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Biomolecules Feb 2023Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6... (Review)
Review
Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT) receptor has been an area of substantial research. 5-HT receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT receptor antagonists. Several 5-HT receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.
Topics: Animals; Serotonin; Alzheimer Disease; Receptors, Serotonin; Serotonin Antagonists
PubMed: 36830678
DOI: 10.3390/biom13020309 -
Best Practice & Research. Clinical... Dec 2020Intraoperative and postoperative nausea and vomiting (IONV and PONV) afflict up to 80% of parturients undergoing cesarean delivery with neuraxial anesthesia. Preventing... (Review)
Review
Intraoperative and postoperative nausea and vomiting (IONV and PONV) afflict up to 80% of parturients undergoing cesarean delivery with neuraxial anesthesia. Preventing nausea and emesis is a top priority for women undergoing cesarean delivery and is included in the quality of recovery measures and enhanced recovery after cesarean delivery protocols. The majority of known perioperative emetic triggers can be avoided or mitigated by optimizing anesthetic and surgical management. IONV may arise from spinal anesthesia-induced hypotension, intraoperative pain, and medications such as uterotonics and antibiotics. Furthermore, uterine exteriorization and peritoneal irrigation increase IONV risk. Conversely, preventing PONV mainly focuses on optimizing analgesia through an opioid-sparing, multimodal strategy. In addition, combination prophylactic antiemetic therapy should be instituted in this high-risk population to further reduce the risk of IONV and PONV.
Topics: Anesthesia, Obstetrical; Antiemetics; Cesarean Section; Dopamine Antagonists; Female; Humans; Injections, Spinal; Intraoperative Complications; Postoperative Nausea and Vomiting; Pregnancy; Serotonin 5-HT3 Receptor Antagonists
PubMed: 33288123
DOI: 10.1016/j.bpa.2020.04.012 -
Dermatitis : Contact, Atopic,... 2019Multiple etiologies contribute to sleep disturbance in atopic dermatitis (AD) patients, including learned scratching behavior and increased monoamines, cutaneous blood... (Review)
Review
Multiple etiologies contribute to sleep disturbance in atopic dermatitis (AD) patients, including learned scratching behavior and increased monoamines, cutaneous blood flow, inflammatory cell activities, and cytokines, as well as decreased melatonin, anti-inflammatory cytokines, and skin barrier function. Insomnia impairs cognitive development in children with AD, leading to behavioral problems and learning disabilities. Insomnia in adults with AD impedes work productivity. In this article, we discuss pearls on improving insomnia through both nonpharmacologic modalities, such as environmental adjustments and massage therapy, and pharmaceutical approaches including melatonin, antihistamines, tricyclic antidepressants, mirtazapine, and benzodiazepine and nonbenzodiazepine sedatives. Future investigations should further delineate the mechanistic link between insomnia and AD exacerbation and identify strategies to combat sleep-related disease burden.
Topics: Antidepressive Agents, Tricyclic; Benzodiazepines; Central Nervous System Depressants; Dermatitis, Atopic; Histamine Antagonists; Humans; Hypnotics and Sedatives; Massage; Melatonin; Mirtazapine; Serotonin Antagonists; Sleep Hygiene; Sleep Initiation and Maintenance Disorders
PubMed: 31524756
DOI: 10.1097/DER.0000000000000523 -
Minerva Anestesiologica Jun 2023Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients... (Review)
Review
INTRODUCTION
Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients who might benefit from specific prophylactic and therapeutic antiemetic treatment. The aim of the present review was to investigate gene polymorphisms that influence 5-hydroxytryptamine (serotonin) type 3 receptor antagonists (5HT3RA) efficacy in PONV.
EVIDENCE AQUISITION
We included articles published from 2005 to 2022, utilizing the electronic databases PUBMED, EMBASE, COHRANE Library and ScienceDirect. To explore the relationship between genetic variations and 5HT3 receptor antagonist efficacy in PONV we focused on three different gene polymorphisms: the cytochrome P450 mono-oxygenase system gene (CYP2D6), the adenosine triphosphate (ATP)-binding cassette subfamily B gene (ABCB1) as well as the 5HT3 receptor gene (5HT3R). We also explored the relationship between the above genetic variations and their impact on 5HT3RA efficacy in the context of chemotherapy induced nausea and vomiting.
EVIDENCE SYNTHESIS
Our search retrieved a total of 70 articles; 29 of them were included in the present review. Regarding polymorphisms of the CYP2D6 gene and the efficacy of serotonin antagonists in PONV, the ultra-rapid metabolizer genotype was associated with reduced efficacy of ondansetron, dolasetron and tropisetron, with the latter presenting more pronounced failure in these patients, while granisetron's efficacy remained unaffected. Regarding variations in the ABCB1 gene, three polymorphisms ("2677G>T/A" in exon 21; "3435C>T" in exon 27; "C1236T" in exon 12) were associated with a better response to ondansetron and ramosetron, while they did not affect palonosetron's efficacy. Additionally, polymporphisms of the 5-HT3B receptor gene were associated with ondancetron's postoperative efficacy; the "100_-102AAG" deletion variant was associated with reduced efficacy, while the Y129S variant did not show any effect on the drug's antiemetic effect.
CONCLUSIONS
This review highlights that inefficacy of a specific drug in managing PONV could be attributed to specific genetic profiles and patients would possibly benefit from a drug switch.
Topics: Humans; Postoperative Nausea and Vomiting; Ondansetron; Pharmacogenetics; Cytochrome P-450 CYP2D6; Antiemetics
PubMed: 36852569
DOI: 10.23736/S0375-9393.22.16983-X -
Neuropharmacology Jan 2021Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a...
Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a delayed onset and low rate of efficacy. Consequently, there remains an ongoing need for antidepressants that are either more effective or better tolerated than existing standards. We previously identified ZY-1408 as a drug with a novel chemical structure and potential anti-depressant-like activity. Specifically, ZY-1408 is a novel serotonin 2C (5-HT) receptor antagonist and serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. In this study, we further investigated the antidepressant-like efficacy of ZY-1408 using in vitro and in vivo behavioral tests. ZY-1408 showed 5-HT receptor antagonist and 5-HT/NE reuptake inhibitor properties in vitro. Meanwhile, ZY-1408 decreased immobility in vivo in a dose-dependent manner in rats (via the forced-swim test) and mice (via the tail-suspension test). The behavioral test results do not appear to result from stimulation of locomotor activity. In chronically stressed rats, repeated ZY-1408 treatment significantly reversed depressive-like behavior, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis showed that administration of ZY-1408 significantly increased extracellular concentrations of 5-HT and NE in the hippocampus of freely moving rats. Thus, ZY-1408 is a potent and orally active 5-HT receptor antagonist and 5-HT/NE reuptake inhibitor with antidepressant-like activity in rodents.
Topics: Animals; Antidepressive Agents; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Male; Norepinephrine; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Selective Serotonin Reuptake Inhibitors
PubMed: 33122031
DOI: 10.1016/j.neuropharm.2020.108376 -
Journal of Molecular Medicine (Berlin,... Mar 2021Memantine is used in Alzheimer's disease treatment as a non-competitive modern-affinity strong voltage-dependent N-methyl-D-aspartate receptor antagonist. The... (Review)
Review
Memantine is used in Alzheimer's disease treatment as a non-competitive modern-affinity strong voltage-dependent N-methyl-D-aspartate receptor antagonist. The fundamental role of these receptors is to bind glutamate: the main excitatory neurotransmitter in the brain, believed to play a crucial role in neuronal plasticity and learning mechanisms. Glutamate transmission plays an important role in all internal CNS structures and maintains the physiological state of the brain. Excessive glutamate transmission can lead to enlarged calcium ion current which may cause neurotoxicity; however, insufficient transmission can drastically alter the information flow in neurons and the brain, potentially causing schizophrenia-like symptoms by replacing lost information with completely new stimuli. Hence, it is possible that the modulation of NMDA activity may give rise to pathophysiological states. Available literature and clinical trials indicate that memantine is well tolerated by patients, with very few and light side effects. There is a belief that memantine may also benefit other conditions such as schizophrenia and depression.
Topics: Alzheimer Disease; Antidepressive Agents; Antipsychotic Agents; Clinical Trials as Topic; Depression; Drug Repositioning; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Memantine; N-Methylaspartate; Neuronal Plasticity; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT3 Receptor Antagonists
PubMed: 33447926
DOI: 10.1007/s00109-020-01982-z -
European Journal of Pharmacology Sep 2020The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and...
The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective α-adrenoceptor antagonist, or methysergide, a non-selective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an α-adrenoceptor play a crucial role in chronic pruriceptive processing.
Topics: Adrenergic Antagonists; Adrenergic Uptake Inhibitors; Animals; Antipruritics; Behavior, Animal; Central Nervous System; Chronic Disease; Disease Models, Animal; Injections, Spinal; Male; Mice, Inbred C57BL; Norepinephrine; Pruritus; Serotonin; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 32619678
DOI: 10.1016/j.ejphar.2020.173319 -
International Journal of Molecular... May 2021Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach,...
Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.
Topics: Arginine; Cell Line, Tumor; Fenclonine; Gastric Acid; Gene Expression; Granisetron; Humans; Hydrogen-Ion Concentration; Parietal Cells, Gastric; Protease Inhibitors; Protons; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Stomach; Tissue Culture Techniques; Tryptophan Hydroxylase
PubMed: 34070942
DOI: 10.3390/ijms22115881 -
The Lancet. Gastroenterology &... Mar 2020This Review summarises recent pharmacological and upcoming alternative interventions for children with functional abdominal pain disorders (FAPDs). Pharmacological... (Review)
Review
This Review summarises recent pharmacological and upcoming alternative interventions for children with functional abdominal pain disorders (FAPDs). Pharmacological targets include prokinetics and drugs affecting gastric accommodation to treat postprandial distress and nausea. Similarly, anti-inflammatory agents, junctional protein regulators, analgesics, secretagogues, and serotonin antagonists have a therapeutic role for irritable bowel syndrome. Non-pharmacological treatments include peripheral electrical nerve field stimulation to the external ear, gastric electrical stimulation, dietary interventions such as low fructose and fibre based diets, and nutraceuticals, which include probiotics, prebiotics, and synbiotics. Newer psychological advances such as exposure-based cognitive behavioural therapy, acceptance and commitment therapy, and mindfulness meditation are being investigated for paediatric functional pain. Lastly, alternative therapies such as acupuncture, moxibustion, yoga, and spinal manipulation are also gaining popularity in the treatment of FAPDs.
Topics: Abdominal Pain; Acceptance and Commitment Therapy; Acupuncture; Adolescent; Analgesics; Anti-Inflammatory Agents; Child; Child, Preschool; Cognitive Behavioral Therapy; Diet Therapy; Dietary Supplements; Electric Stimulation; Female; Humans; Irritable Bowel Syndrome; Male; Manipulation, Spinal; Mindfulness; Moxibustion; Nausea; Postprandial Period; Prebiotics; Probiotics; Psychological Distress; Secretagogues; Serotonin Antagonists; Synbiotics; Treatment Outcome; Yoga; Young Adult
PubMed: 31859185
DOI: 10.1016/S2468-1253(19)30256-0 -
Current Opinion in Supportive and... Sep 2020Cisplatin remains the treatment cornerstone for bladder cancer, either in neoadjuvant or in metastatic (cisplatin-gemcitabine or dose-dense methotrexate, vinblastine,... (Review)
Review
PURPOSE OF REVIEW
Cisplatin remains the treatment cornerstone for bladder cancer, either in neoadjuvant or in metastatic (cisplatin-gemcitabine or dose-dense methotrexate, vinblastine, and doxorubicin). Timely and adequate management of cisplatin's adverse events is important in order to avoid dose reductions, treatment delays, or cessation. Over the last years, several randomized studies and updated guidelines have been published on this subject.
RECENT FINDINGS
The incidence, physiopathology, risk factors, preventive treatment, and optimal management of such complications will be presented, with special focus on cisplatin-associated nausea and vomiting, acute kidney injury (AKI), hypomagnesemia, neurotoxicity, and ototoxicity.
SUMMARY
Optimal prevention of cisplatin-associated nausea and vomiting requires an aggressive approach with the use of a four-drug prophylactic regimen (NK1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone, olanzapine). The use of intensive hydration before and after cisplatin infusion has been the mainstay of AKI prevention. The management of hypomagnesemia and neurotoxicity remains largely symptomatic. In an adult population, no therapy has yet demonstrated benefits in the prevention or treatment of platinum-related ototoxicity.
Topics: Adrenal Cortex Hormones; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug-Related Side Effects and Adverse Reactions; Fluid Therapy; Humans; Randomized Controlled Trials as Topic; Risk Factors; Serotonin 5-HT3 Receptor Antagonists; Urinary Bladder Neoplasms
PubMed: 32740273
DOI: 10.1097/SPC.0000000000000505