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International Journal of Molecular... May 2023Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only...
Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED, von Frey testing) and thermal hyperalgesia (ED, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED and ED for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.
Topics: Mice; Animals; Paclitaxel; Duloxetine Hydrochloride; Rosuvastatin Calcium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pain Measurement; Neuralgia; Hyperalgesia; Analgesics
PubMed: 37176065
DOI: 10.3390/ijms24098359 -
Current Urology Reports Jul 2024Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress... (Review)
Review
PURPOSE OF REVIEW
Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress made in surgical techniques, pharmacotherapy has not yielded substantial outcomes within the clinical domain. This review aims to present a comprehensive overview of the existing pharmacotherapy options for stress urinary incontinence (SUI) and the emerging therapeutic targets in this field.
RECENT FINDINGS
One meta-analysis demonstrated that α-adrenergic medications are more efficacious in improving rather than curing SUI symptoms. One trial showed reduced pad weight gain with PSD-503, a locally administered α-adrenergic receptor agonist. New data show that duloxetine's risk outweighs its benefits. One small-scale trial was found to support the use of locally administered estriol in improving subjective outcomes. Emerging targets include serotonin 5HT agonists, selective inhibitors of norepinephrine uptake, and myostatin inhibitors. Only one of the evaluated drugs, duloxetine, has been approved by some countries. Currently, trials are evaluating novel targets. Systemic adverse effects such as gastrointestinal upset with duloxetine and orthostatic hypotension with α-adrenoceptor agonists have hampered the efficacy of drugs used to treat SUI in women and men.
Topics: Humans; Urinary Incontinence, Stress; Duloxetine Hydrochloride; Female; Male
PubMed: 38727982
DOI: 10.1007/s11934-024-01205-9 -
Molecular Pain 2023Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting...
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients' quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000 Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.
Topics: Rats; Animals; Paclitaxel; Duloxetine Hydrochloride; Bortezomib; Rats, Sprague-Dawley; Quality of Life; Peripheral Nervous System Diseases; Antineoplastic Agents
PubMed: 37338165
DOI: 10.1177/17448069231185694 -
Acta Crystallographica. Section E,... Apr 2023Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride,...
Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride, CHNOS·Cl, which is twice as effective as the ()-enanti-omer in serotonin uptake. Here, we report the crystal structure of duloxetine hydro-chloride in its racemic form (space group 2), where it shows significant differences in the mol-ecular conformation and packing in its extended structure compared to the previously reported ()-enanti-omer crystal structure. Mol-ecules of this type, comprising aromatic groups with a single side chain terminated in a protonated secondary amine, are commonly found in active anti-depressants. A Cambridge Structural Database survey of mol-ecules with these features reveals a strong correlation between side-chain conformation and the crystal packing: an extended side chain leads to mol-ecules packed into separated layers of hydro-phobic and ionic hydro-philic phases. By comparison, mol-ecules with bent side chains, such as racemic duloxetine hydro-chloride, lead to crystal-packing motifs where an ionic hydro-philic phase is encapsulated within a hydro-phobic shell.
PubMed: 37151834
DOI: 10.1107/S2056989023003353 -
Diabetes Research and Clinical Practice Dec 2023Painful Diabetic Peripheral Neuropathy (PDN) is common, affecting around a quarter of patients with both type 1 and type 2 diabetes, and can lead to significant...
Painful Diabetic Peripheral Neuropathy (PDN) is common, affecting around a quarter of patients with both type 1 and type 2 diabetes, and can lead to significant curtailment of functionality and quality of life. Patients may present with unremitting burning, aching or "electric-shock" type pains in their feet, legs and later, in the hands. Conventional management approaches must focus not only on pain relief, but also on concurrent sleep problems, mood disorders and functionality. The mainstay of treatment is pharmacotherapy. Most current international guidelines recommend a choice of four drugs: amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for PDN. Recent evidence from the OPTION-DM trial demonstrated that these drugs and their combinations have equivalent efficacy. Moreover, combination treatment provided significant pain relief to patients with inadequate response to the maximum tolerated dose of monotherapy. PDN refractory to pharmacotherapy can be treated with capsaicin 8% or high frequency spinal cord stimulation.
Topics: Humans; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Quality of Life; Duloxetine Hydrochloride; Pain
PubMed: 38245323
DOI: 10.1016/j.diabres.2023.110765 -
Revista Da Associacao Medica Brasileira... Mar 2022This study aimed to investigate the effects of duloxetine and pregabalin primarily on pain and functional status in patients with knee osteoarthritis and secondarily on... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study aimed to investigate the effects of duloxetine and pregabalin primarily on pain and functional status in patients with knee osteoarthritis and secondarily on quality of life, depression, anxiety, and sleep disturbance.
METHODS
A total of 66 patients with knee osteoarthritis were randomized to use duloxetine or pregabalin. Patients were evaluated by Visual Analog Scale, Neuropathic Pain Diagnostic Questionnaire, Western Ontario and McMaster University Osteoarthritis Index, Short Form-36, Beck Depression Inventory, Beck Anxiety Inventory, and Pittsburg Sleep Quality Index before the treatment and after 4 and 12 weeks of treatment.
RESULTS
Improvements occurred in Visual Analog Scale, Neuropathic Pain Diagnostic Questionnaire, Western Ontario and McMaster University Osteoarthritis Index, Short Form-36 (with an exception of the mental health subgroup scores in duloxetine-treated group), Beck Depression Inventory, and Beck Anxiety Inventory scores in both groups from 4 weeks after baseline. Pittsburg Sleep Quality Index total scores and SF-36 mental health subgroup scores started to improve on the 4th and 12th weeks in pregabalin- and duloxetine-treated groups, respectively.
CONCLUSION
Osteoarthritis pain, a complex outcome with nociceptive and neuropathic components, leads to central sensitization in a chronic phase. Using centrally acting drugs in the control of pain and associated symptoms would increase the probability of treatment success.
Topics: Duloxetine Hydrochloride; Humans; Neuralgia; Osteoarthritis, Knee; Pregabalin; Quality of Life; Treatment Outcome
PubMed: 35442367
DOI: 10.1590/1806-9282.20211047 -
Fukushima Journal of Medical Science Apr 2022Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the... (Review)
Review
Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the prognosis of unresectable PC is poor, it has been dramatically improved by new chemotherapy treatments, such as the combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. However, as oxaliplatin and paclitaxel are common neurotoxic drugs, chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse effect of both treatments. As there are no agents recommended in the ASCO guidelines, we review the methods used to treat CIPN caused by PC treatment. The efficacy of duloxetine was observed in a large randomized controlled trial (RCT). In addition, pregabalin was more effective than duloxetine for CIPN in two RCTs. Although duloxetine and pregabalin can be effective for CIPN, they have several side effects. Therefore, the choice between the two drugs should be determined according to effect and tolerability. Mirogabalin is also used in patients with PC and there is hope it will yield positive outcomes when treating CIPN in the future.
Topics: Antineoplastic Agents; Duloxetine Hydrochloride; Humans; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Peripheral Nervous System Diseases; Pregabalin; Randomized Controlled Trials as Topic
PubMed: 35197393
DOI: 10.5387/fms.2021-32 -
Anesthesia, Essays and Researches 2022Recently, opoids are linked with cancer recurrence. Duloxetine hydrochloride (DH), an anxiolytic may reduce total opoid requirement after cancer surgery.
Effect of Preoperative Duloxetine Hydrochloride on Reducing Postoperative Morphine Requirement after Open Radical Cholecystectomy in Cancer Patients: A Randomized Controlled Study.
BACKGROUND
Recently, opoids are linked with cancer recurrence. Duloxetine hydrochloride (DH), an anxiolytic may reduce total opoid requirement after cancer surgery.
AIMS
We assessed the efficacy of a single dose of DH in reducing the total morphine requirement after open radical cholecystectomy. We also calculated the Visual Analog Scale (VAS) score, patient satisfaction score (PSS), and time taken to the use of the first rescue analgesic.
SETTING AND DESIGNES
This is a prospective, randomized, double blind, controlled study conducted in the patients aged 20-70 years (American Society of Anaesthesiologists classes I-III) undergoing open radical cholecystectomy under general anesthesia for carcinoma gall bladder.
MATERIALS AND METHODS
The patients were divided into two groups of 32 patients each by computer-generated randomization. Group A received oral DH (60 mg); Group B received identical placebo capsules 2 h before surgery with a sip of water. Postoperatively, intravenous morphine was given using a patient-controlled analgesia pump. After 24 h, total morphine consumption, the VAS score, time to the first rescue analgesia, and PSS were recorded.
STATISTICAL ANALYSIS
Statistical Package for the Social Sciences software (SPSS version 22.0, IBM Corp., Chicago, IL, USA 2013). value < 0.05 or 0.001 was considered statistically significant.
RESULTS
The total morphine consumption and VAS score were significantly lower in Group A. No significant effects was observed on PSS.
CONCLUSION
A single 60 mg dose of DH administered 2 h before open radical cholecystectomy reduced total morphine consumption and improved VAS score postoperatively with no effect on PSS.
PubMed: 36620122
DOI: 10.4103/aer.aer_75_22 -
Frontiers in Bioscience (Landmark... Aug 2023This study was carried out to compare the levels of inflammatory markers in the complete blood count before and after they began receiving duloxetine in patients with...
BACKGROUND
This study was carried out to compare the levels of inflammatory markers in the complete blood count before and after they began receiving duloxetine in patients with fibromyalgia syndrome (FMS).
METHODS
The patient and control groups were composed of 40 patients diagnosed with FMS in accordance with the 2016 American College of Rheumatology (ACR) criteria and 40 healthy volunteers, respectively. The data collection tools comprised the sociodemographic information form, the fibromyalgia impact questionnaire (FIQ), and the sleep hygiene index (SHI), which were used to assess patients' sociodemographic characteristics, FMS disease activity, and sleep quality, respectively. The inflammatory markers of the patient group were assessed by complete blood count before and after the duloxetine treatment and compared with those of the control group.
RESULTS
The white blood cell (WBC), neutrophil, and lymphocyte counts were significantly higher in the patient group than in the control group ( < 0.001, = 0.036 and = 0.004, respectively). Moreover, platelet distribution width (PDW) was significantly lower, whereas mean platelet volume (MPV) was significantly higher in the patient group than in the control group ( < 0.001 for both cases). In addition to patients' platelet-to-lymphocyte ratio (PLR) values, C-reactive protein (CRP) levels, and white blood cell (WBC) counts decreasing but not significantly ( = 0.083, = 0.068, and = 0.065, respectively), their neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hgb), and hematocrit (Hct) values declined substantially after commencing duloxetine treatment ( = 0.001, = 0.008, and = 0.001, respectively).
CONCLUSIONS
The significant reduction in NLR, Hgb, and Hct levels following duloxetine treatment may indicate that these parameters can be utilized as biomarkers in determining the efficacy of treatment and in the follow-up of the treatment in FMS patients.
Topics: Humans; Duloxetine Hydrochloride; Fibromyalgia; Leukocytes; Blood Platelets; Neutrophils
PubMed: 37664936
DOI: 10.31083/j.fbl2808161 -
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