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Redox Biology Feb 2023Alcoholic (ASH) and nonalcoholic. (NASH).steatohepatitis are advanced.stages.of.fatty.liver.disease.Methionine adenosyltransferase 1A (MAT1A) plays a key role in hepatic...
Alcoholic (ASH) and nonalcoholic. (NASH).steatohepatitis are advanced.stages.of.fatty.liver.disease.Methionine adenosyltransferase 1A (MAT1A) plays a key role in hepatic methionine metabolism and germline Mat1a deletion in mice promotes NASH. Acid sphingomyelinase (ASMase) triggers hepatocellular apoptosis and liver fibrosis and has been shown to downregulate MAT1A expression in the context of fulminant liver failure. Given the role of ASMase in steatohepatitis development, we investigated the status of ASMase in Mat1a mice and the regulation of ASMase by SAM/SAH. Consistent with its role in NASH, Mat1a mice fed a choline-deficient (CD) diet exhibited macrosteatosis, inflammation, fibrosis and liver injury as well as reduced total and mitochondrial GSH levels. Our data uncovered an increased basal expression and activity of ASMase but not neutral SMase in Mat1a mice, which further increased upon CD feeding. Interestingly, adenovirus-mediated shRNA expression targeting ASMase reduced ASMase activity and protected Mat1a mice against CD diet-induced NASH. Similar results were observed in CD fed Mat1a mice by pharmacological inhibition of ASMase with amitriptyline. Moreover, Mat1a/ASMase double knockout mice were resistant to CD-induced NASH. ASMase knockdown protected wild type mice against NASH induced by feeding a diet deficient in methionine and choline. Furthermore, Mat1a mice developed acute-on-chronic ASH and this outcome was ameliorated by amitriptyline treatment. In vitro data in primary mouse hepatocytes revealed that decreased SAM/SAH ratio increased ASMase mRNA level and activity. MAT1A and ASMase mRNA levels exhibited an inverse correlation in liver samples from patients with ASH and NASH. Thus, disruption of methionine metabolism sensitizes to steatohepatitis by ASMase activation via decreased SAM/SAH. These findings imply that MAT1A deletion and ASMase activation engage in a self-sustained loop of relevance for steatohepatitis.
Topics: Animals; Mice; Amitriptyline; Choline; Diet; Disease Models, Animal; Liver; Methionine; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Racemethionine; Sphingomyelin Phosphodiesterase; Hepatitis
PubMed: 36610223
DOI: 10.1016/j.redox.2022.102596 -
The effect of smoking on the plasma concentration of tricyclic antidepressants: a systematic review.Acta Neuropsychiatrica Feb 2022Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to... (Review)
Review
Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance.
Topics: Amitriptyline; Antidepressive Agents, Tricyclic; Imipramine; Nortriptyline; Smoking
PubMed: 34497000
DOI: 10.1017/neu.2021.28 -
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 -
Pain Research & Management 2022There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary...
There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary use. The aim of this study was to cross-sectionally investigate the current practice of medication in FMS patients in Germany. We systematically interviewed 156 patients with FMS, while they were participating in a larger study. The patients had been stratified into subgroups with and without a decrease in intraepidermal nerve fiber density. The drugs most commonly used to treat FMS pain were nonsteroidal anti-inflammatory drugs (NSAIDs) (41.0% of all patients), metamizole (22.4%), and amitriptyline (12.8%). The most frequent analgesic treatment regimen was "on demand" (53.9%), during pain attacks, while 35.1% of the drugs were administered daily and the remaining in other regimens. Median pain relief as self-rated by the patients on a numerical rating scale (0-10) was 2 points for NSAIDS, 2 for metamizole, and 1 for amitriptyline. Drugs that were discontinued due to lack of efficacy rather than side effects were acetaminophen, flupirtine, and selective serotonin reuptake inhibitors. Reduction in pain severity was best achieved by NSAIDs and metamizole. Our hypothesis that a decrease in intraepidermal nerve fiber density might represent a neuropathic subtype of FMS, which would be associated with better effectiveness of drugs targeting neuropathic pain, could not be confirmed in this cohort. Many FMS patients take "on-demand" medication that is not in line with current guidelines. More randomized clinical trials are needed to assess drug effects in FMS subgroups.
Topics: Acetaminophen; Amitriptyline; Analgesics; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cross-Sectional Studies; Dipyrone; Duloxetine Hydrochloride; Fibromyalgia; Humans; Neuralgia; Pregabalin; Selective Serotonin Reuptake Inhibitors
PubMed: 36247103
DOI: 10.1155/2022/1217717 -
The Medical Letter on Drugs and... Mar 2022
Topics: Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Humans; Pain; Pharmaceutical Preparations
PubMed: 35231019
DOI: No ID Found -
American Journal of Physiology.... Feb 2020We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1...
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
Topics: Amitriptyline; Aniline Compounds; Animals; Atherosclerosis; Benzylidene Compounds; Blood Glucose; Cytokines; Diet, High-Fat; Down-Regulation; Enzyme Inhibitors; Insulin Resistance; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Receptors, LDL; Sphingolipids; Sphingomyelin Phosphodiesterase
PubMed: 31821039
DOI: 10.1152/ajpendo.00181.2019 -
Therapeutic Advances in Urology 2021Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating, systemic pain syndrome with a cardinal symptom of bladder related pain with associated systemic... (Review)
Review
Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating, systemic pain syndrome with a cardinal symptom of bladder related pain with associated systemic symptoms. It is characterized by an inflammation that partially or completely destroys the mucus membrane and can extend into the muscle layer; however, the etiology and pathogenesis is still enigmatic. It has been suggested that mast cell activation, defects in the glycosaminoglycan layer, non-functional proliferation of bladder epithelial cells, neurogenic inflammation, microvascular abnormalities in the submucosal layer, autoimmunity and infectious causes may cause BPS/IC. Available treatment options include general relaxation techniques, patient education, behavioral treatments, physical therapy, multimodal pain therapy, oral (amitriptyline, cimetidine, hydroxyzine) and intravesical treatments (heparin, lidocaine, hyaluronic acid and chondroitin sulfate), hydrodistension and other more invasive treatments. Available treatments are mostly not based on a high level of evidence. Lack of understanding of disease mechanisms has resulted in lack of targeted therapies on this area and a wealth of empirical approaches with usually inadequate efficacy. The aim of this article is to review the available evidence on the pathophysiological mechanisms of BPS/IC as they relate to available treatment options.
PubMed: 34178118
DOI: 10.1177/17562872211022478 -
The Journal of Surgical Research May 2024Previous literature suggests that sphingolipids may impact systemic coagulation and platelet aggregation, thus modulating the risks of thrombotic events. The goal of...
INTRODUCTION
Previous literature suggests that sphingolipids may impact systemic coagulation and platelet aggregation, thus modulating the risks of thrombotic events. The goal of this investigation was to evaluate the role of serum sphingolipids on intrinsic platelet function to assess whether pharmacologic manipulation of sphingolipid metabolites would impact platelet aggregability.
METHODS
C57BL/6J mice were injected with either normal saline, 1 mg/kg FTY720 (synthetic sphingosine-1-phosphate [S1P] receptor analog), or 5 mg/kg SLM6031434 (sphingosine kinase two inhibitor). Mice were sacrificed at 6 h and whole blood (WB) was collected for impedance aggregometry assessing platelet responsiveness to arachidonic acid or adenosine diphosphate. Ex vivo studies utilized WB or platelet-rich plasma that was pretreated with S1P, FTY720, amitriptyline, or d-sphingosine then analyzed by aggregability and flow cytometry for platelet and platelet-derived microvesicle characteristics.
RESULTS
FTY720 and SLM6031434 pretreated induced similar arachidonic acid and adenosine diphosphate-mediated platelet aggregation as controls. Ex vivo WB and platelet-rich plasma treatment with S1P, FTY720, amitriptyline and d-sphingosine did not impact platelet aggregation. The percentages of CD41+, CD62P+ and CD41+/ceramide+, CD62P+/ceramide + platelets, and platelet-derived microvesicle were not significantly different between amitriptyline-treated and normal saline-treated cohorts.
CONCLUSIONS
Sphingolipid modulating agents, such as FTY720, SLM6031434, S1P, amitriptyline, ceramide, and d-sphingosine do not appear to independently impact platelet aggregation in murine models.
PubMed: 38795670
DOI: 10.1016/j.jss.2024.04.063 -
Expert Review of Clinical Pharmacology Feb 2022The identification of the most effective therapy for patients with fibromyalgia (FM) remains controversial. Thus, we conducted a Bayesian network meta-analysis to... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The identification of the most effective therapy for patients with fibromyalgia (FM) remains controversial. Thus, we conducted a Bayesian network meta-analysis to compare several drugs employed as pharmacological management for FM.
AREAS COVERED
The following databases were accessed in October 2021: PubMed, Google Scholar, Embase, and Scopus. All the randomized clinical trials (RCTs) that compare two or more pharmacological management for fibromyalgia were accessed. Only studies involving a minimum of 10 patients with a length of follow-up longer than 4 weeks were included. The data from the fibromyalgia impact questionnaire (FIQ) and the physical and mental subscales short form 36 (SF36) were extracted at last follow-up. Additionally, the number of adverse events leading to the study of discontinuation was extracted. The compounds of interests were duloxetine, pregabalin, fluoxetine, gabapentin, milnacipran, trazodone, placebo, nortriptyline, IGF-I, amitriptyline, and the combination of fluoxetine and amitriptyline, pregabalin, and trazodone.
EXPERT OPINION
According to published evidence, pregabalin, and duloxetine evidenced the greatest improvement of the FIQ and SF36 Physical and Mental subscales, along with the lowest rate of adverse events leading to study discontinuation. The results must be interpreted in light of possible adverse events associated with the use of these drugs.
Topics: Analgesics; Duloxetine Hydrochloride; Fibromyalgia; Gabapentin; Humans; Network Meta-Analysis; Pregabalin
PubMed: 35184627
DOI: 10.1080/17512433.2022.2044792 -
Cardiovascular Journal of Africa Jun 2023Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes....
AIM
Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline (AMT) can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Our aim in this study was to determine how the effects of the concomitant use of empagliflozin and amitriptyline, which have been shown to have effects on sodium and calcium metabolism in cardiomyocytes, would cause an effect on QT and QTc intervals in clinical practice.
METHODS
Twenty-four male Wistar albino rats were randomised into four groups. The control group received only physiological serum (1 ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT + EMPA group ( = 6) received amitriptyline (100 mg/kg) and empagliflozin (10 mg/kg). Under anaesthesia, QT and QTc intervals were measured at baseline, and in the first and second hours.
RESULTS
In the AMT group, QT intervals and QTc values were found to be statistically longer than in the control group ( ≤ 0.001). Empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. In the AMT + EMPA group, QT and QTc intervals were significantly lower compared to that in the AMT group ( < 0.01).
CONCLUSION
In this study, we determined that empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. This effect was probably due to the opposite effects of these two agents in the intracellular calcium balance. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QT and QTc prolongation in diabetic patients receiving amitriptyline.
PubMed: 37285169
DOI: 10.5830/CVJA-2023-017