Receptor Antagonist Ondansetron Research Articles

Lycopene alleviates BCG-induced depressive phenotypes in mice by disrupting 5-HT3 receptor – IDO1 interplay in the brain

The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.

Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests—thermal gradient ring (5–30 °C, 5–50 °C, 15–40 °C, and 25–50 °C), dynamic cold plate (4 °C to −1 °C at −1 °C/min, −1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)—to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to −1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β2-adrenergic receptor antagonist (butoxamine), an α2-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.

Ondansetron and AS19 attenuate morphine tolerance by modulating serotonin 5-HT3 and 5-HT7 receptor expressions in rat dorsal root ganglia

PurposeOpioid drugs are frequently preferred drugs for severe pain, but their long-term use causes tolerance to their analgesic effects. However, the factors that contribute to the development of tolerance to opioids are diverse and not fully understood. In this study, our aim was to investigate the effects of 5-HT3 receptor antagonist ondansetron (ODN) and 5-HT7 receptor agonist AS19 on morphine analgesia and tolerance in rats. Material and methodsEighty-four randomly selected Wistar Albino (230–260 g) male rats were included in the study. To induce morphine tolerance in rats, morphine (10 mg/kg) was administered subcutaneously twice daily for 7 days, and tolerance was assessed by thermal analgesia tests on day 8 for 120 min. After thermal analgesia tests, dorsal root ganglia (DRGs) at spinal L4-S5 level were isolated. 5-HT3 and 5-HT7 receptor expressions in DRGs were measured by immunohistochemical method. ResultsThe results show that co-administration of ODN or AS19 with morphine indicated a significant increase in analgesic effect compared to morphine alone In addition, the difference between the mean of ODN or AS19 combined with morphine and the morphine-tolerant group was statistically significant. H-score analysis significantly increased 5-HT3 receptor expressions in the morphine-tolerant rats, and administration of ODN prevented this. Similarly, 5-HT7 receptor expressions were significantly decreased in the morphine tolerant group, and the administration of AS19 increased this expression. ConclusionThese study results suggest that both ODN and AS19 alter the 5-HT3 and 5-HT7 receptor expressions in the DRG and possibly attenuate morphine tolerance in this way.

D2 dopamine receptor-mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine.

The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions.

Prophylactic anti-emetic use to counter opioid adverse effects in the emergency department: Is it doing more harm than good?

Madam, Pain is a subjective and multifaceted issue in the ER that presents in both acute and chronic versions. Patients often present in the ER with complaints of pain and are assessed by physicians and hospital staff immediately for pain-relief medication. In recent studies it was proved that complaints of pain have an emerging high prevalence. In a study comprising of 1665 patients, 61.2% had pain mentioned and recorded on the chart, 34.1% did not have pain, and 4.7% were procedures. The Pain was a chief complaint for 52.2% of the visits1. The most common manner of treatment in the ER for pain management is the use of analgesic medicine, especially in the category of opioids. The most common parenteral opioids administered in trauma centres and emergency departments are meperidine, fentanyl, morphine, and hydromorphone. Although opioids serve a very integral and pivotal role in alleviating the pain in patients, it has certain adverse effects, including respiratory depression, drowsiness, pruritis, nausea and vomiting2, of which nausea and vomiting tend to be the most recurrent and frequent concerns. Patients feel that the severity of these side effects is more important than controlling the pain itself. For this reason, physicians routinely prescribe anti-emetic prophylaxis along with opioid medication. Anti-emetic categories used to prevent these side effects include Serotonin receptor antagonists (Ondansetron), Dopamine receptor antagonists (Metoclopramide) and Neurokinin receptor antagonists (aprepitant)3. Conversely, these anti-emetics have drastic adverse effects including, constipation or diarrhoea, headache, fatigue, blurred vision and dry mouth. However, serotonin and neurokinin inhibitors’ side effects of headaches and constipation are more pronounced4. Recently, a study on 3785 individuals and after removing duplicate copies, 3157 were not aligned with the scope of the review, so they were removed during the preliminary screening stage. Eight articles were reviewed and three studies were selected for inclusion. This meta-analysis did not exhibit positive findings for anti-emetics having prophylactic effects on patients given opioid pain management. Hence, this analysis showed that antiemetic treatment with opioids did not affect the risk of nausea or vomiting5. Conclusively, as a result of the abovementioned meta-analysis, it is imperative to understand that anti-emetics gives little benefit to the patient and do not alleviate side effects. Instead, they outweigh the analgesic benefits of giving opioids altogether, not just by causing discomfort but also by eliminating the cost-effectiveness of the medical treatment regimen.

Antidepressant Potential of a Functionalized 3-Selanyl Benzo[b]Furan Compound in Mice: Focus on the Serotonergic System.

The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[b]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) was then selected. Dose-response and time-response curves revealed that SeBFZ3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT1A; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/C; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT3; 1 mg/kg, i.p.) blocked the SeBZF3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study.

Basic studies show that selective 5-hydroxytryptamine type 3 (5-HT3) serotonin-receptor antagonists can protect organs from inflammatory injury and have shown lung protection. Whether 5-HT3 receptor antagonists ondansetron benefits patients with mechanical ventilation is unclear in the intensive care unit (ICU). The Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was reviewed to identify patients on mechanical ventilation (aged >16 years) in the ICU, which was divided into two groups according to whether ondansetron is used. Demographic characteristics, medical history data, clinical parameters, diagnosis and treatment measures were included as covariates. Ondansetron use was defined as any kind of ondansetron administration regardless of the dose before the induction of mechanical ventilation. The primary outcome was in-hospital death. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by multivariable Cox regression. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to further adjust for confounding factors. Kaplan-Meier (KM) curves with log-rank test were also performed. A total of 18,566 patients on mechanical ventilation were included (5,735 with ondansetron use). The overall in-hospital mortality rate of patients on mechanical ventilation was 18.9% (3,512/18,566). Approximately 13.0% (746/5,735) and 21.6% (2,766/12,831) in-hospital mortality rates occurred in the ondansetron and non-ondansetron use groups, respectively. Multivariable regression indicated that ondansetron usage was associated with a 33% and 32% lower risk of in-hospital and 60-day death (HR =0.77, 95% CI: 0.70-0.85, P<0.001; HR =0.68, 95% CI: 0.62-0.75, P<0.001) in the whole sample. Multivariable regression post-PSM indicated that ondansetron usage was associated with a 38% and 31% lower risk of in-hospital and 60-day death (HR =0.62, 95% CI: 0.56-0.68, P<0.001; HR =0.69, 95% CI: 0.62-0.77, P<0.001). Log-rank test for the KM curve of ondansetron and 60-day death was statistically significant (P<0.001). The duration of ventilator use pre- and post-PSM was statistically different (P<0.001 and P=0.007) in the two groups. Ondansetron usage was significantly associated with a lower mortality risk of ventilated patients in the ICU. The 5-HT3 receptor antagonist use is may be new potential adjunctive therapeutic strategy for patients on mechanical ventilation in the ICU.

Nicotine neurotoxicity exacerbation following engineered Ag and Cu (50-60nm) nanoparticles intoxication. Neuroprotection with nanowired delivery of antioxidant compound H-290/51 together with serotonin 5-HT3 receptor antagonist ondansetron.

Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking that is about 12.8% higher than civilian populations. Nicotine smoking triggers oxidative stress and are linked to several neurodegenerative diseases such as Alzheimer's disease. Nicotine neurotoxicity induces significant depression and oxidative stress in the brain leading to neurovascular damages and brain pathology. Thus, details of nicotine neurotoxicity and factors influencing them require additional investigations. In this review, effects of engineered nanoparticles from metals Ag and Cu (50-60nm) on nicotine neurotoxicity are discussed with regard to nicotine smoking. Military personnel often work in the environment where chances of nanoparticles exposure are quite common. In our earlier studies, we have shown that nanoparticles alone induces breakdown of the blood-brain barrier (BBB) and exacerbates brain pathology in animal models. In present investigation, nicotine exposure in with Ag or Cu nanoparticles intoxicated group exacerbated BBB breakdown, induce oxidative stress and aggravate brain pathology. Treatment with nanowired H-290/51 a potent chain-breaking antioxidant together with nanowired ondansetron, a potent 5-HT3 receptor antagonist significantly reduced oxidative stress, BBB breakdown and brain pathology in nicotine exposure associated with Ag or Cu nanoparticles intoxication. The functional significance of this findings and possible mechanisms of nicotine neurotoxicity are discussed based on current literature.

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Background: Basic studies show that selective 5-hydroxytryptamine type 3 (5-HT3) serotonin-receptor antagonists can protect organs from inflammatory injury and have shown lung protection. Whether 5-HT3 receptor antagonists ondansetron benefits patients with mechanical ventilation is unclear in the intensive care unit (ICU).

Intranasal ondansetron microemulsion counteracting the adverse effects of cisplatin: animal study

BackgroundCisplatin is considered one of the most effective and commonly used chemotherapeutic drugs, but despite its high therapeutic effectiveness, most patients treated with cisplatin suffer from nausea and vomiting, neurotoxic side effects, and cerebral psychiatric disorders such as depression. Therefore, the aim of the current work was to explore whether a selective 5-HT3 receptor antagonist (Ondansetron) administered via the oral route or intranasally in microemulsion form would alleviate cisplatin’s adverse effects.MethodsThe selected ondansetron microemulsion was characterized in vitro for particle size, polydispersity, zeta potential, morphology, and nasal permeation, and in vivo in terms of anti-emetic and antidepressant activity, with the assessment of biochemical markers in brain homogenates.ResultsResults revealed that both orally administered ondansetron and intranasally administered microemulsion were able to counteract the pica effect by increasing food consumption, water intake, and decreasing kaolin intake. They were also able to increase BDNF, normalize IL-6, increase serotonin, and normalize NOx, MDA, GSSH/GSH as well as 8OHdG levels in rats’ brain homogenates. The intranasal ondansetron microemulsion displayed superiority compared to oral conventional ondansetron in terms of increasing food intake, reduction of stomach content, and normalization of serotonin turnover.ConclusionOndansetron microemulsion can be administered by an alternative route of administration (intranasal) rather than oral, for patients on cisplatin chemotherapy.Graphical

5-HT3 receptors modulate changes in voiding pattern and bladder contractility in water avoidance stress-induced bladder overactivity in male mice.

Chronic psychological stress aggravates painful bladder syndrome symptoms. Previous studies suggest roles of 5-HT3 receptors in regulating micturition and bladder hypersensitivity. This study aimed to investigate the roles of 5-HT3 receptors in modulating voiding patterns and spontaneous bladder contractile properties in water avoidance stress-induced mice. Voiding patterns in sham stress (SS), water avoidance stress (WS), and water avoidance stress with daily oral gavage of ondansetron (1mg/kg BW) (WA) groups were analyzed after exposure to repeated water avoidance stress for 10days. Changes in contractile activity of isolated bladder in response to KCl, carbachol, and 5-hydroxytryptamine were determined. Bladder mast cell quantification was examined using toluidine blue staining. Urine voided area was significantly decreased in WS group after exposure to 10days of the stress protocol, which was reversed in the WA group. The WS group had a higher number of urine spots than the SS group. Increased mast cell degranulation was observed in the stressed mice. Bladder strips of the WS group showed higher tonic and amplitude of spontaneous contraction than the SS group, which were normalized by ondansetron administration. Increased response to carbachol-induced bladder contraction was observed in the bladder of stressed mice, which was attenuated with ondansetron pre-incubation. Water avoidance stress-induced mice exhibited changes in voiding pattern, which was reversed by oral administration with a 5-HT3 receptor antagonist (ondansetron). Enhanced contractile response to cholinergic stimulation in the urinary bladder of the psychological stress-induced bladder overactivity was mediated through 5-HT3 receptors.

Optimizing a therapy for opiate use disorders: Characterizing ondansetron pharmacokinetics in blood and brain.

Administration of a widely used 5-hydroxytryptamine receptor (5HT3A R) antagonist (ondansetron) potently inhibited the development of experimentally induced opioid dependence and withdrawal responses in mice and humans. However, in several studies examining withdrawal symptoms in subjects with chronic opioid use disorders (OUDs), ondansetron exhibited reduced or absent efficacy. Because attenuation of opioid withdrawal symptomatology is mediated within the brain, this study examined single-dose ondansetron pharmacokinetics in the blood and brain of mice. We demonstrate that ondansetron concentrations in the brain (Cbrain ng/mg) are 1000-fold lower than the blood concentrations (Cblood ng/ml) and decrease rapidly after ondansetron administration; and that a large percentage of brain ondansetron remains in the ventricular fluid. These results indicate that the ondansetron dose, and the time window between ondansetron and opioid administration, and when withdrawal is assessed are critical considerations for clinical studies involving subjects with chronic OUD. The pharmacokinetic results and the dosing considerations discussed here can be used to improve the design of subsequent clinical trials, which will test whether a more prolonged period of ondansetron administration can provide a desperately needed therapy that can prevent the development of neonatal opioid withdrawal syndrome in babies born to mothers with chronic OUD.

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20μmol/L) and palosetron (10μmol/L), but not 5-HT3 receptor agonist m-CPBG (30μmol/L) and SR 57,727 (10μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10μmol/L) and eptapirone (10μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10μmol/L) and p-MPPI (10μmol/L). Intrathecal injection of ondansetron (0.1mg/kg) but not m-CPBG (0.1mg/kg), 8-OH DPAT (0.1mg/kg), and WAY-100635 (0.1mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Peripheral N-methyl-d-aspartate receptor activation contributes to monosodium glutamate-induced headache but not nausea behaviours in rats

Monosodium glutamate induces behaviors thought to reflect headache and nausea in rats. We explored the effects of the N-methyl-d-aspartate receptor antagonist (2R)-amino-5-phosphonovaleric acid, the inotropic glutamate receptor antagonist kynurenic acid, and the CGRP receptor antagonist olcegepant, on monosodium glutamate-induced increases in nocifensive, headache-like and nausea behaviours. Effects of these antagonists on motor function were examined with a rotarod. The effect of the dopamine receptor antagonist metoclopramide and the serotonin 3 receptor antagonist ondansetron on nausea behaviour was also assessed. (2R)-amino-5-phosphonovaleric acid, and to a lesser extent, kynurenic acid and olcegepant, reduced nocifensive and headache-like behaviours evoked by monosodium glutamate. No alteration in motor function by (2R)-amino-5-phosphonovaleric acid, kynurenic acid or olcegepant was observed. No sex-related differences in the effectiveness of these agents were identified. Nausea behaviour was significantly more pronounced in male than in female rats. Olcegepant, ondansetron and metoclopramide ameliorated this nausea behaviour in male rats. Ondansetron and metoclopramide also reduced headache-like behaviour in male rats. These findings suggest that peripheral N-methyl-d-aspartate receptor activation underlies monosodium glutamate-induced headache-like behaviour but does not mediate the nausea behaviour in rats.

Olanzapine versus fosaprepitant for prevention of chemotherapy induced nausea and vomiting in patients receiving carboplatin (AUC ≥ 4) containing chemotherapy regimen: A phase 3 randomized, double-blind, placebo-controlled trial.

TPS12149 Background: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse effect affecting quality of life of patients of cancer undergoing chemotherapy. Carboplatin alone or in combination with various other chemotherapy drugs is one of the most commonly used drug in solid malignancies. It is categorised as a highly emetogenic drug in doses above AUC≥4 and multiple past studies revealed high CINV incidence. Current international antiemetic guidelines suggest NK1 receptor antagonist based triplet drugs as an effective regimen of CINV control in these patients. However, the nausea control rates are largely inadequate. Olanzapine, an atypical antipsychotic drug, is another drug that has shown significant activity in CINV control and is an integral part of current chemotherapy induced emesis and nausea prevention. However, robust comparative studies of olanzapine based triplets with NK1 based combination have been lacking. Hence we planned this study to compare efficacy of olanzapine containing triplet with NK1 receptor antagonist (fosaprepitant) based triplet drug combination in a phase 3 randomised study. Methods: This study is an investigator initiated phase 3 prospective randomised double blind placebo controlled trial comparing efficacy of olanzapine, 5HT3 receptor antagonist(ondansetron) and dexamethasone (experimental arm) against fosaprepitant, 5HT3 receptor antagonist(ondansetron) and dexamethasone (standard arm) for prevention of CINV among chemo-naïve patients (aged ≥18 years) receiving carboplatin (AUC ≥4) based chemotherapy regimen. Primary objective is to compare the number of patients with no nausea during overall periods (0-120 hours post-chemotherapy). Secondary objectives are to compare complete response (no emetic episodes and no use of rescue medication) in the acute(0-24 hr), delayed(25-120 hr),overall periods(0-120 hr) and to assess the frequency of rescue medication use. The other secondary objective includes assessment of adverse events in both the arms. Statistical Design: Planned accrual is total 214 patients including 10% drop out rate. It is a superiority design with an absolute improvement of 20% in the proportion of patients with no nausea from a baseline prevalence of 40% in the standard arm and two sided alpha of 5% as well as power of 80%. Conduct to date :Study activation : March 2021. Enrolment : 138 subjects. Clinical trial information: CTRI/2021/03/032165.

Antidepressant-Like Effect of a Selenoindolizine in Mice: In Vivo and In Silico Evidence for the Involvement of the Serotonergic 5-HT2A/C Receptors.

The monoaminergic dysfunction plays a central role in major depressive disorder (MDD), a mental disturbance associated with constant feeling of sadness and lack of interest. The available treatments do not present a desirable efficacy and some of them provoke several adverse effects. In this context, organoselenium compounds and molecules containing the indolizine nucleus have demonstrated interesting pharmacological properties, including antidepressant-like effects. In this study, the antidepressant-like effect of 2-phenyl-1-(phenylselanyl)indolizine (SeI), a selenium-containing indolizine derivative, was investigated on the forced swimming test (FST) and on the tail suspension test (TST) in male Swiss mice. The involvement of the serotonergic system in this effect was also accessed. The selenium compound SeI (10-100 mg/kg, intragastrical (i.g.)) was administered 0.5 h before the behavioral tests, and it diminished the immobility on both FST and TST experiments, which is an indication of antidepressant-like effect. No changing in the locomotor motion was observed in the open-field test (OFT). The anti-immobility effect of SeI was not altered by the preadministration of the selective serotonergic receptor antagonists ondansetron (1 mg/kg, intraperitoneally (i.p.), antagonist of 5-HT3 receptor) and WAY100635 (0.1 mg/kg, subcutaneous route (s.c.), antagonist of 5-HT1A receptor). In contrast, the preadministration of ketanserin (1 mg/kg, i.p., antagonist of 5-HT2A/C receptor) blocked this effect, demonstrating that the antidepressant-like effect of SeI involves 5-HT2A/C. In addition, molecular docking studies showed a strong interaction between SeI and the receptors of 5-HT2A and 5-HT2C. The toxicological results demonstrated that SeI has low potential to cause adverse effects in mice. It was found that the antidepressant-like effect of SeI is related to modulation of the serotonergic system, and this selenium compound could be included in new treatment approaches for MDD.

Unique green chromatography method for the determination of serotonin receptor antagonist (Ondansetron hydrochloride) related substances in a liquid formulation, robustness by quality by design-based design of experiments approach.

Serotonin receptor antagonist drug Ondansetron hydrochloride injectable formulation containing all related substances was identified and quantified by a single, simple, sensitive, eco-friendly, and green high-performance liquid chromatography method. The disseverment of all impurities was achieved with the Discovery Cyano (250 × 4.6) mm, 5μm column. The gradient program was composed of pH 5.7 phosphate buffer as mobile phase A and acetonitrile as mobile phase B. The flow rate, column compartment temperature, and detection wavelengths were 0.9 mL/min, 30°C, and 216 nm, respectively. The method was validated as per current regulatory guidelines. The obtained %relative standard deviation for the precision results was between 0.55 and 2.72% for all impurities. The correlation coefficient values from the linearity experiment for impurities and analyte were more than 0.995. The accuracy results were obtained between 88.4 and 113.0% for all impurities. Both sample and standard solutions showed 24 h stability at benchtop and refrigerator conditions. All impurities and analytes met the specificity and mass balance for all forced degradation conditions. Quality-by-design-based design of experiments was utilized to establish the method's robustness. Method greenness was assessed by using the current advanced tool green analytical procedure index, National Environmental Methods Index, and analytical eco-scale.

Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population.

Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure. DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs). One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426). Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.

Comparison of Ramosetron, Ondansetron, and Granisetron in Attenuating Maternal Hypotension after Spinal Anesthesia in Patients Undergoing Lower Segment Caesarean Section

Abstract Background: Spinal anesthesia (SA) has many advantages in lower segment caesarean section (LSCS), but hypotension is the main issue that can be managed in different ways. This study was conducted to know the effectiveness of three intravenous serotonin receptor antagonists (ramosetron, ondansetron, and granisetron) in the prevention of bradycardia and hypotension during LSCS under SA. Patients and Methods: A total of 160 parturients posted for LSCS under SA were enrolled in this study and divided equally into four groups. Five minutes before SA, Group R received intravenous (IV) 0.3 mg ramosetron, Group O received 4 mg ondansetron IV, Group G received 1 mg granisetron IV, and Group S received IV normal saline. All solutions were diluted with normal saline to 5 mL to blind the drugs. Heart rate (HR), systolic and diastolic blood pressure, and mean arterial pressure were recorded. The total consumption of vasopressor and side effects were recorded. Results: The decrease in mean arterial pressure and mean HR was significantly lower in group R than other groups at all intervals (P &lt; 0.05). The incidence of hypotension was 25% in group R compared with 42.5%, 55%, and 72.5% in groups O, G, and S, respectively. Conclusion: Premedication with intravenous ramosetron significantly reduced hypotension, HR, and total vasopressor usage in LSCS parturients. Intravenous ondansetron and granisetron had lesser effects than ramosetron.

Spinal γ-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain

Systemic administration of morphine increases serotonin (5-HT) in the spinal dorsal horn (SDH), which attenuates the analgesic effects of morphine on neuropathic pain through spinal 5-HT3 receptors. We hypothesized that dysfunction of the descending serotonergic system, including the periaqueductal gray (PAG), contributes to attenuate the efficacy of morphine on neuropathic pain through spinal 5-HT3 receptors and GABA neurons. Morphine (100 ng) injected into the PAG produced analgesic effects in normal rats, but not in spinal nerve ligation (SNL) rats. In vivo microdialysis showed that PAG morphine increased the SDH 5-HT concentration in both groups. Intrathecal injection of the 5-HT3 receptor antagonist ondansetron and the GABAA receptor antagonist bicuculline attenuated the analgesic effects of PAG morphine in normal rats, but increased the effects in SNL rats. The increased analgesic effect of PAG morphine induced by bicuculline was reversed by pretreatment with the tropomyosin receptor kinase B (TrkB) antagonist K252a. Activation of spinal 5-HT3 receptors by 2-methyl-5-HT increased the GABA concentration in both groups. Morphine activates GABAergic interneurons in the SDH by activating descending serotonergic neurons. Functional changes in GABAA receptors from inhibitory to facilitatory through the activation of TrkB receptors may contribute to the attenuated efficacy of morphine against neuropathic pain. PerspectiveAlthough morphine provides strong analgesia against acute pain, it has limited efficacy against neuropathic pain. This article demonstrates that functional changes in GABAA receptors in the spinal dorsal horn after nerve injury might strongly contribute to the attenuation of opioid-induced analgesia for neuropathic pain.