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Steroids Oct 2023Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs...
Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects.
Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40-2.74 ng/g tissue, DPX: 1.48-3.83 ng/g tissue and PRL: < 0.40-2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.
Topics: Animals; Rats; Brain; Duloxetine Hydrochloride; Neurosteroids; Pharmaceutical Preparations; Pharmacophore; Pregnanolone; Propranolol; Propylamines
PubMed: 37468115
DOI: 10.1016/j.steroids.2023.109272 -
Orthopaedics & Traumatology, Surgery &... Feb 2024Recent studies have indicated that depression is associated with persistent postoperative pain and decreased satisfaction following foot and ankle surgery. This study...
Perioperative duloxetine improves postoperative outcomes after anterior talofibular ligament repair for chronic lateral ankle instability for patients with depression: A prospective randomized clinical trial.
BACKGROUND
Recent studies have indicated that depression is associated with persistent postoperative pain and decreased satisfaction following foot and ankle surgery. This study aimed to evaluate the effect of perioperative duloxetine on postoperative outcomes of anterior talofibular ligament (ATFL) surgical repair for chronic ankle instability (CAI) in patients with depression. We further sought to evaluate patients' satisfaction and side effects related to duloxetine.
MATERIAL AND METHODS
Patients undergoing ATFL repair were screened for depression preoperatively with the Patient Health Questionnaire (PHQ-9). Among 249 patients who underwent arthroscopic or open surgical Brostrom repair of the ATFL, 120 patients were identified as being "possibly depressed" and were included in the study. Sixty patients were randomly assigned to the duloxetine group (one day preoperatively and for 6 weeks postoperatively), and the other sixty were randomized to the placebo group. Painkillers and opioid consumption, pain scores, and patient satisfaction were recorded at 12, 24, 48, and 72hours postoperatively and at follow-up visits 1, 3, and 6 months after surgery. Patient-reported outcome measures (PROMs) were assessed preoperatively and at 3, 6, 12 and 24 months postoperatively. Duloxetine-related side effects such as nausea/vomiting and fatigue were also recorded.
RESULTS
The patients in the duloxetine group reported a significantly longer time to rescue analgesic and reduced opioid requirements (including celecoxib, pregabalin, acetaminophen, and tramadol). The patients experienced decreased pain intensity and greater satisfaction with their pain management at 24, 48, 72h and 1 and 3 months after surgery (p<0.05). The duloxetine group also had significantly better clinical and functional outcomes at 3 and 6 months of follow-up compared to the placebo group (p<0.05). The occurrence and rate of symptoms of duloxetine side effects were not significant.
DISCUSSION
Depression is an important factor to consider and address because its presence before surgery can predict poor postoperative outcomes, including more severe postoperative pain, persistent postoperative pain, and increased consumption of painkillers and opioids.
CONCLUSION
Perioperative administration of duloxetine following ATFL repair for CAI in patients with depression increased the time to first postoperative rescue analgesic request and reduced both opioid consumption and postoperative pain. This approach also led to a high level of patient satisfaction. In addition, duloxetine improved the quality of recovery without leading to significant side effects.
LEVEL OF EVIDENCE
I; prospective randomized controlled trial.
PubMed: 38355009
DOI: 10.1016/j.otsr.2024.103837 -
Toxicology and Applied Pharmacology May 2024Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are...
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.
Topics: Animals; Duloxetine Hydrochloride; Gastric Mucosa; Male; Indomethacin; Proto-Oncogene Proteins c-akt; Chemokine CCL5; Signal Transduction; Rats; Vascular Endothelial Growth Factor A; Rats, Sprague-Dawley; Stomach Ulcer; Serotonin; Phosphatidylinositol 3-Kinases
PubMed: 38701902
DOI: 10.1016/j.taap.2024.116950 -
BMC Psychiatry Jun 2024Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a...
OBJECTIVE
Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD.
METHODS
A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40-60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment.
RESULTS
Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1β, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05).
CONCLUSIONS
These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.
Topics: Humans; Duloxetine Hydrochloride; Depressive Disorder, Major; Female; Male; Cytokines; Adult; Middle Aged; Antidepressive Agents; Case-Control Studies; Inflammation
PubMed: 38877455
DOI: 10.1186/s12888-024-05910-0 -
AAPS PharmSciTech Jul 2023The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced...
The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced the dose and dosing frequency by enhancing bio-performance of the drug. A transdermal DIA patch having Duro-Tak 87-2287 as DIA polymer and Transcutol P as permeation enhancer loaded with 40% drug previously complexed with MeβCD duly characterised (FTIR, DSC, and SEM) was developed for in vivo study. Pharmacokinetic parameters of developed formulation were assessed and compared with oral route of administration. Among various permeation enhancers (PEs), Transcutol P exhibited most enhanced permeation (ER ≈ 1.99) in terms of flux and Q compared to control group having. Mean of maximum plasma concentration (C) and area under time-concentration curve (AUC) in Wistar rats (n = 6) for transdermal patch (10 mg/kg) was found to be 70.31 ± 11.2 ng/ml and 2997.29 ± 387.4 ng/ml*h, respectively, and were considerably higher than oral dose of DLX (20 mg/kg and 10 mg/kg). Albeit, T was higher in case of transdermal delivery, but this was due to sustained behaviour of delivery system. These findings highlight the significance of both inclusion complexation and transdermal delivery of DLX using DIA patch for efficient drug absorption.
Topics: Rats; Animals; Skin Absorption; Duloxetine Hydrochloride; Rats, Wistar; Administration, Cutaneous; Adhesives; Transdermal Patch; Skin
PubMed: 37466741
DOI: 10.1208/s12249-023-02607-7 -
Therapeutic Drug Monitoring Apr 2024Trazodone is prescribed for several clinical conditions. Multiple factors may affect trazodone to reach its therapeutic reference range. The concentration-to-dose (C/D)...
BACKGROUND
Trazodone is prescribed for several clinical conditions. Multiple factors may affect trazodone to reach its therapeutic reference range. The concentration-to-dose (C/D) ratio can be used to facilitate the therapeutic drug monitoring of trazodone. The study aimed to investigate factors on the concentrations and C/D ratio of trazodone.
METHODS
This study analyzed the therapeutic drug monitoring electronic case information of inpatients in the First Hospital of Hebei Medical University from October 2021 to July 2023. Factors that could affect the concentrations and C/D ratio of trazodone were analyzed, including body mass index, sex, age, smoking, drinking, drug manufacturers, and concomitant drugs.
RESULTS
A total of 255 patients were analyzed. The mean age was 52.44 years, and 142 (55.69%) were women. The mean dose of trazodone was 115.29 mg. The mean concentration of trazodone was 748.28 ng/mL, which was in the therapeutic reference range (700-1000 ng/mL). 50.20% of patients reached the reference range, and some patients (36.86%) had concentrations below the reference range. The mean C/D ratio of trazodone was 6.76 (ng/mL)/(mg/d). A significant positive correlation was found between daily dose and trazodone concentrations (r 2 = 0.2885, P < 0.001). Trazodone concentrations were significantly affected by dosage, sex, smoking, drinking, and concomitant drugs of duloxetine or fluoxetine. After dosage emendation, besides the above factors, it was influenced by age ( P < 0.05, P < 0.01, or P < 0.001).
CONCLUSIONS
This study identified factors affecting trazodone concentrations and C/D ratio. The results can help clinicians closely monitor patients on trazodone therapy and maintain concentrations within the reference range.
Topics: Humans; Female; Middle Aged; Male; Trazodone; Fluoxetine; Duloxetine Hydrochloride; Reference Values; Smoking
PubMed: 38287895
DOI: 10.1097/FTD.0000000000001178 -
Luminescence : the Journal of... Mar 2024Antidepressants can cause sexual dysfunction side effects, necessitating the co-administration of phosphodiesterase type 5 inhibitors. The simultaneous determination of...
Environmentally benign first derivative synchronous spectrofluorimetry for the analysis of two binary mixtures containing duloxetine with avanafil or tadalafil in spiked plasma samples.
Antidepressants can cause sexual dysfunction side effects, necessitating the co-administration of phosphodiesterase type 5 inhibitors. The simultaneous determination of these drugs in biological fluids is critical for therapeutic drug monitoring. For the first time, two binary mixtures containing duloxetine with either avanafil or tadalafil were estimated utilizing simple green spectrofluorimetric methods without the need for a previous separation step. The study was based on first derivative synchronous spectrofluorimetry in ethanol using a change in wavelength difference (∆λ) of 20 and 25 nm for the first and second combinations, respectively. Duloxetine and avanafil were estimated at 297.7 and 331 nm in their binary mixture, while duloxetine and tadalafil were determined at 290.3 and 297.7 nm, respectively. The linearity was achieved over the ranges of 0.1-1.5 μg mL for both duloxetine and avanafil and 0.01-0.40 μg mL for tadalafil, with limits of detection of 0.013, 0.022, and 0.004 μg mL for duloxetine, avanafil, and tadalafil, respectively. Successful application of the developed approaches was accomplished for the estimation of the two mixtures in dosage forms as well as human plasma with excellent percentage recoveries (96-103.75% in plasma), which supports their suitability for use in quality control laboratories and pharmacokinetic studies. Moreover, the adopted approaches' greenness was evidenced by applying three tools.
Topics: Humans; Tadalafil; Duloxetine Hydrochloride; Pyrimidines; Pharmaceutical Preparations; Spectrometry, Fluorescence
PubMed: 38494193
DOI: 10.1002/bio.4696 -
Journal of Orthopaedic Surgery (Hong... 2023
Topics: Humans; Analgesics; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Duloxetine Hydrochloride; Pain, Postoperative
PubMed: 37694724
DOI: 10.1177/10225536231198768 -
Journal of Oral Rehabilitation Mar 2024Conditioned pain modulation (CPM) is a potential predictor of treatment response that has not been studied in temporomandibular disorders (TMD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Conditioned pain modulation (CPM) is a potential predictor of treatment response that has not been studied in temporomandibular disorders (TMD).
OBJECTIVES
We conducted a randomised, double-blind, placebo-controlled trial (RCT) of duloxetine in addition to self-management (SM) strategies to investigate its efficacy to reduce pain intensity in painful TMD patients. Moreover, we investigated whether baseline CPM would predict the duloxetine efficacy to reduce TMD pain intensity.
METHODS
Eighty participants were randomised to duloxetine 60 mg or placebo for 12 weeks. The primary outcomes were the change in the pain intensity from baseline to week-12 and CPM-sequential paradigm at baseline. Safety, physical and emotional functioning outcomes were also evaluated.
RESULTS
Of 80 participants randomised, 78 were included in intention-to-treat analysis. Pain intensity decreased for SM-duloxetine and SM-placebo but did not differ between groups (p = .82). A more efficient CPM was associated with a greater pain intensity reduction regardless of the treatment group (p = .035). Physical and emotional functioning did not differ between groups, but adverse events (p = .014), sleep impairment (p = .003) and catastrophizing symptoms (p = .001) were more prevalent in SM-duloxetine group.
CONCLUSION
This study failed to provide evidence of a beneficial effect of adding duloxetine to SM strategies for treatment of painful TMD. Nonetheless, this RCT has shown the feasibility of applying pain modulation assessment to predict short-term treatment response in painful TMD patients, which confirms previous finds that CPM evaluation may serve a step forward in individualising pain treatment.
Topics: Humans; Double-Blind Method; Duloxetine Hydrochloride; Pain; Self-Management; Temporomandibular Joint Disorders; Treatment Outcome
PubMed: 37994185
DOI: 10.1111/joor.13628 -
Pain May 2024Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and...
Duloxetine improves chronic orofacial pain and comorbid depressive symptoms in association with reduction of serotonin transporter protein through upregulation of ubiquitinated serotonin transporter protein.
Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients.
Topics: Humans; Duloxetine Hydrochloride; Serotonin Plasma Membrane Transport Proteins; Depression; Serotonin; Up-Regulation; Chronic Pain; Facial Pain
PubMed: 38227563
DOI: 10.1097/j.pain.0000000000003124