Serotonin Inhibitor Research Articles

Fibromyalgia Diagnosis and Treatment Receipt in the U.S. Military Health System.

Meta-analytic findings and clinical practice guidance recommend pharmacological (e.g., pregabalin, duloxetine, and milnacipran) and non-pharmacological (e.g., exercise and sleep hygiene) interventions to reduce symptoms and improve quality of life in people living with fibromyalgia. However, some of these therapies may lack robust evidence as to their efficacy, have side effects that may outweigh benefits, or carry risks. Although the annual prevalence of fibromyalgia in active duty service members was estimated to be 0.015% in 2018, the likelihood of receiving a fibromyalgia diagnosis was 9 times greater in patients assigned female than male and twice as common in non-Hispanic Black than White service members. Therefore, the primary goal of this retrospective study is to examine co-occurring conditions and pain-management care receipt in the 3 months before and 3 months after fibromyalgia diagnosis in active duty service members from 2015 to 2022. Medical record information from active duty service members who received a fibromyalgia diagnosis between 2015 and 2022 in the U.S. Military Health System was included in the analyses. Bivariate analyses evaluated inequities in co-occurring diagnoses (abdominal and pelvic pain, insomnia, psychiatric conditions, and migraines), health care (acupuncture and dry needling, biofeedback and other muscle relaxation, chiropractic and osteopathic treatments, exercise classes and activities, massage therapy, behavioral health care, other physical interventions, physical therapy, self-care management, and transcutaneous electrical nerve stimulation), and prescription receipt (anxiolytics, gabapentinoids, muscle relaxants, non-opioid pain medication, opioids, selective serotonin and norepinephrine inhibitors, and tramadol) across race and ethnicity and assigned sex. Pairwise comparisons were made using a false discovery rate adjusted P value. Overall, 13,663 service members received a fibromyalgia diagnosis during the study period. Approximately 52% received a follow-up visit within 3 months of index diagnosis. Most service members received a co-occurring psychiatric diagnosis (35%), followed by insomnia (24%), migraines (20%), and abdominal and pelvic pain diagnoses (19%) fibromyalgia diagnosis. At least half received exercise classes and activities (52%), behavioral health care (52%), or physical therapy (50%). Less commonly received therapies included other physical interventions (41%), chiropractic/osteopathic care (40%), massage therapy (40%), transcutaneous electrical nerve stimulation (33%), self-care education (29%), biofeedback and other muscle relaxation therapies (22%), and acupuncture or dry needling (14%). The most common prescriptions received were non-opioid pain medications (72%), followed by muscle relaxers (44%), opioids (32%), anxiolytics (31%), gabapentinoids (26%), serotonin-norepinephrine reuptake inhibitor (21%), selective serotonin reuptake inhibitors (20%), and tramadol (15%). There were many inequities identified across outcomes. Overall, service members diagnosed with fibromyalgia received variable guideline-congruent health care within the 3 months before and after fibromyalgia diagnosis. Almost 1 in 3 service members received an opioid prescription, which has been explicitly recommended against use in guidelines. Pairwise comparisons indicated unwarranted variation across assigned sex and race and ethnicity in both co-occurring health conditions and care receipt. Underlying reasons for health and health care inequities can be multisourced and modifiable. It is unclear whether the U.S. Military Health System has consolidated patient resources to support patients living with fibromyalgia and if so, the extent to which such resources are accessible and known to patients and their clinicians.

The GLP-1 Receptor Agonist Liraglutide Decreases Primary Bile Acids and Serotonin in the Colon Independently of Feeding in Mice.

Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.

Effects of LP533401 on vascular and bone calcification in hyperlipidemic mice

Peripheral serotonin levels are associated with cardiovascular disease risk. We previously found that serum serotonin levels are higher in hyperlipidemic mice than wild-type mice. Evidence also suggests that serotonin regulates biomineralization, in that serotonin treatment augments TNF-a-induced matrix calcification of aortic valve interstitial cells and that a selective inhibitor of peripheral serotonin, LP533401, rescues bone loss induced by ovariectomy in mice. Thus, in the present study, we examined the effects of LP533401 on both skeletal bone mineral density (BMD) and aortic calcification in both young and older hyperlipidemic mice susceptible to calcific atherosclerosis and bone loss. By serial in vivo microCT imaging, we assessed BMD and aortic calcification of Apoe−/− mice fed an atherogenic (high cholesterol) diet alone or mixed with LP533401. Results show that in the young mice, LP533401 blunted skeletal bone loss in lumbar vertebrae but not in femurs. LP533401 also blunted the initial development of aortic calcification but not its progression. Echocardiographic analysis showed that LP533401 blunted both hyperlipidemia-induced cardiac hypertrophy and left ventricular dysfunction. In the older mice, LP533401 increased the BMD of lumbar vertebrae but not of femurs. The aortic calcification progressed in both controls and LP533401-treated mice, but, at post-treatment, LP533401-treated mice had significantly less aortic calcification than the controls. These findings suggest that LP533401 mitigates adverse effects of hyperlipidemia on skeletal and vascular tissues in site- and stage-dependent manners.

Spasmolytic Effect of Flopropione Does Not Involve Catechol-O- methyltransferase (COMT) Inhibition.

Flopropione (Flo) has been used for gallstone and urolithiasis as a spasmolytic agent almost exclusively in Japan. According to the package insert, its main mechanism is catechol-O-methyltransferase (COMT) inhibition and anti-serotonergic effect. This is obviously contrary to pharmacological common sense, but it is described that way in pharmacology textbooks and occurs in questions in the National Examination for Pharmacists in Japan. As this is a serious problem in education, we re-examined the action of Flo. The guinea pig ureter was hardly contracted by serotonin, but noradrenaline (NA) elicited repetitive twitch contraction, which was inhibited by Flo. The sphincter of Oddi (SO) exhibited a spontaneous repetitive twitch contraction, which was inhibited by NA and Flo. The inhibitory effect of NA was reversed by α- and β-blockers, whereas that of Flo was not. Entacapone, a representative COMT inhibitor, did not affect the movement of the ureter and the SO. Nifedipine suppressed carbachol-induced contraction of the taenia coli, spontaneous movement of the SO, and NA-induced contraction of the ureter to almost the same extent, whereas Flo did not inhibit the taenia coli, but inhibited the contraction of the SO and the ureter. The inhibitory pattern of Flo resembled that of the ryanodine receptor agonist 4-chloro-m-cresol and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate. It is concluded that COMT inhibition or serotonin inhibition is not involved in the spasmolytic action of Flo. Flo might act on ryanodine receptors and/or IP3 receptors, which are responsible for periodic Ca release from Ca stores, to disrupt coordinated Ca dynamics.

Identification of Potentially Repurposable Drugs for Lewy Body Dementia Using a Network-Based Approach.

The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

Comparative analysis of the anti-depression effects of lorazepam, acupuncture, and curcumin utilizing the forced swimming test in experimental rats models

Introductionlorazepam is one of benzodiazepine medication that is usually used for its sedative and anxiolytic effect and has anti-depressant like effects. Turmeric is a plant that contain curcumin as main active compound that exert its antidepressant action inhibit monoamine oxidase and increase levels of dopamine and serotonin in brain. Aimthe present study investigate the depression effect of curcumin (natural selective serotonin inhibitors) in comparison with acupuncture and lorazepam. Method32 adult rats weighing (150 g−280 g) were divided equally into 8 groups each group contain 4 rats. The first 3 group of rats were treated with lorazepam, mixture of (curcumin, black pepper and olive oil) and pricked with insulin needle at point gb39, respectively, while second 4 groups of rats were received lorazepam and mixture, lorazepam and acupuncture, mixture and acupuncture, and lorazepam, mixture and acupuncture, separately, and the eighth group is control group don't receive any drugs. After 35 days, forced swimming test was made for all rats. ResultsLiver parameters: - GOT increased in all group, GPT increased in rat's group that received lorazepam, mixture group and lorazepam+ mixture group, This indicates the existence of problems previously with the liver of the rat used, and what remains is the high levels of GOT and GPT in the control group, while TSB is within the normal range for all groups. Kidney parameters:-blood urea levels increased in all groups and S. creatinine levels within normal range for all groups. Conclusionthe evaluation of natural SERMs in the forced swimming test showed promising antidepressant-like effects, comparable to lorazepam and acupuncture. Further research is needed to understand the mechanisms and determine optimal dosage and safety. Natural selective serotonin inhibitors hold potential as alternative or complementary treatments for depression.

Chronic exposure to bisphenol A induces behavioural, neurochemical, histological, and ultrastructural alterations in the ganglia tissue of the date mussels Lithophaga lithophaga.

Bisphenol A (BPA), a common plastic additive, has been demonstrated mechanistically to be a potential endocrine disruptor and to affect a variety of body functions in organisms. Although previous research has shown that BPA is toxic to aquatic organisms, the mechanism of neurotoxic effects in marine bivalves remains unknown. The current study aimed to elucidate the neurotoxic effects of BPA when administered at different concentrations (0.25, 1, 2, and 5 µg/L) for twenty-eight days in the ganglia of a bivalve model, the Mediterranean mussel (Lithophaga lithophaga), which is an ecologically and economically important human food source of bivalve species in the Mediterranean Sea. Our findings revealed an increase in behavioural disturbances and malondialdehyde levels in treated mussel ganglia compared to the control group. Furthermore, superoxide dismutase activity increased in the ganglia of L. lithophaga treated with 0.25 and 2 µg/L. However, at BPA concentrations of 1 and 5 µg/L, SOD activity was significantly reduced, as was total glutathione concentration. BPA causes neurotoxicity, as evidenced by concentration-dependent inhibition of acetylcholinesterase, dopamine, and serotonin. After chronic exposure to BPA, neurons showed distortion of the neuronal cell body and varying degrees of pyknosis. The ultrastructure changes in BPA-treated groups revealed the lightening of the nucleoplasm and a shrunken nuclear envelope. Overall, our findings suggest that BPA exposure altered antioxidation, neurochemical biomarkers, histopathological, and ultrastructural properties, resulting in behavioural changes. As a result, our findings provide a basis for further study into the toxicity of BPA in marine bivalves.

Regulation of REM sleep in mice: The role of dopamine and serotonin function in the basolateral amygdala

Animals have a sleep cycle that involves the repetitive occurrence of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. In a previous study, we discovered that a transient increase in dopamine (DA) levels in the basolateral amygdala (BLA) during NREM sleep terminates NREM sleep and initiates REM sleep by acting on Drd2-positive neurons (Hasegawa et al., 2022). In this study, we identified the neurons activated by the transient increase of DA in the BLA and found that chemogenetic excitation of these neurons increased REM sleep. Additionally, we demonstrated that acute inhibition of serotonin (5HT) in the BLA elicited a transient increase in DA in the BLA, which triggered REM sleep.

Correlates of Early Dental Implant Failure: A Retrospective Study.

To examine whether patient-level disease diagnoses, drug treatments, and dental clinical factors are correlates of early implant failure. This historical, nested case-control study used electronic medical records to retrieve patient-level data on individuals with implant failure occurring up to 6 months after implantation, including demographics, clinical information (number, location, and complicated status of implants), underlying diseases (osteoporosis, diabetes, hypertension, inflammatory bowel disease [IBD], myocardial infarction [MI]), and drug purchases (chemotherapy, bisphosphonates, selective serotonin inhibitors, antihypertensive medications, proton pump inhibitors [PPIs], disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal anti-inflammatory drugs) among adult members of a large, state-mandated health provider in Israel between 2015 and 2020. Individuals with implant extraction occurring up to 6 months after implantation were matched 1:1 to controls. Univariate and adjusted multivariate conditional logistic regression models were used to examine the odds ratios (ORs) of all dental implant risk factors among the patients. A total of 585 individuals with implant failure (mean age, 53 years [42,62], 51.3% females and 49.7% males) were identified among 29,378 eligible patients. Compared to controls, patients who experienced implant failure (ie, cases) were more likely to have smoked in their lifetime (18% vs 11.5%, P = .009), experienced IBD (1.5% vs 0.02%, P = .059), and consumed PPIs within 6 months of the implant surgery (40.0% vs 32.5%, P = .028). Clinical factors, including the number of implants per person (individuals with two implants, OR = 1.53; individuals with at least four implants, OR = 3.33; P < .01), location of implant (maxilla; OR = 1.59; 95% CI: 1.2-2.04), and smoking (OR = 1.57; 95% CI: 1.09-2.26) were significant correlates of early implant failure among the included cases. Crohn's disease, MI, and osteoporosis were found to be borderline significant correlates of early dental implant failure. Among the factors examined, the number of implants, the location of implants, and smoking history were significant correlates of early implant failure, while Crohn's disease, MI, and osteoporosis were found to not be significant. Larger patient-level studies are needed to examine the individual and combined effects of diseases, medications, and clinical factors on early implant failure.

Evaluation of the antiedematogenic and anti-inflammatory properties of Ximenia americana L. (Olacaceae) bark extract in experimental models of inflammation

Edema is one of the obvious indicators of inflammation and a crucial factor to take into account when assessing a substance's capacity to reduce inflammation. We aimed to evaluate the antiedematogenic and anti-inflammatory profile of the hydroethanolic barks extract of Ximenia americana (HEXA). The possible antiedematogenic and anti-inflammatory effect of EHXA (50, 100 mg/kg and 250 mg/kg v.o) was evaluated using the paw edema induced by carrageenan, zymosan, dextran, CFA and by different agents inflammatory (serotonin, histamine, arachidonic acid and PGE2), and pleurisy model induced by carrageenan and its action on IL-1β and TNF-α levels was also evaluated. HEXA demonstrated a significant antiedematogenic effect at concentrations of 50, 100 and 250 mg/kg on paw edema induced by carrageenan, zymosan and dextran. However, the concentration of 50 mg/kg as standard, demonstrating the effect in the subchronic model, induced CFA with inhibition of 59.06 %. In models of histamine-induced paw edema, HEXA showed inhibition of − 30 min: 40.49 %, 60 min: 44.70 % and 90 min: 48.98 %; serotonin inhibition - 30 min: 57.09 %, 60 min: 66.04 % and 90 min: 61.79 %; arachidonic acid inhibition - 15 min: 36.54 %, 30 min: 51.10 %, 45 min: 50.32 % and 60 min: 76.17 %; and PGE2 inhibition - 15 min: 67.78 %, 30 min: 62.30 %, 45 min: 54.25 % and 60 min: 47.92 %. HEXA significantly reduced (p < 0.01) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1β levels in pleural lavage (p < 0.0001). The results showed that HEXA has the potential to have an antiedematogenic impact in both acute and chronic inflammation processes, with a putative mode of action including the suppression or regulation of inflammatory mediators.

Pro-Con Debate: Role of Methadone in Enhanced Recovery After Surgery Protocols-Superior Analgesic or Harmful Drug?

Enhanced recovery after surgery (ERAS) protocols are standardized and designed to provide superior analgesia, reduce opioid consumption, improve patient recovery, and reduce hospital length of stay. Yet, moderate-to-severe postsurgical pain continues to afflict over 40% of patients and remains a major priority for anesthesia research. Methadone administration in the perioperative setting may reduce postoperative pain scores and have opioid-sparing effects, which may be beneficial for enhanced recovery. Methadone possesses a multimodal profile consisting of µ-opioid agonism, N-methyl-d-aspartate (NMDA) receptor antagonism, and reuptake inhibition of serotonin and norepinephrine. Furthermore, it may attenuate the development of chronic postsurgical pain. However, caution is advised with perioperative use of methadone in specific high-risk patient populations and surgical settings. Methadone's wide pharmacokinetic variability, opioid-related adverse effects, and potential negative impact on cost-effectiveness may also limit its use in the perioperative setting. In this PRO-CON commentary article, the authors debate whether methadone should be incorporated in ERAS protocols to provide superior analgesia with no increased risks.

A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to verify the efficacy and safety of ansofaxine (LY03005) for major depressive disorder

Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, −20.0; 160 mg, −19.9) vs. placebo (−14.6; p < 0.0001). All doses of ansofaxine were generally well-tolerated. Treatment-emergent adverse events (TEAEs) were reported by 137 (74.46%) patients in ansofaxine 80 mg group, 144 (78.26%) patients in ansofaxine 160 mg and 125 (67.93%) patients in the placebo group. The incidence of treatment-related adverse events (TRAEs) was 59.2% (109 patients), 65.22% (120 patients) in the 80, 160 mg ansofaxine groups, and 45.11% (83 patients) in the placebo group. The initial results of this trial indicate that ansofaxine at both the 80 mg/day and 160 mg/day was effective and safe in adult patients with MDD. ClinicalTrials.gov Identifier: NCT04853407.

How do the top 10 known offending drug classes associated with decreased bone mineral density affect total shoulder arthroplasty outcomes?

Many regularly prescribed classes of drugs are known to negatively impact bone health. However, it is unclear if perioperative use of these drugs impacts total shoulder arthroplasty (TSA) outcomes. The purpose of this study was to analyze the impact of perioperative use of 10 drug classes with known negative effects on bone health on prosthesis-related outcomes of TSA. Patients who underwent primary TSA were retrospectively identified in the PearlDiver database. Within this population, patients prescribed proton pump inhibitors (PPIs), thiazolidinediones (TZDs), loop diuretics, glucocorticoids, aromatase inhibitors, calcineurin inhibitors, selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs (AEDs), first-generation antipsychotics (FGAs), and second-generation antipsychotics (SGAs) within 6 months before or 6 months after primary TSA were identified (n=23,748). These patients were propensity score matched 1:1 with controls (n=23,748) on age, sex, and several comorbidities. After matching, patients with perioperative drug exposure were divided into 10 subgroups (ie, 1 for each drug class). Rates of prosthesis-related complications among patients taking each medication class vs. controls were compared with multivariable logistic regression. Relative to controls, SGA exposure was associated with significantly higher rates of all-cause revision (odds ratio [OR] 1.68) and aseptic revision (OR 1.57). Loop diuretic exposure was associated with significantly higher rates of all-cause revision (OR 1.44) and aseptic revision (OR 1.43). Glucocorticoid exposure was associated with significantly higher rates of all-cause revision (OR 1.32) and aseptic revision (OR 1.30). SSRI exposure was associated with significantly higher rates of all-cause revision (OR 1.27) and aseptic revision (OR 1.24). Periprosthetic fracture, aseptic loosening, and septic revision was comparable for all drug cohorts compared to matched controls (all P>.05). Patients with perioperative exposure to PPIs, TZDs, FGAs, AEDs, aromatase inhibitors, and calcineurin inhibitors displayed comparable rates of all queried complications compared with controls (all P>.05). Compared with matched controls, patients with perioperative exposure to SGAs, loop diuretics, glucocorticoids and SSRIs exhibited significantly higher rates of all-cause and aseptic revisions following primary TSA. Several other medications that are risk factors for osteoporosis and fragility fractures did not demonstrate significant associations with any complications, including periprosthetic fracture. These results highlight the need for a thorough review of patients' medical history and current medication usage prior to preoperative risk counseling for patients seeking TSA.

The effect of triple reuptake inhibitor toludesvenlafaxine on neurological function in cerebral ischemic rats.

Purpose: The aim is to investigate the effect of toludesvenlafaxine (Tdv), a reuptake inhibitor of serotonin, norepinephrine, and dopamine, on the neurological function in cerebral ischemic rats and the underlying mechanisms. Material and Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) model was induced in rats and the neuroprotective effects of Tdv were evaluated by infarct size, Garcia test, and beam walking test. Neuronal apoptosis in the peri-infarct area was observed by TUNEL staining. And the apoptosis-related proteins were evaluated with Western blotting. The role of CREB pathway in effect of Tdv was also investigated using Western blotting and immunofluorescence. Results: In the MCAO/R model, administration of Tdv reduced the infarct size, promoted neural functional recovery, decreased the expression of Bax and Caspase-3, and increased the expression of Bcl-2 and BDNF. In addition, Tdv reduced neuronal apoptosis in the peri-infarct area. Tdv increased the expression of phosphorylated CREB. The application of the specific CREB inhibitor, compound 666-15, could reverse the anti-ischemic cerebral injury of Tdv in MCAO/R rats. Conclusion: Tdv ameliorated cerebral ischemic injury through reducing neuronal apoptosis and increasing the expression of BDNF via the activation of CREB pathway.

The role of serotonin inhibition within the treatment of carcinoid syndrome.

Carcinoid syndrome is the most frequent hormonal complication associated with neuroendocrine neoplasms. It was first reported in 1954, and the classical symptoms are diarrhoea, flushing and abdominal pain. It is caused by the secretion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patient's quality of life. There are a variety of management options for carcinoid syndrome including medical, surgical and loco-regional interventional radiological procedures. The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues. It has also been shown to have a significant improvement in bowel movement frequency which was associated with a significant improvement in quality of life. Peptide receptor radionuclide therapy has proven symptomatic improvement in patients with uncontrolled symptoms. Chemotherapy is primarily reserved for patients with high proliferation tumours, with limited research on the efficacy in reducing symptoms. Surgical resection remains the optimal treatment due to being the only one that can achieve a cure. Liver-directed therapies are considered in patients where curative resection is not possible. There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.

The involvement of hyperhomocysteinemia in the development of characterized depressive disorder in children and adolescents

IntroductionElevated blood levels of homocysteine have been associated with several psychiatric and neurodegenerative disorders such as schizophrenic disorders, Alzheimer’s disease, Parkinson’s disease and depression. The hypothesis is that genetic and environmental factors elevate homocysteine levels, which causes vascular diseases of the brain, and/or changes in neurotransmitters, which cause various mental disorders.ObjectivesThe objective of our work is to discuss the association between hyperhomocysteinemia and the characterized depressive disorderMethodswe conducted our study through the discussion of a clinical vignetteResultsWe report here a case of hyperhomocysteinemia with vitamin B 12 deficiency in a 16-year-old female patient who presented with a characterized depressive disorder.She was initially treated with a selective serotonin inhibitor combined with parenteral injections of vitamin B12. The patient’s clinical condition improved after the first week. The discussion will attempt to clarify the role of vitamin therapy in the improvement of the patient’s depressive symptoms and its relationship with hyperhomocysteinemia.We report here a case of hyperhomocysteinemia with vitamin B 12 deficiency in a 16-year-old female patient who presented with a characterized depressive disorder.She was initially treated with a selective serotonin inhibitor combined with parenteral injections of vitamin B12. The patient’s clinical condition improved after the first week. The discussion will attempt to clarify the role of vitamin therapy in the improvement of the patient’s depressive symptoms and its relationship with hyperhomocysteinemia.ConclusionsStatistical data, physiological and genetic aspects seem to point to the involvement of hyperhomocysteinemia in the development of characterized depressive disorder. However, the results remain variable, even contradictory, and several confounding factors must be considered in these studies: ethnic, geographical, cultural (in terms of diet) and age factors are all elements that seem to intervene and that do not always make it possible to know whether hyperhomocysteinemia is a direct cause of depression or the consequence of mechanisms linked to folate and B12 deficiencies.Disclosure of InterestNone Declared

Serotonin- and eicosanoid-dependent rapid hemocyte aggregation in the hemolymph is the first step in nodule formation in Bombyx mori larvae

Nodule formation is a well-known process in cellular immunity of insects. However, few studies have investigated the role of hemocytes in rapid aggregation before tissue adhesion. In addition, since nodule formation is usually elicited by injecting large quantities of microbes, it remains unclear whether nodule formation is a natural response. The present study addressed these issues. A small number of nodules adhered to the dorsal vessels 1 min after Saccharomyces cerevisiae injection, while numerous aggregates of hemocytes and S. cerevisiae cells were observed in the hemolymph. The aggregate number decreased sharply after 5 min, corresponding to a rapid increase in the number of nodules. This suggests that aggregates formed in the hemolymph in response to S. cerevisiae injection eventually attached to the tissues. Nodules were induced using conditions that do not occur in nature, i.e., injection of nearly 2,000,000 S. cerevisiae cells. However, many aggregates contained only one S. cerevisiae cell, suggesting that aggregate formation can begin with the invasion of a single cell and that nodule formation is not an unnatural response. Biosynthesis inhibitors of serotonin (5-HT) and eicosanoids inhibited aggregate and nodule formation. In addition, injection of 5-HT and prostaglandin E2 induced hemocyte aggregation within 1 min in the hemolymph, along with hemocytin release. This suggested that 5-HT and eicosanoids induce rapid aggregation in response to invading microorganisms.

Design and characterization of fast dissolving buccal film of imipramine HCL

In depressed individuals, Imipramine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Imipramine hydrochloride having variable bioavailability i.e. ranging from 29-77% due to first pass metabolism, peak plasma concentration is usually attained 2-6 hours. Absorption is unaffected by food. It is freely soluble in water. The objective of this research work is to improve the bioavailability of the drug and fast the onset of action to decrease the depressant activity. The Buccal bioavailability of Imipramine HCL is only 29-77% for this reason drug can be administered into Buccal mucosa using mucoadhesive film. It can be made fast drug release and directly enter into blood circulation through Buccal mucosa and increase the drug bioavailability. Fast dissolving Buccal films were prepared by solvent casting method using various polymers like hydroxyl propyl methyl cellulose E15, PVP, PVA and sodium saccharin, plasticizer and vanillin as flavouring agent. Dissolution profile as studied in USP dissolution apparatus type 1 using pH 6.8 simulated saliva. The influence of variable like polymer type and concentration on Imipramine HCL release profile was studied. The formulation was optimized on the basis of various evaluation parameters like drug content and in vitro drug release. Formulation F3 successfully fast the release of drug within 8 minutes. The IR Spectra revealed the absence of interaction between drug and selected polymer, results of stability studies were as per ICH guide lines and results indicated that the selected formulation was stable.

Leki przeciwdepresyne typu SNRI — medycyna oparta na faktach i doświadczeniu

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants are drugs registered for the treatment of depression and anxiety disorders. These drugs affect the reuptake of both serotonin and noradrenaline. There are two such drugs available in Poland: venlafaxine and duloxetine. The mechanism of venlafaxine’s antidepressant effect in humans is believed to be related to increased neurotransmitter activity in the central nervous system (CNS). Preclinical studies have shown that venlafaxine and its major metabolite (O-demethylenlafaxine, ODV) are serotonin and norepinephrine reuptake inhibitors. Venlafaxine is also a weak dopamine reuptake inhibitor. Venlafaxine acts by blocking neurotransmitter transport and reuptake proteins and acts through postsynaptic terminals, ultimately enhancing postsynaptic stimulation. Duloxetine is an inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake (e.g. in frontal regions), and has no significant affinity for histamine, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular serotonin and norepinephrine concentrations in different brain areas in animals. In this paper we will discuss the most important literature data concerning the above mentioned drugs, as well as define a patient profile that could most benefit from individually selected treatment.