5-HT3 Antagonist Research Articles

One Pot Synthesis and Pharmacological Evaluation of Aryl Substituted Imidazoles as Potential Atypical Antipsychotics

Background: Second generation or “atypical” antipsychotics demonstrate an improved therapeutic profile over conventional neuroleptics. These are effective in both positive and negative symptoms of the disease and have a lower propensity to induce adverse symptoms. Objective: The main objective of the research was in silico design and synthesis of potential atypical antipsychotics with combined antiserotonergic / antidopaminergic effect. Methods: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in animal models for dopaminergic and serotonergic antagonism. The compounds were designed based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to 5-HT2A and D2 receptors. Results: Results from the docking studies with respect to 5-HT2A and D2 receptors suggested a potential atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggested a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential atypical profile for the test compounds 1-5. Further, the activity of compounds in DOI assay indicated a 5-HT2 antagonistic profile (5-HT2 antagonism). Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic and antiserotonergic (5-HT2A) activity with a potential atypical antipsychotic profile.

The efficacy of aprepitant in salvage treatment of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy for patients with gastrointestinal cancer.

To evaluate the efficacy of aprepitant and its effect on the quality of life when added to standard antiemetic therapy as salvage therapy. This is an open-label, noncomparative prospective phase II clinical trial. A total of 224 patients receiving initial moderately emetogenic chemotherapy (MEC) were enrolled. Patients received standard antiemetic treatment (5-hydroxytryptamine (5-HT3) antagonists + dexamethasone) in the first cycle. Patients failing to achieve a complete response (CR) during cycle 1 entered cycle 2 with the addition of aprepitant as salvage treatment. Of the 224 patients eligible for cycle 1, 159 (71.0%, 95% CI 65.0-77.0) had a CR, and 65 patients with a noncomplete response (NCR) proceeded to cycle 2 to receive aprepitant-based salvage therapy. Then, 49 (75.4%, 95% CI 64.6-84.1) of these patients achieved a CR. The Functional Living Index-Emesis (FLIE) questionnaire showed that NCR patients in cycle 1 had an improved quality of life after receiving aprepitant-based salvage therapy in cycle 2 (cycle 1 and 2: 80.3 vs 114.0, P < 0.001). Failing to achieve a CR had a significant impact on the quality of life in both cycle 1 (FLIE score of NCR and CR patients: 80.3 vs 119.7, P < 0.001) and cycle 2 (FLIE score of NCR and CR patients: 88.3 vs 122.4, P < 0.001). The addition of aprepitant as salvage therapy for patients with gastrointestinal cancer is effective and has a positive effect on quality of life.

Human corticospinal-motoneuronal output is reduced with 5-HT2 receptor antagonism.

Animal models indicate that serotonin (5-HT) release onto motoneurons facilitates motor output, particularly during strong motor activities. However, evidence for 5-HT effects during human movement are limited. This study examined how antagonism of the 5-HT2 receptor, which is a 5-HT receptor that promotes motoneuron excitability, affects human movement. Ten healthy participants (24.2 ± 1.9 yr) ingested 8 mg of cyproheptadine (competitive 5-HT2 antagonist) in a double-blinded, placebo-controlled, repeated-measures design. Transcranial magnetic stimulation (TMS) of the motor cortex was used to elicit motor evoked potentials (MEPs) from biceps brachii. First, stimulus-response curves (90%-160% active motor threshold) were obtained during very weak elbow flexions (10% of maximal). Second, to determine if 5-HT effects are scaled to the intensity of muscle contraction, TMS at a fixed intensity was applied during elbow flexions of 20%, 40%, 60%, 80%, and 100% of maximal. Cyproheptadine reduced the size of MEPs across the stimulus-response curves (P = 0.045). Notably, MEP amplitude was 22.3% smaller for the cyproheptadine condition for the strongest TMS intensity. In addition, cyproheptadine reduced maximal torque (P = 0.045), lengthened the biceps silent period during maximal elbow flexions (P = 0.037), and reduced superimposed twitch amplitude during moderate-intensity elbow flexions (P = 0.035). This study presents novel evidence that 5-HT2 receptors influence corticospinal-motoneuronal output, which was particularly evident when a large number of descending inputs to motoneurons were active. Although it is likely that antagonism of 5-HT2 receptors reduces motoneuron gain to ionotropic inputs, supraspinal mechanisms may have also contributed to the study findings.NEW & NOTEWORTHY Voluntary contractions and responses to magnetic stimulation of the motor cortex are dependent on serotonin activity in the central nervous system. 5-HT2 antagonism decreased evoked potential size to high-intensity stimulation, and reduced torque and lengthened inhibitory silent periods during maximal contractions. We provide novel evidence that 5-HT2 receptors are involved in muscle activation, where 5-HT effects are strongest when a large number of descending inputs activate motoneurons.

Regioselective assembly of fused pyrazole-azepine heterocycles: Synthesis of the 5-HT7 antagonist 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine

The synthesis of the 5-HT7 antagonist 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine is described using a regioselective assembly of a pyrazole ring fused to an azepine ring. Two different approaches were examined for the construction of the fused pyrazole-azepine heterocyclic core. These were based on the timing and method of installation of the appended aryl ring and construction of the fused heterocycle. The team focused on a route that featured a palladium coupling reaction to introduce the aryl ring via a pyrazole triflate and a selective alkylation to set the position of benzyl moiety on the pyrazole nitrogen. This led to a scalable synthesis of 1 (JNJ-18038683) allowing the discovery team to select and advance a clinical candidate.

Role of peripheral 5-HT1D, 5-HT3 and 5-HT7 receptors in the mechanical allodynia induced by serotonin in mice

Serotonin (5-HT) acts as a neurotransmitter in the central nervous system (CNS) and as a mediator released by enterochromaffin cells to regulate intestinal motility. However, this amine also plays an important role as an inflammatory mediator and induces phenotypic changes of nociceptors. Despite the wide knowledge of the role of 5-HT in nociception, most studies have focused on its role in the CNS, while a clear information about its role in peripheral tissues is still lacking. In the present study, we investigated the role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan in mice by using antagonists that target different 5-HT receptors. Mechanical nociceptive threshold was measured with an analgesimeter and evaluated after intraplantar (i.pl.) injection of 5-HT or carrageenan. 5-HT antagonists were injected via the i.pl. route. 5-HT (10, 20, 40 or 80 μg/paw) or carrageenan (100 μg/paw) induced mechanical allodynia. Pretreatment with isamoltane (5 μg; 5-HT1B antagonist) or ketanserine (1 μg; 5-HT2A antagonist) did not affect the mechanical allodynia induced by 5-HT. This response was inhibited by BRL 15572 (10 μg; 5-HT1D antagonist) or SB 269970 (25 μg; 5-HT7 antagonist). On the other hand, mechanical allodynia induced by 5-HT or carrageenan was exacerbated by ondansetron (10, 20 or 40 μg; 5-HT3 antagonist). The results indicate that activation of 5-HT1D and 5-HT7 receptors plays a role in the mechanical allodynia induced by 5-HT in mice. This study also demonstrates the inhibitory role of peripheral 5-HT3 receptors in the nociceptive response induced by 5-HT or carrageenan.

Zingiber officinale Roscoe Rhizomes Attenuate Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 μg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 μg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 μg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain.

Drug design of new 5-HT6R antagonists aided by artificial neural networks

Alzheimer’s Disease (AD) is the most frequent illness and cause of death amongst the age related-neurodegenerative disorders. The Alzheimer’s Disease International (ADI) reported in 2019 that over 50 million people were living with dementia in the world and this number could potentially be around 152 million by 2050.5-hydroxtryptamine subtype 6 receptor (5-HT6R) has been identified as a potential anti-amnesic drug target and therefore, the administration of 5-HT6R antagonists can likely mitigate the memory loss and intellectual deterioration associated with AD. Herein, computational tools were applied to design new 5-HT6 antagonists and their biological activity values were predicted by our QSAR model obtained from Artificial Neural Networks (ANN). The proposed compounds here from the QSAR-ANN model presented significant biological activity values and some of them have achieved pKi above 9.00. Furthermore, our results suggest that the presence of halogen atoms (especially bromine) linked to the aromatic ring at para-position (HYD) contribute considerably to the increase of the biological activity values while bulky groups in the PI position do not culminate with the increase antagonist activity of compounds here analyzed. Finally, the ADME/Tox profile as well as the synthetic accessibility of new proposed compounds qualify them to go on further with experimental procedures and thenceforward their antagonist effects can be confirmed.

Neuropeptide W, an endogenous NPBW1 and NPBW2 ligand, produced an analgesic effect via activation of the descending pain modulatory system during a rat formalin test.

Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we examined whether NPW microinjected into the descending pain inhibitory system, such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM), produces an analgesic effect using a rat formalin test. Microinjections of NPW into the PAG ipsilateral and contralateral to the formalin-injected side, LC ipsilateral and contralateral to the formalin-injected side, and RVM produced an analgesic effect. In the RVM study, the analgesic effect was antagonized by WAY100135, a 5-HT1A antagonist, and enhanced by prazosin, an α1 antagonist, and SB269970, a 5-HT7 antagonist. Naloxone, an opioid antagonist, also antagonized the effect of NPW in the RVM study. In the ipsilateral LC study, the analgesic effect was antagonized by WAY100135, idazoxan, an α2 antagonist, and naloxone and was enhanced by prazosin and SB269970. In the contralateral LC study, the analgesic effect was antagonized by prazosin, idazoxan, SB269970, and naloxone. The analgesic effect was antagonized by WAY100135, SB269970, idazoxan, and naloxone in the ipsilateral and contralateral PAG studies. These findings strongly suggest that NPBW1/W2 activation by NPW microinjection into the RVM, LC, and PAG affect the descending pain modulatory system and produce anti-nociceptive and pro-nociceptive effects in the rat formalin test.

COVID-19 Pathophysiology: Are Platelets and Serotonin Hiding in Plain Sight?

Established evidence suggests that in ARDS, platelets may exhibit a dysregulated state that exacerbates lung injury. We review evidence that suggests this platelet-mediated lung injury, while present in ARDS in general, is amplified in COVID-19 ARDS in particular. Driven by a quantifiably higher degree of platelet activation and ensuing platelet serotonin liberation into plasma compared to ARDS of other etiologies, the plasma serotonin excess in COVID-19 may be responsible for many of the devastating pulmonary and extra-pulmonary clinical manifestations of the severe disease. There is ample evidence and biologic plausibility to suggest that effective serotonin receptor (5HT-2) antagonism may reverse serotonin-mediated pulmonary vasoconstriction, lessen pulmonary platelet trapping, inhibit platelet activation and aggregation, normalize increased respiratory drive, mitigate risk of pulmonary fibrosis, and counteract adverse renal, neurologic, and cardiovascular phenomena in severe COVID-19. Given we have a well-tolerated, safe, and inexpensive oral 5HT-2 antagonist, cyproheptadine, we hope to build consensus for the need to urgently investigate 5HT-2 receptor antagonism as a treatment option for severe COVID-19.

Comparison of intravenous ramosetron and ondansetron as prophylaxis for postoperative nausea and vomiting following general anesthesia

Objective: To compare the efficacy and side effects of 5HT3 antagonists, ramosetron, and ondansetron as prophylaxis for postoperative nausea and vomiting (PONV) following general anesthesia. Materials and Methods: One hundred and ten patients of the American Society of Anesthesiology Grade I–II, between the age group of 18 to 60 years weighing 40 to 70 kg, undergoing general anesthesia were studied. Group 1 received ramosetron 0.3 mg intravenous (IV) and Group 2 received ondansetron 8 mg IV 15 min before the end of surgery. The incidence of PONV, need for rescue antiemetic, and side effects were evaluated in both the groups. QTc interval prolongation was also evaluated in both the groups by taking electrocardiograms at regular intervals. Results: This study showed that there was no statistically significant difference in the incidence of PONV between the ondansetron group and the ramosetron group during the first 24 h after surgery. For PONV score of ≥2 during the first 6 h, the incidence was 3.59% and 1.81% for ramosetron and ondansetron, respectively, and during 6–24 h, the incidence was 1.81% for both the drugs. Conclusion: IV ramosetron 0.3 mg is as effective as IV ondansetron 8 mg in preventing PONV in patients undergoing general anesthesia.

Efficacy of ondansetron and palonosetron in prevention of shivering under spinal anesthesia: A prospective randomized double-blind study in patients undergoing elective LSCS.

Background and Aims:Postanesthesia shivering (PAS) is a common, distressing experience. Ondansetron, the classical 5HT3 antagonist has been in use for its prevention since long. Palonosetron, a newly introduced potent antiemetic drug with better pharmacodynamics is currently in use by clinicians. Hence, a study was conducted to compare the efficacy of ondansetron and palonosetron in preventing PAS in patients undergoing elective lower segment caesarean section (LSCS) under spinal anaesthesia.Material and Methods:A total of 84 patients scheduled for elective LSCS under spinal anesthesia were randomly allocated to one of the two study groups (Group O & P). Accordingly, 8 mg of ondansetron or 0.075 mg palonosetron was administered in the same volume intravenously 30 min preoperatively. Sublingual temperature was recorded regularly. All patients were observed for 90 min postspinal for PAS. Observations were analyzed statiscally.Results:No statistically significant intergroup difference was observed in the duration of surgery, and sublingual temperature. However, statistically significant difference was recorded for PAS (23.8% in ondansetron group, 9.5% in palonosetron group).Conclusion:Prophylactic administration of palonosetron significantly reduced incidence of PAS compared to ondansetron. However, further studies with larger sample size and more heterogeneous groups are suggested.

Comparative effectiveness of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: a network meta-analysis of randomized controlled studies.

BackgroundThere is evidence demonstrating the beneficial effects of 5-hydroxytryptamine 3 receptor antagonists (5-HT3) for the treatment of non-constipated irritable bowel syndrome (NC-IBS). We aimed to determine the comparative effectiveness of 5-HT3 antagonists in NC-IBS, as evidenced by the results of a network meta-analysis (NWM) of published relevant randomized controlled trials (RCTs).MethodsWe searched the PubMed/Medline, EMBASE, and Cochrane Library databases for relevant RCTs through September 2020 and data from each selected RCT were extracted. A Bayesian NWM was then performed to investigate the efficacy of 5-HT3 antagonists and to explore the effectiveness rank order in treating NC-IBS patients.ResultsTwenty-one eligible RCTs were identified and entered into this NWM. They included a total of 10,421 NC-IBS patients, randomized to alosetron, cilansetron, ondansetron, ramosetron, placebo, and mebeverine. The cumulative ranking probability for each intervention at the end of treatment period, was evaluated by means of surfaces under cumulative ranking (SUCRA) values. These results showed that alosetron had the best performance for global symptom improvement (SUCRA 0.82), cilansetron showed the best performance (SUCRA 0.90) for abdominal pain/discomfort improvement, while ondansetron (SUCRA 0.98) was by far the best choice concerning bowel habits/consistency improvement. The control regimens (mebeverine and placebo) represented the least efficacious interventions.ConclusionsThis NWM showed that 5-HT3 receptor antagonists performed better in comparison to control drugs. Consequently, this class of drugs may play an important role in improving the debilitating symptoms in NC-IBS patients, in particular those with diarrhea.

Rotatory nystagmus after granisetron administration

Background: Granisetron is a popular antiemetic medication used in the emergency department to control nausea and vomiting with an excellent side effect profile among adults and pediatric, in both healthy and oncology patients. Case Presentation: Our patient received granisetron for nausea and vomiting then developed torsional nystagmus, asymmetrical abnormal muscle contractions, and electrocardiography showed QTc prolongation 487 ms. The patient did improve after IV lorazepam and magnesium sulphate administration. Conclusion: QTc prolongation increases the risk of developing Torsades de Pointes and sudden death. Extrapyramidal syndrome caused by granisetron is rare and should not be confused with seizure. Both are significant effects associated with 5-HT3 antagonists administration to be aware of and if they occurred, should be managed in a timely fashion.

Granisetron, a selective 5-HT3 antagonist, reduces L-3,4-dihydroxyphenylalanine-induced abnormal involuntary movements in the 6-hydroxydopamine-lesioned rat.

Administration of L-3,4-dihydroxyphenylalanine (L-DOPA) provides Parkinson's disease patients with effective symptomatic relief. However, long-term L-DOPA therapy is often marred by complications such as dyskinesia. We have previously demonstrated that serotonin type 3 (5-HT3) receptor blockade with the clinically available and highly selective antagonist ondansetron alleviates dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to explore the antidyskinetic efficacy of granisetron, another clinically available 5-HT3 receptor antagonist. Rats were rendered hemi-parkinsonian by 6-OHDA injection in the medial forebrain bundle. Following induction of stable abnormal involuntary movements (AIMs), granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle was acutely administered in combination with L-DOPA and the severity of AIMs, both duration and amplitude, was determined. We also assessed the effect of granisetron on L-DOPA antiparkinsonian action by performing the cylinder test. Adding granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) to L-DOPA resulted in a significant reduction of AIMs duration and amplitude, with certain parameters being reduced by as much as 38 and 45% (P < 0.05 and P < 0.001, respectively). The antidyskinetic effect of granisetron was not accompanied by a reduction of L-DOPA antiparkinsonian action. These results suggest that 5-HT3 blockade may reduce L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. However, a U-shaped dose-response curve obtained with certain parameters may limit the therapeutic potential of this strategy and require further investigation.

Effectiveness of Granisetron in Prevention of Hypotension Following Spinal Anaesthesia in Patients Undergoing Elective Caesarean Section.

Background and aim: Spinal anesthesia is the most common type of anesthesia administered for caesarean section and it is frequently associated with hypotension. When post-spinal hypotension is accompanied with bradycardia, the condition may become more complicated. Numerous pharmacological agents have therefore been tried for prevention of hypotension and 5HT3 antagonists are the latest in the armamentarium. However, studies have shown conflicting evidence regardings the effectiveness of 5HT3 inhibitors (ondansetron and granisetron) in preventing spinal hypotension. We have tried to address this controversy and also wanted to explore the adverse effects of granisetron on the foetus, if any.Materials and methods: Two hundred patients were included in the study and divided into two groups of 100 patients each. Group S patients received 5ml of 0.9% normal saline while Group G patients received IV granisetron 1mg (diluted to 5ml) 10 minutes prior to administration of spinal anesthesia. Analysis of variance (ANOVA) test was used for comparing the data, Student t-test was applied to compare the difference between the two means and Chi-Square test was used to test significance of difference of proportions.Results: The incidence of hypotension in Group S was 69%, whereas it was 37% in Group G (p<0.001), hence patients of Group S required a significantly higher (p=0.001) amount of mephentermine. Haemodynamic parameters were well maintained throughout the study period in patients of Group G. The neonatal outcome was assessed by Apgar score at 0 minutes, one minute, and five minutes after delivery, and it was comparable between the two study groups.Conclusion: Intravenous granisetron 1mg if administered before administering spinal anesthesia can effectively attenuate hypotension in parturients without any adverse effects on the mother and the neonate.

Gastrointestinal Events and Management Strategies for Patients with Acute Myeloid Leukemia (AML) in First Remission Receiving CC-486 in the Randomized, Placebo-Controlled, Phase III QUAZAR AML-001 Maintenance Trial

INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001. METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory. RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55-86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization. Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1-2, 3-4, and 5-6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients. DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes. Disclosures Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag:Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah:Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase:Novartis Australia: Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dombret:Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.

P.467 Safety, pharmacokinetics, and pharmacodynamics of LB-102, a selective D2 / 5-HT7 antagonist, in healthy volunteers

P.467 Safety, pharmacokinetics, and pharmacodynamics of LB-102, a selective D2 / 5-HT7 antagonist, in healthy volunteers

Analgesic and Antiallodynic Effects of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide in a Murine Model of Pain.

IntroductionPhysical, chemical, thermal injuries along with infectious diseases lead to acute pain with associated inflammation, being the primary cause of hospital visits. Moreover, neuropathic pain associated with diabetes is a serious chronic disease leading to high morbidity and poor quality of life.ObjectiveEarlier multiple sulphonamides have been reported to have an antinociceptive and antiallodynic profile. 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS), a synthetic sulfonamide with reported carbonic anhydrase inhibitory activity, was investigated for its potential effects in mice model of acute and diabetic neuropathic pain.Methods and Results4-FBS was given orally (p.o.) one hour before the test and then mice were screened for antinociceptive activity by using the tail immersion test, which showed significant antinociceptive effect at both 20 and 40 mg/kg doses. To explore the possible mechanisms, thermal analgesia of 4-FBS was reversed by the 5HT3 antagonist ondansetron 1mg/kg intraperitoneally (i.p.) and by the µ receptor antagonist naloxone (1 mg/kg i.p.), implying possible involvement of serotonergic and opioidergic pathways in the analgesic effect of 4-FBS. Diabetes was induced in mice by a single dose of streptozotocin (STZ) 200 mg/kg i.p. After two weeks, animals first became hyperalgesic and progressively allodynic in the fourth week, which was evaluated through behavioral parameters like thermal and mechanical tests. 4-FBS at 20 and 40 mg/kg p.o. significantly reversed diabetes-induced hyperalgesia and allodynia at 30, 60, 90, and 120 minutes.ConclusionThese findings are significant and promising while further studies are warranted to explore the exact molecular mechanism and the potential of 4-FBS in diabetic neuropathic pain.

Delirium And Visual Loss After İntravenous Ondansetron Application in a Pediatric Patient: A Case Report

Ondansetron is a selective 5-hydroxytryptamine receptor (5HT-3) antagonist caused by cancer treatment and put into clinical practice as an antiemetic for anesthesia-related nausea and vomiting. Delirium is an organic mental disorder that develops in a short period of time and manifests itself with impairments in various cognitive functions, especially consciousness. In this case report, we aimed to present the patient who presented to the another hospital due to vomiting, who received intravenous (IV) ondansetron treatment, followed by blurred consciousness and vision loss, and to draw attention to the side effects that may occur after ondansetron

Dexamethasone dosing for prevention of acute chemotherapy-induced vomiting in pediatric patients: A systematic review.

A systematic review was undertaken to describe dexamethasone doses studied for chemotherapy-induced vomiting (CIV) prophylaxis in pediatric patients and their effects on achieving complete acute CIV control. No dose-finding studies were identified. However, 16 studies assessing pediatric patients who received dexamethasone were included and classified according to the emetogenicity of chemotherapy administered. Eight different total daily dexamethasone doses were administered to patients on day 1 of highly emetogenic chemotherapy: three in conjunction with aprepitant/fosaprepitant plus a 5HT3 antagonist and five in conjunction with a 5HT3 antagonist. Five different total daily dexamethasone doses were administered in conjunction with a 5HT3 antagonist to patients on day 1 of moderately emetogenic chemotherapy. Due to the heterogeneity of studies identified, meta-analysis was not possible. The optimal dexamethasone dose to control acute CIV and to minimize harms in pediatric patients remains uncertain. This is a key area for future research.