Serotonin Receptor Antagonist Research Articles

Evaluation of Cisplatin-Induced Acute Kidney Injury in Patients Co-Prescribed Serotonin Receptor Antagonists: A Retrospective Analysis.

Cisplatin is an effective first line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to acute kidney injury (AKI). Anti-emetic drugs such as 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are commonly prescribed to prevent this complication. Preclinical studies suggest first generation 5-HT3RAs may alter the renal clearance and increase cisplatin toxicity. This retrospective study evaluated whether different 5-HT3RAs modify the risk of AKI in patients receiving cisplatin. Patients with cancer who received cisplatin between January 1, 2010 and December 31, 2016 were included. Patients over 18 years old with available data for baseline and post-treatment serum creatinine, cisplatin cumulative dose, and administration of 5-HT3RAs including first generation (ondansetron, granisetron, and ramosetron) and second generation (palonosetron) were analyzed. AKI defined as 1.5x increase in serum creatinine. Fisher's exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and AKI, and logistic regression for multivariable associations with AKI. Of 8703 patients identified with cisplatin exposure, 6889 were included. A total of 3881 (56.3%) patients received at least one 5-HT3RA, including palonosetron (3750, 54.4%), ondansetron (1399, 20.3%) and granisetron (11, 0.2%). AKI developed in 1666 (24.2%) patients following cisplatin. Patients who received any 5-HT3RAs were less likely to experience AKI as compared to patients that did not (22.6% vs 26.2%, p=0.001). Older age, male gender, African ethnicity, and cumulative cisplatin dose were univariately associated with higher risk for AKI (P<0.001). After adjusting for these variables, use of any of these antiemetic drugs was protective for AKI (OR 0.84, 95% CI: 0.75, 0.94; P= 0.003) with no difference detected between type of 5-HT3RA. Nephrotoxicity continues to be a concern following cisplatin therapy. Given its emetogenic nature, use of antiemetic drugs such as 5-HT3RAs can lessen emesis and lower risk of kidney injury. This retrospective analysis supports use of any 5-HT3RAs to lower risk of AKI.

Implications of Pimavanserin in Patients with Dementia-related Psychosis: A Systematic Review

Psychosis in patients with dementia-related disorders has long been a challenging issue to be tackled by the medical fraternity. Although atypical antipsychotics (AP) are in use for the same reason, there has always been a question regarding their safety and tolerability in this group of patients. Pimavanserin, a serotonin receptor inverse agonist or antagonist, is the only drug that is Food and Drug Administration-licensed to be used for the treatment of Parkinson’s disease psychosis. This systematic review, which was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020, had the objective of examining the effects of pimavanserin in patients with dementia-related psychosis (DRP). Among the publications (January 1, 2013–July 12, 2023) we gathered and examined were case–control and cohort studies, systematic reviews, meta-analyses, clinical trials, literature reviews, and randomized and nonrandomized control trials. The databases used to construct this list of publications were PubMed, Cochrane Library, and Google Scholar. These three databases yielded 157 reports in total once the relevant filters were applied. They were then further screened and put through quality evaluation processes, which led to the final nine papers that were included in this systematic review. We concluded from our review that pimavanserin proves to be a promising alternative for the treatment of DRP, showing significant improvements and fewer side effects compared to other atypical AP.

Preparation, In-vitro, and Ex-vivo Evaluation of Ondansetron Loaded Invasomes for Transdermal Delivery

Invasomes are newly developed types of nanovesicles. A vesicular drug delivery system is considered one of the approaches for transdermal delivery to enhance permeation and improve drug bioavailability. Ondansetron is a serotonin receptor antagonist used for treating vomiting associated with different clinical cases. The study aimed to prepare invasomal dispersions for improving permeation of ondansetron across the skin with a controlled release pattern. Twenty-seven formulas of ondansetron-loaded invasomes were prepared by a modified mechanical dispersion method. These formulas were optimized by studying the effect of variables on entrapment efficiency. Vesicle size, polydispersity, zeta potential, in-vitro release and ex-vivo permeation studies were done for the optimized formulas. The selected formula was )F25( had )88.24%±0.04 (entrapment, (317.7 nm) vesicle size, (0.29) polydispersity, and (-31.5mV) zeta potential. In-vitro release study showed That (F25) had 75% release after (12) hrs., and dissolution followed the Korsmeyer-Peppas model with anomalous diffusion. Ex-vivo permeation study showed steady-state flux was 340.2 µg/cm2.hr with no lag time using rat skin tissue. A transmission electron microscope was done to visualize the selected formula. Invasomes are considered promising drug delivery systems for transdermal delivery of ondansetron, ensuring efficient permeation with a sustained release pattern.

Solubility Enhancement and Formulation Development of an Oral Film of Ondansetron Hydrochloride Monohydrate using Mix-solvency Concept

This research paper presents the formulation and evaluation of ondansetron hydrochloride monohydrate oral film using the mix-solvency concept. Ondansetron hydrochloride monohydrate a selective serotonin receptor antagonist is commonly prescribed to prevent chemotherapy or surgery-induced nausea and vomiting. The aim of the study was to enhance the solubility of ondansetron hydrochloride monohydrate which has been enhanced by the blend of varying aqueous solubilizers poly ethylene glycol, niacinamide, and caffeine. The oral film formulation was prepared using a solvent casting method, incorporating polymers, plasticizers and different solvents. Various formulation variables, including solvent type and concentration, polymer-to-plasticizer ratios, and drug loading, were optimized systematically the resulting oral film was investigated for various parameters such as thickness, drug content, disintegration time, folding endurance and surface pH. The % in-vitro release of drug of the best two formulations F3 and F5 was 99.70 and 96.62%, respectively.

2023 Updated MASCC/ESMO Consensus Recommendations: prevention of radiotherapy- and chemoradiotherapy-induced nausea and vomiting

PurposeRadiotherapy and chemoradiotherapy-induced nausea and vomiting (RINV and C-RINV) are common and distressing, and there is a need for guidance for clinicians to provide up to date optimal antiemetic prophylaxis and treatment. Through a comprehensive review of the literature concerning RINV and C-RINV, this manuscript aims to update the evidence for antiemetic prophylaxis and rescue therapy and provide a new edition of recommendations for the MASCC/ESMO antiemetic guidelines for RINV and C-RINV.MethodsA systematic review of the literature including data published from May 1, 2015, to January 31, 2023, was performed. All authors assessed the literature.ResultsThe searches yielded 343 references; 37 met criteria for full article review, and 20 were ultimately retained. Only one randomized study in chemoradiation had the impact to provide new recommendations for the antiemetic guideline. Based on expert consensus, it was decided to change the recommendation for the “low emetic risk” category from “prophylaxis or rescue” to “rescue” only, while the drugs of choice remain unchanged.ConclusionAs for the previous guideline, the serotonin receptor antagonists are still the cornerstone in antiemetic prophylaxis of nausea and vomiting induced by high and moderate emetic risk radiotherapy. The guideline update provides new recommendation for the management of C-RINV for radiotherapy and concomitant weekly cisplatin. To avoid overtreatment, antiemetic prophylaxis is no longer recommended for the “low emetic risk” category.

Citrate-coated silver nanoparticles loaded with agomelatine provide neuronal therapy in acute cerebral ischemia/reperfusion of rats by inhibiting the oxidative stress, endoplasmic reticulum stress, and P2X7 receptor-mediated inflammasome.

Cerebral ischemia and reperfusion are related to various situations like injuries after various traumas, oxidative stress, increased calcium ion, capillary hypoperfusion, microvascular hyperpermeability, leukocyte infiltration, and blood-brain barrier disruption. An antidepressant Agomelatine which is a melatonin receptor (MT1/MT2) agonist and serotonin receptor (5-HT2C) antagonist has been reported by studies to have antioxidant and anti-inflammatory effects. In our study, we aimed to detect the effects of citrate-coated silver nanoparticle-loaded agomelatine application on neurodegeneration, endoplasmic reticulum stress, autophagic and apoptotic cell death, inflammation, and P2X7R expression in the cerebral ischemia-reperfusion model to facilitate the passage of blood-brain barrier. Forty two Sprague-Dawley rats in total were divided into six equal groups (n:7) and applications were performed. Acute cerebral injury in the ischemia-reperfusion model was created 2 h after internal carotid artery ligation in rats and then at the 2nd hour of reperfusion citrate-coated silver nanoparticles loaded with Agomelatine were applied. Twenty four hours later, neurologic analysis on animals in experimental groups was performed, animals were decapitated and GSH, GPx, SOD, CAT, MDA, IL-1β, and TNF-α parameters were examined after taking blood and the cerebral tissue samples. As a result, it was determined that ischemia-reperfusion caused endoplasmic reticulum stress in the cerebral tissues and thus caused cellular injury.

Influence of the descending pain-inhibiting serotonergic pathway on the antihyperalgesic effect of gabapentin in neuropathic pain model rats

Gabapentinoids are used worldwide as first-line agents for the treatment of neuropathic pain. Accumulating evidence indicates that one of the antihyperalgesic mechanisms of gabapentinoids is through activation of the noradrenergic pathway of the descending pain inhibition system. However, the involvement of the serotonin pathway is unclear. We investigated the effects of gabapentin (GBP) on the serotonergic pathway of the descending inhibitory system using the spinal nerve ligation (SNL) rat model. As in previous reports, administration of GBP to SNL rats improved paw withdrawal thresholds (PWT). Intrathecally administered serotonin receptor antagonists abolished GBP's amelioration in PWT. GBP did not ameliorate PWT in noradrenaline-depleted SNL rats by DSP-4. However, GBP ameliorated PWT in serotonin-depleted SNL rats by para-chlorophenylalanine, which was not inhibited by intrathecal administration of a serotonin receptor antagonist. Immunohistochemical analysis of serotonin in the spinal dorsal horn revealed a slight, albeit statistically insignificant, increase in 5-HT levels in SNL rats compared to naive rats. However, no apparent changes were observed before or after GBP administration in naive and SNL rats. In conclusion, the involvement of the serotonergic pathway in the antihyperalgesic effects of GBP on the spinal cord is secondary, although it cooperates with the noradrenergic system to produce analgesia.

Neuromodulation Through Magnetic Fields Irradiation with AT-04 Improves Hyperalgesia in a Rat Model of Neuropathic Pain via Descending Pain Modulatory Systems and Opioid Analgesia

Neuromodulation through magnetic fields irradiation with ait® (AT-04), a device that irradiates a mixed alternating magnetic fields (2 kHz and 83.3 MHz), has been shown to have high efficacy for fibromyalgia and low back pain in our previous clinical trials. The aim of this study was to elucidate the underlying analgesic mechanism of the AT-04 using the partial sciatic nerve ligation (PSL) model as an animal model of neuropathic pain. AT-04 was applied to PSL model rats with hyperalgesia and its pain-improving effect was verified by examining mechanical allodynia using the von Frey method. The results demonstrated a significant improvement in hyperalgesia in PSL model rats. We also examined the involvement of descending pain modulatory systems in the analgesic effects of AT-04 using antagonism by serotonin and noradrenergic receptor antagonists. These antagonists significantly reduced the analgesic effect of AT-04 on pain in PSL model rats by approximately 50%. We also measured the amount of serotonin and noradrenaline in the spinal fluid of PSL model rats using microdialysis during AT-04 treatment. Both monoamines were significantly increased by magnetic fields irradiation with AT-04. Furthermore, we evaluated the involvement of opioid analgesia in the analgesic effects of AT-04 using naloxone, the main antagonist of the opioid receptor, and found that it significantly antagonized the effects by approximately 60%. Therefore, the analgesic effects of AT-04 in PSL model rats involve both the endogenous pain modulation systems, including the descending pain modulatory system and the opioid analgesic system.Graphical

Methiothepin downregulates SNAP-23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow-derived mast cells.

In the present study, we found that methiothepin (a nonselective 5-hydroxytryptamine [5-HT] receptor antagonist) inhibited antigen-induced degranulation in rat basophilic leukemia cells and mouse bone marrow-derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5-HT) by exocytosis and mast cells express several types of 5-HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca2+ concentration, phosphorylated critical upstream signaling components (Src family tyrosine kinases, Syk, and PLCγ1), and suppressed TNF-α secretion via inhibition of Akt (a Ser/Thr kinase activated by PI3K)and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin-induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase β phosphorylates synaptosomal associated protein 23, which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin-induced phosphorylation of synaptosomal associated protein 23 by inhibiting its interaction with IκB kinase β. Together with the results of selective 5-HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5-HT1A receptor. Our findings provide that 5-HT antagonists may be used to relieve allergic reactions.

The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors.

The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or 5.6 mg/kg). Despite showing in vitro that DPT is a serotonin 5-HT2A, 5-HT1B, and 5-HT1A receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/βγ biosensors), pretreatment with selective inhibitors of 5-HT2A/2C, 5-HT1B, or 5-HT1A receptors did not block DPT's antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT1A receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose-response experiment to evaluate DPT's engagement of 5-HT1A receptors in vivo. DPT elicited 5-HT1A-dependent effects only at doses greater than 10 mg/kg, further supporting that DPT's antiepileptic effects were not 5-HT1A-mediated. We also observed that the selective sigma1 receptor antagonist, NE-100, did not impact DPT's antiepileptic effects, suggesting DPT engagement of sigma1 receptors was not a crucial mechanism. Separately, we observed that DPT and NE-100 at high doses caused convulsions on their own that were qualitatively distinct from AGS. In conclusion, DPT dose-dependently blocked AGS in Fmr1 knockout mice, but neither serotonin nor sigma1 receptor antagonists prevented this action. Thus, DPT might have neurotherapeutic effects independent of its serotonergic psychedelic properties. However, DPT also caused seizures at high doses, showing that DPT has complex dose-dependent in vivo polypharmacology.

Antinociceptive effects of nefopam activating descending serotonergic modulation via 5-HT2 receptors in the nucleus raphe magnus.

Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam. The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra-nucleus raphe magnus (NRM) pre-treatment with the serotonin (5-HT) receptor antagonist or 5-HT2 receptor antagonist. The change in extracellular 5-HT levels was measured by spinal cord microdialysis. Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre-treatment with 5-HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5-HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5-HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra-NRM cinanserin pre-treatment. The increase in spinal level of 5-HT by systemic nefopam was attenuated by intra-NRM cinanserin pre-treatment. The antinociceptive effects of systemically administered nefopam are mediated by 5-HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. This study revealed supraspinal mechanisms of nefopam-produced analgesia mediated by 5-HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

Clinical Guidance on the Monitoring and Management of Trastuzumab Deruxtecan (T-DXd)-Related Adverse Events: Insights from an Asia-Pacific Multidisciplinary Panel.

Trastuzumab deruxtecan (T-DXd)-an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)-improved outcomes of patients with HER2-positive and HER2-low metastatic breast cancer. Guidance on monitoring and managing T-DXd-related adverse events (AEs) is an emerging unmet need as translating clinical trial experience into real-world practice may be difficult due to practical and cultural considerations and differences in health care infrastructure. Thus, 13 experts including oncologists, pulmonologists and a radiologist from the Asia-Pacific region gathered to provide recommendations for T-DXd-related AE monitoring and management by using the latest evidence from the DESTINY-Breast trials, our own clinical trial experience and loco-regional health care considerations. While subgroup analysis of Asian (excluding Japanese) versus overall population in the DESTINY-Breast03 uncovered no major differences in the AE profile, we concluded that proactive monitoring and management are essential in maximising the benefits with T-DXd. As interstitial lung disease (ILD)/pneumonitis is a serious AE, patients should undergo regular computed tomography scans, but the frequency may have to account for the median time of ILD/pneumonitis onset and access. Trastuzumab deruxtecan appears to be a highly emetic regimen, and prophylaxis with serotonin receptor antagonists and dexamethasone (with or without neurokinin-1 receptor antagonist) should be considered. Health care professionals should be vigilant for treatable causes of fatigue, and patients should be encouraged to use support groups and practice low-intensity exercises. To increase treatment acceptance, patients should be made aware of alopecia risk prior to starting T-DXd. Detailed monitoring and management recommendations for T-DXd-related AEs are discussed further.

The effect of risperidone on behavioral reactions and gene expression of pro- and anti-inflammatory cytokines in neuropathic pain model induced by chronic constriction injury of the sciatic nerve in rat.

Neuropathic pain results from lesions or diseases affecting the somatosensory system. The management of a patient with chronic neuropathic pain remains a challenge several studies report the analgesic effect of serotonin receptor antagonists in different models of experimental pain. The present study was designed to study the effect of systemic administration of risperidone, on behavioral scores of neuropathic pains in chronic constriction (CCI) model in rats. Inducing neuropathic pain with the CCI model which causes heat hyperalgesia, heat, and mechanical allodynia was performed on rats, and then, in two phases, risperidone effect was determined. In the acute phase, risperidone 1, 2, 4mg was administered for three groups half an hour before behavioral tests on the 7th, 14th, and 21st day after surgery, and in the chronic phase, risperidone 1, 2, and 4mg was administered for three different groups from the 1st to 14th days after surgery than on 14th-day behavioral scores were performed. For gene expression analysis, samples are taken from spinal cord tissues in lumbar segments. This study shows chronic administration of risperidone as an antipsychotic drug was effective on heat hyperalgesia and allodynia. However, only the max dosage (4mg) of risperidone showed meaningful improvement in increasing mechanical allodynia. However, acute administering of risperidone did not show any meaningful changes in behavioral tests on neuropathic pain induced by chronic constriction injury of the sciatic nerve in rats. In addition, gene expression results showed an increase in IL-4 and IL-10 gene expression in the risperidone group compared to the sham group. This study suggests the helpful preventive effects of risperidone in developing and increasing neuropathic pain, but it does not have any instant effect.

Epigenetic Processes of DNA Methylation Are Selectively Involved in the Mechanisms of Retrograde and Anteograde Amnesia.

The participation of DNA methylation processes in the mechanisms of anterograde and retrograde amnesia caused by impaired reconsolidation of conditioned food aversion memory by NMDA glutamate receptor antagonists or serotonin receptor antagonists, respectively, were studied on grape snails. Anterograde amnesia was characterized by impaired formation of long-term memory during repeated learning. Administration of a DNA methyltransferase (DNMT) inhibitor to amnestic animals resulted in accelerated formation of long-term memory during 1 day of repetitive training vs 3 days during initial training. In serotonin-dependent retrograde amnesia, repeated learning without DNMT inhibitor administration or after inhibitor injections led to the formation of long-term memory. The dynamics of memory formation was similar in both cases and did not differ from that during the initial training: the memory was formed within 3 days of training. Thus, epigenetic processes of DNA methylation are selectively involved in the mechanisms of anterograde amnesia, but do not participate in the mechanisms of retrograde amnesia.

Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5′-Modified (N)-methanocarba-adenosine derivatives

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N6-alkyl groups. N6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N6-dicyclohexyl-methyl derivative 35 showed weak 5-HT2AR affinity (Ki 3.6 μM). The highest 5-HT2BR affinities were Ki 11–23 nM (N6-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5′-deoxy-5′-methylthio 15 and N6-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and Ki 73 nM at 5-HT2CR for 36. Direct comparison of adenine ribosides and their corresponding rigid (N)-methanocarba derivatives (cf. 51 and MRS8099 45) indicated a multifold affinity enhancement with the bicyclic ring system. Compounds 43, 45 and 48 were functional 5-HT2BR (KB 2–3 nM) and 5-HT2CR (KB 79–328 nM) antagonists in a Gq-mediated calcium flux assay, with 5-HT2BR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (Ki, A1AR < Ki, A3AR < Ki, A2AAR) was still present in this series, suggestive of dual acting compounds: 5-HT2B antagonist and A1AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT2BR binding selectivity (32-fold vs. 5-HT2CR, 4-fold vs. A1AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.

The effects of orally administered trazodone on ambulation and recumbency in healthy horses.

Trazodone, a serotonin receptor antagonist and reuptake inhibitor, might be a useful adjunctive treatment in the initial management of horses with acute laminitis if it minimizes ambulation or encourages recumbency. (1) Evaluate the effects of PO trazodone on ambulatory activity and recumbency in healthy horses; and (2) assess the pharmacokinetics of multiple PO doses of trazodone. In a randomized cross-over design, 8 healthy horses received placebo or trazodone at 2 doses (2.5 and 7.5 mg/kg) PO q12h for 48 hours with a 14-day washout period between treatments. Forelimb step frequency was measured using a hoof-mounted accelerometer and continuous video monitoring was used to detect recumbency. Groups were compared using repeated measures analysis of variance with Tukey's post hoc test. Trazodone and m-chlorophenylpiperazine (m-CPP) plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry and pharmacokinetics were analyzed using noncompartmental methods. Step frequency was lower in horses receiving 7.5 mg/kg trazodone than in the control group (mean step reduction: 44% ± 11%). Steps-area under the curve were significantly lower in the 7.5 mg/kg group (mean ± SD: 3375 ± 525 steps × hour) as compared to the 2.5 mg/kg group (mean ± SD: 5901 ± 2232; P = .02) and compared to control (mean ± SD: 6590 ± 1241; P = .001). No difference was found in the number of recumbent episodes (P = .92) or total duration of recumbency (P = .9). Trazodone and m-CPP achieved steady-state concentrations, with an accumulation ratio of 1.45 ± 0.2. Although it did not affect recumbency, trazodone at 7.5 mg/kg q12h decreased step frequency by approximately 44%.

Computational, Molecular modelling and Anxiolytic potential of 5-HT3 receptor antagonist

Serotonin-3 receptor antagonists are useful for treating nausea and vomiting induced by a variety of reasons. These have an impact on a variety of neuropsychiatric illnesses. As a result, we attempted to investigate the anxiolytic potential of the test drug,6j{2-[4-(4-nitro-phenyl)-piperazin-1-yl]-[1,8]naphthyridine-3-carbonitrile}and compare it to the typical 5-HT3 receptor antagonist, ondansetron. To determine the drug-likeness, computational experiments were conductedusing Molinspiration and Swiss ADME and toxicity profile using ProTox-IItools. Binding affinity of the test and standard drug with the 5-HT3 receptor (pdb id: 6HIS) was assessed by in-silico molecular modelling studies using AutoDoc Vina. Anxiolytic screening was performed using mouse elevated plus maze model. Both the test and standard drugs have good pharmacokinetic (ADME) and same level of toxicity profiles. The test drug, 6j, showed better binding affinity (-8.5 vs. -7.7 kcal/mol) with the receptor protein compared to ondansetron. In anxiolytic animal model, 6jand ondansetron showed anxiolytic potential at 10 mg/kg dose.

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial

BackgroundSYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms. ObjectivesWe evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD). MethodsIn a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI). ResultsEighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028). ConclusionsSYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study. RegistrationClinicaltrials.gov as NCT02258152.

Ondansetron-induced QT prolongation among various age groups: a systematic review and meta-analysis

BackgroundOndansetron is a selective 5-hydroxytryptamine type 3 serotonin-receptor antagonist with antiemetic properties used inadvertently in the emergency department for controlling nausea. However, ondansetron is linked with a number of adverse effects, including prolongation of the QT interval. Therefore, the purpose of this meta-analysis was to assess the occurrence of QT prolongation in pediatric, adult, and elderly patients receiving oral or intravenously administered ondansetron.MethodsA thorough electronic search was conducted on PubMed (Medline) and Cochrane Library from the databases' inception to August 10, 2022. Only those studies were considered in which ondansetron was administered orally or intravenously to participants for the treatment of nausea and vomiting. The prevalence of QT prolongation in multiple predefined age groups was the outcome variable. Analyses were conducted using Review manager 5.4 (Cochrane collaboration, 2020).ResultsA total of 10 studies involving 687 ondansetron group participants were statistically analyzed. The administration of ondansetron was associated with a statistically significant prevalence of QT prolongation in all age groups. An age-wise subgroup analysis was conducted which revealed that the prevalence of QT prolongation among participants younger than 18 years was not statistically significant, whereas it was statistically significant among participants aged 18–50 years and among patients older than 50 years.ConclusionsThe present meta-analysis provides further evidence that oral or intravenous administration of Ondansetron may lead to QT prolongation, particularly among patients older than 18 years of age.

Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats.

Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model. Selective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology. Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1-25 Hz; however, decreases in 25-40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT2A antagonist while other drugs had no effect. These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.