involves the disruption of serotonergic neurotransmission

Neurotoxicity is a frequent side effect of cisplatin (CisPt)-based anticancer therapy whose pathophysiology is largely vague. Here, we exploited C. elegans as a 3R-compliant in vivo model to elucidate molecular mechanisms contributing to CisPt-induced neuronal dysfunction. To this end, we monitored the impact of CisPt on various sensory functions as well as pharyngeal neurotransmission by recording electropharyngeograms (EPGs). CisPt neither affected food and odor sensation nor mechano-sensation, which involve dopaminergic and glutaminergic neurotransmission. However, CisPt reduced serotonin-regulated pharyngeal pumping activity independent of changes in the morphology of related neurons. CisPt-mediated alterations in EPGs were fully rescued by addition of serotonin (5-HT) (≤ 2 mM). Moreover, the CisPt-induced pharyngeal injury was prevented by co-incubation with the clinically approved serotonin re-uptake inhibitory drug duloxetine. A protective effect of 5-HT was also observed with respect to CisPt-mediated impairment of another 5-HT-dependent process, the egg laying activity. Importantly, CisPt-induced apoptosis in the gonad and learning disability were not influenced by 5-HT. Using different C. elegans mutants we found that CisPt-mediated (neuro)toxicity is independent of serotonin biosynthesis and re-uptake and likely involves serotonin-receptor subtype 7 (SER-7)-related functions.In conclusion, by measuring EPGs as a surrogate parameter of neuronal dysfunction, we provide first evidence that CisPt-induced neurotoxicity in C. elegans involves 5-HT-dependent neurotransmission and SER-7-mediated signaling mechanisms and can be prevented by the clinically approved antidepressant duloxetine. The data highlight the particular suitability of C. elegans as a 3R-conform in vivo model in molecular (neuro)toxicology and, moreover, for the pre-clinical identification of neuroprotective candidate drugs.

Bioaccumulation of therapeutic drugs by human gut bacteria.

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

3D-Printed Aldo-keto reductase within biocompatible polymers as catalyst for chiral drug intermediate

Aldo-keto reductases (AKRs) are an important class of enzymes that can catalyze the asymmetric reduction of the first-line antidepressant duloxetine intermediate. Although the aldehyde ketone reductase has great application potential, the free state of the enzyme is unstable and difficult to recover, which greatly limits its practical applications in industry. In this work, we used 3D printing technology to immobilize the aldehyde ketone reductase AKR-IA to improve its reusability. After optimizing the preparation conditions of the 3D printing AKR-IA ink, it was determined that the concentrations of sodium alginate and CaCl2 were 1 wt% and 3.28 wt%, and the crosslinking time was 2 min. And the ink is determined to be printable. Scanning electron microscopy showed that the 3D printed AKR-IA was uniformly loaded in calcium alginate. Importantly, the reusability of 3D printed AKR-IA was also studied, the 3D printed AKR-IA still remains more than 57% enzyme activities after 6 repeated uses. Finally, we 3D printed the AKR-IA catalytic substrate DKTP, and the results showed that the conversion rate of the 3D printed AKR-IA catalytic product S-DHTP reached 70% with 96% optical purity. This study shows that 3D printing AKR-IA has certain application potential in the industrial production of the antidepressant duloxetine.

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis

Cardiovascular disease (CVD) is the leading cause of death. Patients with major depressive disorder (MDD) are at higher risk of developing CVD. It has been shown that serotonin plays a key role in the biochemical mechanisms of MDD as well in primary hemostasis mediated by potentiation platelet activity. Consequently, drugs targeting serotonin reuptake such as the FDA-approved duloxetine are commonly prescribed for MDD. Since platelets also express the serotonin transporter (SERT) and serotonin is known to enhance platelet aggregation, this drug can potentially be repurposed as an antiplatelet medication and could be useful in MDD patients who have a higher risk of developing CVD. Based on these considerations, we investigated the antiplatelet activity of duloxetine by employing a host of in vitro and in vivo platelet assays using human blood and mouse model. Our results show that duloxetine has the capacity to dose-dependently inhibit agonist-induced platelet aggregation in vitro. Furthermore, agonist induced dense and α- granule secretion, αIIbβ3 integrin activation, phosphatidylserine expression, and clot retraction were inhibited in duloxetine treated platelets compared to those treated with vehicle control. Moreover, in the carotid artery injury thrombosis model, duloxetine-treated mice had a significantly prolonged occlusion time in comparison with those treated with vehicle control. Collectively, our data indicate that the duloxetine exerts antiplatelet effects and protects against thrombosis. Consequently, duloxetine can serve as a potential antiplatelet drug in MDD patients who have a higher risk of developing CVD.

Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital

BackgroundCombinations of antidepressant duloxetine (at doses of 40–60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.Case presentationThe patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient’s plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.ConclusionEven if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.