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Cancer Research Communications Nov 2022Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of...
UNLABELLED
Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons . Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines and were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin.
SIGNIFICANCE
We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.
Topics: Humans; Mice; Animals; Oxaliplatin; Antineoplastic Agents; Duloxetine Hydrochloride; Peripheral Nervous System Diseases; Neurotoxicity Syndromes
PubMed: 36506732
DOI: 10.1158/2767-9764.crc-22-0172 -
The Journal of Neuroscience : the... Jan 2022Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it...
Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN. Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.
Topics: Analgesics; Animals; Antineoplastic Agents; Corticosterone; Duloxetine Hydrochloride; Female; Male; Oxaliplatin; Paclitaxel; Pain Management; Pain Threshold; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley
PubMed: 34880120
DOI: 10.1523/JNEUROSCI.1691-21.2021 -
ACS Chemical Neuroscience Apr 2023Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin...
Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin transporters at presynaptic terminals raises extracellular concentrations of norepinephrine. The α1- and α2-adrenergic receptor agonists inhibit glutamatergic input from primary afferent nerves to the spinal dorsal horn. However, the contribution of spinal α1- and α2-adrenergic receptors to the analgesic effect of antidepressants and associated synaptic plasticity remains uncertain. In this study, we showed that systemic administration of duloxetine or amitriptyline acutely reduced tactile allodynia and mechanical and thermal hyperalgesia caused by spinal nerve ligation in rats. In contrast, duloxetine or amitriptyline had no effect on nociception in sham rats. Blocking α1-adrenergic receptors with WB-4101 or α2-adrenergic receptors with yohimbine at the spinal level diminished the analgesic effect of systemically administered duloxetine and amitriptyline. Furthermore, intrathecal injection of duloxetine or amitriptyline similarly attenuated pain hypersensitivity in nerve-injured rats; the analgesic effect was abolished by intrathecal pretreatment with both WB-4101 and yohimbine. In addition, whole-cell patch-clamp recordings in spinal cord slices showed that duloxetine or amitriptyline rapidly inhibited dorsal root-evoked excitatory postsynaptic currents in dorsal horn neurons in nerve-injured rats but had no such effect in sham rats. The inhibitory effect of duloxetine and amitriptyline was abolished by the WB-4101 and yohimbine combination. Therefore, antidepressants attenuate neuropathic pain predominantly by inhibiting primary afferent input to the spinal cord via activating both α1- and α2-adrenergic receptors. This information helps the design of new strategies to improve the treatment of neuropathic pain.
Topics: Rats; Animals; Duloxetine Hydrochloride; Amitriptyline; Rats, Sprague-Dawley; Antidepressive Agents; Spinal Cord Dorsal Horn; Norepinephrine; Posterior Horn Cells; Hyperalgesia; Yohimbine; Neuralgia; Analgesics; Receptors, Adrenergic
PubMed: 36930958
DOI: 10.1021/acschemneuro.2c00780 -
IBRO Reports Dec 2020In attempt to conquer the major concerns of oral duloxetine hydrochloride (like low bioavailability, intolerable side-effects and no regeneration of demyelinated nerve...
OBJECTIVE
In attempt to conquer the major concerns of oral duloxetine hydrochloride (like low bioavailability, intolerable side-effects and no regeneration of demyelinated nerve fibres) for the management of chemotherapy-induced peripheral neuropathy (CIPN), an alternative delivery of duloxetine hydrochloride was aimed for optimization.
METHODS
A film forming dermal gel consisting of duloxetine hydrochloride was formulated and enriched with methylcobalamin and geranium oil. The formulated gel successfully qualified the various pharmaceutical characteristics of gel. Administration of paclitaxel (8 mg/kg/ in four divided doses) for 4 alternate days induced the symptoms of peripheral neuropathy in rats. On 14th day, the responses to noxious stimulus (mechanical hyperalgesia, cold allodynia, and heat hyperalgesia) were increased and reached to its maximum. Thereafter, drug treatment with formulated dermal gel and oral duloxetine hydrochloride (30 mg/kg, once daily) was initiated for 2 weeks in different group of animals. On the 28th day animals were sacrificed to isolate sciatic nerve, to assess biochemical changes (TBARS, reduced GSH, total protein, TNF-α, IL-6) and for histopathological examinations of nerve sections using Hematoxylin-Eosin and Toludine blue staining methods.
RESULTS
Application of formulated dermal gel to paclitaxel-treated rats significantly improved paw-withdrawal latency responses during noxious stimulus testing, reduced the levels of TBARS, TNF-α, IL-6 and elevated the levels of reduced GSH as compared to paclitaxel treated rats. Histographs also indicated marked regeneration of the damaged nerve fibers. Topical delivery of duloxetine hydrochloride produced similar results in disparity to oral route. However, no significant disparity in responses was obtained with twice application of formulated dermal gel when compared to once daily application.
CONCLUSION
Tremendous recovery from nociception, oxidation and inflammation in addition to nerve degeneration was achieved through dermal application of duloxetine hydrochloride in peripheral neuropathy.
PubMed: 32760845
DOI: 10.1016/j.ibror.2020.07.006 -
International Journal of Molecular... Feb 2022While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million...
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.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Duloxetine Hydrochloride; Hemostasis; Humans; Mice; Norepinephrine; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Serotonin; Serotonin Antagonists; Thrombosis
PubMed: 35269729
DOI: 10.3390/ijms23052587 -
Journal of Diabetes Jul 2021To analyze the efficacy and safety of duloxetine and gabapentin in painful diabetic neuropathy (PDN). (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
To analyze the efficacy and safety of duloxetine and gabapentin in painful diabetic neuropathy (PDN).
METHODS
A randomized, open-label, active control, 12-week trial was conducted. A total of 86 participants were randomized in 1:1 ratio into gabapentin 300 mg and duloxetine 60 mg groups. The primary efficacy objective was comparison of mean change in Visual Analogue Scale (VAS) (0-100 points) scores between duloxetine and gabapentin. The symptom scores and adverse events were assessed as secondary outcomes.
RESULTS
Statistically significant (P value<.001) improvement was observed in VAS scores in both duloxetine group and gabapentin group at 12 weeks as compared to baseline. However, no significant difference in VAS scores between duloxetine and gabapentin. Similar improvement in diabetic neuropathy symptoms (DNS), diabetic neuropathy examination (DNE), and neuropathic disability score (NDS) was observed in either group over 12 weeks. There were no significant differences in DNS (P = 0.578), DNE (P = 0.410), and NDS (P = 0.071) scores between the two treatment groups. The overall safety evaluation of both duloxetine and gabapentin were similar. The most common adverse events reported were gastrointestinal.
CONCLUSION
The results indicated that both drugs were effective for the symptomatic relief from PDN and had similar efficacy. Follow-up of patients was only for 12 weeks and therefore the long-term efficacy and safety of the study drugs could not be assessed.
Topics: Adolescent; Adult; Aged; Case-Control Studies; Diabetes Mellitus; Diabetic Neuropathies; Duloxetine Hydrochloride; Excitatory Amino Acid Antagonists; Female; Follow-Up Studies; Gabapentin; Humans; India; Male; Middle Aged; Prognosis; Serotonin and Noradrenaline Reuptake Inhibitors; Young Adult
PubMed: 33340245
DOI: 10.1111/1753-0407.13148 -
Journal of Clinical Anesthesia Aug 2020Duloxetine administered during the acute perioperative period has been associated with lesser postoperative pain and analgesic consumption. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Duloxetine administered during the acute perioperative period has been associated with lesser postoperative pain and analgesic consumption.
STUDY OBJECTIVES
The study aimed to quantify the pooled effects of duloxetine on postoperative pain, analgesic consumption, and side-effects in the first 48 postoperative (PO) hours.
DESIGN
Systematic review with meta-analysis.
SETTING
Postoperative pain management.
PATIENTS
Adult patients undergoing elective surgery. Search strategy and study selection. Medline, Cochrane, EMBASE, CENTRAL, and Web of Science were searched without language restrictions for prospective, parallel randomized controlled trials comparing duloxetine to placebo for the management of postoperative pain in adult patients.
MEASUREMENTS
Pain scores (11-point scales), opioid consumption (i.v. morphine equivalents), and frequency of side-effects were compared between duloxetine and placebo. Effect sizes were summarized as mean differences (MD), standardized mean differences (SMD) or risk ratios (RR) with the respective 95% confidence intervals (95% CI). Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria were used to classify the quality of evidence.
RESULTS
Thirteen studies were included. Duloxetine decreased pain at 24 h (MD = -0.66 points; 95% CI = -1.14 to -0.19 points; SMD = -0.59; 95% CI = -1.06 to -0.12; p = 0.01; I2 = 88%), and at 48 PO hours (MD = -0.90 points; 95% CI = -1.54 to -0.26 points; SMD = -0.66; 95% CI = -0.94 to -0.38; p = 0.01; I2 = 93%); and opioid consumption at 24 PO hours (MD = -8.21 mg; 95% CI = -13.32 mg to -3.10 mg; SMD = -2.17; 95% CI = -3.10 to -1.24; p < 0.001; I2 = 95%), and at 48 PO hours (MD = 7.71 mg; 95% CI = -13.86 mg to -1.56 mg; SMD = -2.13; 95% CI = -3.51 to -0.75; p = 0.02; I2 = 97%). Duloxetine did not affect the prevalence of postoperative nausea and/or vomiting (PONV) pruritus, headache or dizziness. High inter-study heterogeneity and within-study bias resulted in very-low quality of evidence for the primary outcomes.
CONCLUSIONS
Although statistically significant effects of duloxetine were found on postoperative pain and opioid consumption during the first 48 postoperative hours, the effect sizes were below the expected minimal clinically relevant differences. Also, high risk-of-bias and inter-study heterogeneity caused the very-low quality of evidence (GRADE). We conclude that the currently available evidence does not support the clinical use of duloxetine for the management of acute postoperative pain.
Topics: Adult; Analgesics, Opioid; Duloxetine Hydrochloride; Humans; Pain Measurement; Pain, Postoperative; Prospective Studies
PubMed: 32179396
DOI: 10.1016/j.jclinane.2020.109785 -
Clinical Toxicology (Philadelphia, Pa.) Sep 2022Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical...
OBJECTIVE
Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical effects following duloxetine overdose.
METHODS
We undertook a retrospective review of duloxetine overdoses (>120 mg) admitted to two tertiary toxicology units between March 2007 and May 2021. Demographic information, details of ingestion (dose, co-ingestants), clinical effects, investigations (ECG parameters including QT interval), complications (coma [GCS < 9], serotonin toxicity, seizures and cardiovascular effects), length of stay [LOS] and intensive care unit [ICU] admission were extracted from a clinical database.
RESULTS
There were 241 duloxetine overdoses (>120 mg), median age 37 years (interquartile range [IQR]: 25-48 years) and there were 156 females (65%). The median dose was 735 mg (IQR: 405-1200 mg). In 177 patients, other medications were co-ingested, most commonly alcohol, paracetamol, quetiapine, diazepam, ibuprofen, pregabalin and oxycodone. These patients were more likely to be admitted to ICU (12 [7%] vs. none; = 0.040), develop coma (16 [9%] vs. none; = 0.008) and hypotension [systolic BP < 90 mmHg] (15 [8%] vs. one; = 0.076). Sixty four patients ingested duloxetine alone with a median dose of 840 mg (180-4200 mg). The median LOS, in the duloxetine only group, was 13 h (IQR:8.3-18 h), which was significantly shorter than those taking coingestants, 19 h (IQR:12-31 h; = 0.004). None of these patients were intubated. Six patients developed moderate serotonin toxicity, without complications and one had a single seizure. Tachycardia occurred in 31 patients (48%) and mild hypertension (systolic BP > 140 mmHg) in 29 (45%). One patient had persistent sympathomimetic toxicity, and one had hypotension after droperidol. Two patients of 63 with an ECG recorded had an abnormal QT: one QT 500 ms, HR 46 bpm, which resolved over 3.5 h and a second with tachycardia (QT 360 ms, HR 119 bpm). None of the 64 patients had an arrhythmia.
CONCLUSION
Duloxetine overdose most commonly caused sympathomimetic effects and serotonin toxicity, consistent with its pharmacology, and did not result in coma, arrhythmias or intensive care admission, when taken alone in overdose.
Topics: Acetaminophen; Adult; Antidepressive Agents; Arrhythmias, Cardiac; Coma; Diazepam; Droperidol; Drug Overdose; Duloxetine Hydrochloride; Female; Humans; Hypotension; Ibuprofen; Middle Aged; Norepinephrine; Oxycodone; Pregabalin; Quetiapine Fumarate; Seizures; Serotonin; Sympathomimetics; Tachycardia
PubMed: 35658766
DOI: 10.1080/15563650.2022.2083631 -
Anais Da Academia Brasileira de Ciencias 2022This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal...
This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were 18.5 µg/mL, and the combination with fluconazole (FLZ) reduced the MIC value by 16-and 4-fold for DH and FLZ, respectively. The capsule size decreased by 67% and 16% when treated with DH and DH with FLZ, respectively. Therefore, this study showed that DH is active against C. neoformans alone and in combination with FLZ, leading to the reduction of the capsule size of this yeast.
Topics: Antifungal Agents; Cryptococcus neoformans; Duloxetine Hydrochloride; Fluconazole; Microbial Sensitivity Tests
PubMed: 35544847
DOI: 10.1590/0001-3765202220211021 -
Annals of Palliative Medicine Mar 2021A comprehensive approach to pain management often requires multimodal therapy and a combination of medications. Oncology patients may be prescribed methadone and...
BACKGROUND
A comprehensive approach to pain management often requires multimodal therapy and a combination of medications. Oncology patients may be prescribed methadone and duloxetine as single agents or in combination for cancer-related pain, particularly neuropathic pain. Duloxetine is also prescribed for depression or anxiety in patients with cancer.
METHODS
A retrospective chart review on patients with cancer-related pain prescribed duloxetine and methadone combination therapy at the Virginia Commonwealth University supportive care clinic (SCC) between 2012 and 2019. Edmonton Symptom Assessment System (ESAS) scores reported by patients on monotherapy were compared to scores after they started combination therapy. Of 131 patients identified on combination therapy, 43 met study criteria (2 with incomplete ESAS scores).
RESULTS
ESAS total and subscores after combination therapy were lower than on monotherapy. Combination therapy decreased total, pain, and emotion subscores by 5.6 (SD =17.3, dz =-0.32, P=0.046), 0.9 (SD =3.0, dz =-0.30, P=0.052), and 1.8 (SD =5.1, dz =-0.36, P=0.023), respectively. On combination therapy, 28% of patients reported at least a two-point reduction in pain scores. All study participants reported cancer pain with neuropathic components; most had mixed pain syndromes comprising nociceptive and neuropathic components. Adherence rates were high as 81% of patients with follow-up appointments continued therapy.
CONCLUSIONS
These results suggest the combination of duloxetine and methadone reduces cancer-related pain and emotional symptom burden compared to either medication as a single agent.
Topics: Cancer Pain; Duloxetine Hydrochloride; Humans; Methadone; Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 33474965
DOI: 10.21037/apm-20-1455