Serotonin 5-HT3 Receptor Antagonists Research Articles

Recent Advances in the Treatment of Irritable Bowel Syndrome: Addressing Diarrhea, Constipation, and Abdominal Pain

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder characterized by abdominal pain, bloating, and changes in bowel habits. This paper aim was to provide an overview of recent advancements in the treatment of IBS, focusing on the management of its main symptoms: diarrhea, constipation, and abdominal pain. For individuals with IBS-D, various therapeutic options are available, including rifaximin, peripheral opioid agonists, mixed opioid agonists/antagonists, bile acid sequestrants, and serotonin 5-HT3 receptor antagonists. Rifaximin, a nonabsorbable antibiotic, has demonstrated significant effectiveness in reducing IBS symptoms, such as bloating and loose stools, with good tolerability and safety. Also the repeated use of rifaximin for managing recurrent IBS symptoms. In IBS-C patients, bulking agents, osmotic laxatives, and prokinetic agents like lubiprostone have shown efficacy in improving constipation and overall symptoms. Linaclotide, a drug that increases intestinal chloride secretion, has demonstrated significant improvement in bowel movements and abdominal pain in IBS-C patients. However, it may cause diarrhea in some individuals. IBS-M, characterized by alternating constipation and diarrhea, poses a challenge in terms of specific drug treatments. A comprehensive assessment of potential underlying causes and careful history taking is crucial for effective management. Abdominal pain is a common symptom in IBS, regardless of subtype. Antispasmodic drugs, peppermint oil, and trimebutine have shown effectiveness in reducing pain and improving symptoms. Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may offer relief by modulating pain pathways and influencing gastrointestinal motility. Benzodiazepines, particularly dextofisopam, have shown potential in improving stool consistency but require further evaluation. In conclusion, recent advancements in the treatment of IBS have provided a range of therapeutic options targeting its main symptoms. However, further research is needed to develop tailored treatments for specific IBS subtypes and to explore the efficacy of potential alternatives, including benzodiazepines. Improved management of IBS symptoms can significantly enhance the quality of life for affected individuals.

Risperidone Associated With Acute Pulmonary Thromboembolism: A Case Report

Antipsychotic drugs (APs) are widely used drugs for schizophrenia. For decades, these agents are frequently associated with some side-effects, including increased the risk of Venous Thromboembolism (VTE). A case of a man (53 years old) with schizophrenia was reported in this study. The man with no identified risk factor for thromboembolism, and developed Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT) after treatment with risperidone 2 years. The current case indicates that use of risperidone for long time can be associated with the risk of PTE and DVT. Risperidone is a Second-Generation Antipsychotic medication (SGA), as a mixed serotonin 5HT2 and dopamine D2 receptor antagonist possibly implicated in this adverse event. As suggested by this observation, VTE and PTE risk not just appears to new users, so they should be vigilant monitored to ensure early detection and prompt treatment of VET and PTE during medication.

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.

Hemorrhagic Posterior Reversible Encephalopathy Syndrome in a Patient With Larynx Carcinoma.

Significance Statement Posterior reversible encephalopathy syndrome (PRES) is characterized by variable neurological findings such as headache, deterioration in mental condition, loss of consciousness and visual loss. The disease results with impairment of the cerebral blood flow autoregulation. Ondansetron, serotonin (5HT-3) receptor antagonist, may cause the haemorrhagic PRES.

Stress induced exacerbation of Alzheimer's disease brain pathology is thwarted by co-administration of nanowired cerebrolysin and monoclonal amyloid beta peptide antibodies with serotonin 5-HT6 receptor antagonist SB-399885.

Alzheimer's disease is one of the devastating neurodegenerative diseases affecting mankind worldwide with advancing age mainly above 65 years and above causing great misery of life. About more than 7 millions are affected with Alzheimer's disease in America in 2023 resulting in huge burden on health care system and care givers and support for the family. However, no suitable therapeutic measures are available at the moment to enhance quality of life to these patients. Development of Alzheimer's disease may reflect the stress burden of whole life inculcating the disease processes of these neurodegenerative disorders of the central nervous system. Thus, new strategies using nanodelivery of suitable drug therapy including antibodies are needed in exploring neuroprotection in Alzheimer's disease brain pathology. In this chapter role of stress in exacerbating Alzheimer's disease brain pathology is explored and treatment strategies are examined using nanotechnology based on our own investigation. Our observations clearly show that restraint stress significantly exacerbate Alzheimer's disease brain pathology and nanodelivery of a multimodal drug cerebrolysin together with monoclonal antibodies (mAb) to amyloid beta peptide (AβP) together with a serotonin 5-HT6 receptor antagonist SB399885 significantly thwarted Alzheimer's disease brain pathology exacerbated by restraint stress, not reported earlier. The possible mechanisms and future clinical significance is discussed.

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.

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron is a serotonin (5HT3) receptor antagonist used for the prevention and treatment of postoperative nausea and vomiting. It is available in many dosage forms in the market. Various analytical methods used for the determination of Ondansetron have been studied in this review article such as UV spectroscopy, mass spectroscopy, high-performance liquid chromatography, high-performance thin layer chromatography, a new electrospray ionization mass spectrometry etc. Ondansetron in human plasma can be estimated using this method. With time many advances have been made in the formulation aspects of Ondansetron, such as now a days it is available in floating drug delivery, transdermal as well as gastroretentive and orodispersible drug delivery system. New novel technologies are also mentioned in this review article related to 3D printing, nanofibers etc

Effect of ondansetron for preventing of ovarian hyperstimulation syndrome: in an experimental rat model

Objective: Ovarian hyperstimulation syndrome is an iatrogenic condition that occurs in the treatment of infertility. There is no specific treatment available for OHSS. Cabergoline is a dopamine receptor 2 agonist and VEGF-VEGF2 receptor antagonist . Recently, cabergoline has been widely used to prevent the development of OHSS and reduce its severity Serotonin is known as a neurotransmitter and thought to have a role in the mechanism of angiogenesis and in signaling in endothelial cells. Serotonin is said to have similar effects to VEGF . Ondansetron is Selective Serotonin (5-HT3) Receptor Antagonist . It works by blocking the action of serotonin, a natural substance that may cause nausea and vomiting. In the clinical practice today, there is no choice other than cabergoline, to prevent occurrence and reduce severity of OHSS, and sometimes its effects are limited. Methods: In our study, we compared the effect of cabergoline and ondansetron. 32 immature rats were used and the OHSS model was created. Parameters such as hematocrit value , ovarian size, the number of follicles in the ovary, endometrial capillary congestion and thickness values were evaluated and compared. Results: As a result, in our study, it was seen that ondansetron was effective on OHSS in many parameters. It is thought to be as effective as cabergoline. When we look at the literature, this is the first study in which ondansetron was evaluated for this purpose. It would be good to show this effect of ondansetron with other studies.

Selective 5HT3 antagonists and sensory processing: a systematic review

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson’s disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide derivatives as selective serotonin 5-HT6 receptor antagonists: Design, synthesis, and biological evaluation

Serotonin 5-HT6 receptor, which is predominantly expressed in the central nervous system, is a valuable therapeutic target. Serotonin 5-HT6 receptor antagonists have potential for the treatment of various diseases that include psychotic disorders, dementia, depression, and obesity. In this study, we designed and synthesized the N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide-based library as a potential serotonin 5-HT6 receptor antagonist. The library was subjected to a series of binding affinity tests to identify the lead compound, and check the selectivity of test compounds towards the 5-HT6 receptor. Accordingly, compound 6m was identified as the most active compound, with IC50 = 87 nM. The binding affinity of 95.3% of 6m (10 μM) with the 5-HT6 receptor among other serotonin 5-HT1a, 5-HT2a, 5-HT2c, and 5-HT7, and dopamine receptors D1, D2, D3, and D4, demonstrated the high selectivity of 6m towards the 5-HT6 receptor.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, HEC30654, in Healthy Chinese Subjects.

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer’s disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects.Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples.Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4–12 h), t1/2 of 10–60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (<10%), and HEC30654 was mainly eliminated unchanged through feces.Conclusion: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated. Based on preclinical efficacy in various models of cognition, HEC30654 may represent a therapeutic option for symptomatic treatment of cognitive disorders.

Drug-Induced Immune Thrombocytopenia (DITP) Caused By Multiple Drug-Dependent Platelet-Reactive Antibodies (DDAbs) in Patients Undergoing Oxaliplatin-Containing Combination Chemotherapy for Metastatic Colon Cancer

DITP is caused by drug-dependent antibodies that bind to platelets and cause their destruction only when drug is present. The chemotherapeutic agents oxaliplatin (OX) and irinotecan (IR) are recognized causes of DITP. OX is often given every other week together with 5-fluorouracil (5-FU) and leucovorin (LE) (FOLFOX) without or with irinotecan (FOLFOXIRI). To prevent chemotherapy-induced nausea and vomiting, patients treated with these regimens are usually conditioned with anti-emetics, including serotonin 5-HT3 receptor antagonist, corticosteroids and anti-histamines. We characterized two patients treated for metastatic colon cancer with these regimens who acutely developed profound thrombocytopenia (TP) and bleeding requiring platelet transfusions after 20 and 18 cycles of treatment, respectively. In each case, platelets returned to normal in about one week. On the suspicion that TP was caused by DDAbs, OX (Patient 1) and IR (Patient 2) were omitted from the next round of treatment, but bleeding and profound TP recurred in both cases. Patient 1 had a third episode of severe TP when both OX and LE were replaced by IR and Patient 2 had two further episodes when first OX then OX + LE were omitted.Studies were then performed to determine whether DDAbs were present. Using a standard flow cytometric assay, both patients were found to have IgG antibodies that reacted with normal platelets in the presence of OX, LE, IR and dexamethasone (DX) and in addition ondansetron (ON)-DDAbs were found in Patient 2. No DDAbs specific for 5-FU, polonosetron, diphenhydramine, famotidine, or lorazepam, to which the patients had also been exposed, were identified. Using a multiplex platelet antibody bead array assay (PABA) (Curtis, Transfusion 2017, 57:1724-33), the DX- and LE-DDAbs from Patient 1 and the IR-DDAbs from Patient 2 reacted very strongly with GPIIb/IIIa and the OX-DDAbs from Patient 2 reacted weakly with GPIb/IX. Targets recognized by the remaining DDAbs are not yet defined. To determine whether the patients had multiple antibodies, each specific for a different drug, or a single antibody that cross-reacted with multiple drugs, serum was absorbed with platelets in the presence of one drug, dialyzed, and then tested for DDAbs by flow cytometry. Absorption of Patient 1 serum in the presence of DX, LE and OX removed abs specific for the drug used in absorption but not abs specific for the other two. Similar findings were made with Patient 2 when absorption was done in the presence of IR, LE and DX.Chemotherapy was continued in both patients using medications other than those for which the identified DDAbs were specific and no further episodes of thrombocytopenia were observed. To investigate how often patients treated with chemotherapy regimens that include OX produce multiple DDAbs, we screened 10 sera from patients previously found to have OX-specific DDAbs for DDAbs specific for LE, IR, DX and ON and identified 3 LE- and one ON-specific DDAbs. Twelve samples from OX-treated patients found not to contain OX-specific DDAbs were similarly screened. One was found to contain DDAbs specific for LE, DX and ON.Our findings suggest that 1) patients treated with combination chemotherapeutic regimens containing OX are prone to make multiple DDAbs that are specific for cytotoxic agents and/or supportive care medications which are capable of causing severe thrombocytopenia, 2) Patients who experience acute, severe thrombocytopenia while undergoing treatment with combination chemotherapy including OX should be tested for DDAbs specific for all medications to which they were exposed, 3) Identification of DDAbs can guide treatment regimens to avoid DITP. DisclosuresCurtis:Ionis Pharmaceuticals: Consultancy. Podoltsev:Ariad: Consultancy; Incyte: Consultancy; Alexion: Consultancy; CTI biopharma/Baxalta: Consultancy. Aster:BloodCenter of Wisconsin: Patents & Royalties: A patent application has been filed related to the PF4-dependent P-selectin expression assay (Method of Detecting Platelet- Activating Antibodies That Cause Heparin-Induced Thrombocytopenia/Thrombosis; PCT/US14/62591)., Research Funding.

Does Intravenous Ondansetron Affect the Intestinal Motility Pattern in Healthy Donkeys (Equus asinus)?

The current study was undertaken to investigate the effect of intravenous administration of ondansetron on the small and large intestinal motility in donkeys (Equus asinus) using non-invasive transabdominal ultrasonography. The current prospective, randomized, placebo-controlled, crossover study was conducted on thirty healthy donkeys (15 males and 15 females). The selected donkeys underwent two trials; the first was performed by intravenous administration of saline solution as a placebo, while the second was carried out by intravenous administration of ondansetron hydrochloride. The contractility of selected portions of both the small intestine (duodenum and jejunum) and the large intestine (left colon, right colon, and cecum) was counted over a period of 3 minutes before administration (zero time) and at 15, 30, 60, 90, 120, 180, and 240 minutes after administration. The results of this study showed that ondansetron significantly altered the small and large intestinal contractility compared to normal saline. Intravenous administration of ondansetron induced a significant decrease in the duodenal, jejunal and cecal contractility compared to placebo at 30, 60, 90, and 120 minutes after administration. Likewise, ondansetron induced a significant decrease in the left colon and right colon contractility when compared with placebo at 30, 60, 90, 120, and 180 minutes following administration. Ondansetron can be used as a highly specific and selective serotonin 5-HT3 receptor antagonist for reducing the small and large intestinal motility in donkeys, and is therefore highly suggested for treating spasmodic colic in equine.

Modern approaches to drug treatment for vestibular vertigo

In recent years, some progress has been achieved in elaborating the algorithms and standards for the treatment of many conditions accompanied by vertigo. The current possibilities of treating vestibular vertigo consist of a gradually expanding arsenal of symptomatic and pathogenetic drugs. Among the drugs used for the symptomatic treatment of vestibular vertigo, there are vestibular suppressants (antihistamines, benzodiazepines, and calcium antagonists) and antiemetics (dopamine antagonists and serotonin 5-HT3 receptor antagonists). The paper discusses the possibilities of using betahistine and vitamin D as pathogenetic agents for recurrent benign paroxysmal positional vertigo; diuretics, betahistine (including the new prolonged release formulation Betaserc® Long), glucocorticoids, and gentamicin for Meniere's disease; triptans, beta-blockers, tricyclic antidepressants, and anticonvulsants for vestibular migraine; glucocorticoids, antiviral agents, and drugs that accelerate vestibular compensation for acute unilateral peripheral vestibulopathy (vestibular neuritis and Ramsey Hunt syndrome).The emergence of new drugs, as well as the design of new dosage forms that enhance patient adherence to the prescribed treatment, can improve quality of life in patients suffering from diseases that have recently led to long-term disability or even incapacitation.

What is the ideal combination antiemetic regimen?

Postoperative nausea and vomiting (PONV) and post-discharge nausea and vomiting (PDNV) are frequent unpleasant complaints that patients and clinicians report after surgery. PONV and PDNV have been associated with postoperative complications and hospital discharge delays. Despite the extensive evidence describing the use of several regimens in different surgical populations, the ideal regimen has not been established. Several antiemetic drugs have been evaluated in more than 1000 clinical controlled trials for management of this complex emetogenic pathway, including the 5-hydroxytryptamine (5-HT3) receptor antagonists, dopamine receptor antagonists, neurokinin-type receptor antagonists, antihistaminics, anticholinergics, and corticosteroids, with the 5-HT3 receptor antagonists being the most commonly used for PONV prophylaxis. Because of the complex emetogenic pathway and multifactorial etiology of PONV, a multimodal approach using two or more drugs that act at different neuro-receptor sites is suggested in patients with one or more risk factors to successfully address PONV and reduce its incidence. Nevertheless, the most studied regimens in randomized clinical trials (RCTs) are the combination of serotonin 5-HT3 receptor antagonists with dexamethasone or dopamine receptor antagonists (droperidol). Therefore, the safest and more effective combination regimen appears to be the use of serotonin 5-HT3 receptor antagonist antiemetic drugs with dexamethasone.

Procognitive profiling of a serotonin 5-HT6 receptor antagonist in a complex model system in rats: A novel translational approach for clinical prediction

IntroductionThe serial clinical failures of novel cognitive enhancer candidates point out the lack of predictive power in the preceding animal experimentation. For a more predictive profiling of putative procognitive drugs in rodents, we recently elaborated a methodical approach which consists of three fundamental steps: 1. teaching various learning tasks representing different cognitive domains to the same cohort of animals with the aim to create a population with ‘widespread knowledge’. 2. Applying a cognitive deficit-inducing intervention to transform this cohort of animals to a ‘patient population’. 3. Testing putative procognitive drugs with a ‘clinical trial-like’ design on the wide spectrum of cognitive (dys)functions in the actual ‘patient population’. The present study has been the first trial to test the feasibility and utility of the proposed system. MethodsThe population with ‘widespread knowledge’ consisted of 2 year old male Long-Evans rats with a learning history in five-choice serial reaction time task (5-CSRTT, attentional paradigm), Morris water maze (MWM, spatial learning), a cooperative task carried out in pairs (social learning), and a skill-learning task, „pot-jumping”. For inducing cognitive deficit, thus creating a ‘patient population’ we increased the difficulty of the tasks. For the cognitive enhancer mechanism to test in the system we chose a serotonin 5-HT6 receptor antagonist compound, RO4368554. Animals were randomly assigned to vehicle- and drug treated groups based on their baseline learning performance and their response in a pilot test of increase in task difficulty. During the 13-day long treatment with 3 mg/kg ip. RO4368554 all the learning paradigms were repeatedly run with increased difficulty supplemented with a novel object recognition test (NOR, episodic memory). ResultsIn the 5-CSRTT, reducing the stimulus duration from 1 s to 0.25 s caused a significant decrease in the percentage of correct responses (from 52 % to 31 % in the control group) which was not affected by the 5-HT6 receptor antagonist treatment (correct responses decreased from 58 % to 31 %). In the MWM, replacing the escape platform to a new location did not mean a hard challenge for the rats. Members of both groups could find it within a relatively short time: mean escape latencies were 83 s and 65 s at the first replacement trial and 58 s and 74 s at the second one in the control and drug-treated groups, respectively. In the cooperation paradigm, where the rats had to perform simultaneous nose-pokes to get a reward, task difficulty was increased by requiring two consecutive simultaneous nose-poking from the animals. This caused a fall in the percentage of successful trials in both groups (from 48 % to 12 % and from 50 % to 20 % in the saline – and drug-treated group, respectively), however, by the end of the treatment RO4368554-treated animals showed significantly higher performance (29 %) than saline treated rats (2%). The NOR test, carried out with a 5 -h delay, revealed poor recognition memory in both groups (discrimination index (DI) values were 0.13 and 0.06 for saline and RO4368554, respectively). Performance in the pot jumping test was also not improved by the drug-treatment. ConclusionsThe applied study design allowed parallel measurements of the action of the test compound on several cognitive functions and to follow its time course. RO4368554 did not show notable effects on impaired attention and visual recognition; nor did it affect spatial and procedural learning, but it exerted beneficial effect on cooperative behaviour. The revealed activity pattern highlight the cognitive domain most sensitive to the particular drug effect and may give hints for further target validating and clinical studies.

A Photo Stability Indicating HPLC technique for Validation of Netupitant and Palonosetron in Bulk and Formulations

Analytical chemistry is the science that seeks ever improved means of measuring the chemical composition of natural and artificial materials.Netupitant Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 receptors. Palonosetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally and peripherally in turn inhibits the visceral afferent stimulation of the vomiting center.The mobile phase used was orthophosphoric and acetate 70% buffer pH 3 and 30% methanol.The assay of Netupitant and Palanosetron was performed with tablets and the % assay was found to be 100.08 and 100.04, The linearity was found to be linear with a correlation coefficient of 0.999, the precision 0.8 and 0.3 for Netupitant and Palanosetron which shows that the method is precise.The validation of developed method shows that the accuracy is well within the limit, which shows that the method is capable of showing good accuracy and reproducibility. The LOD and LOQ for Netupitant were found to be 3.02 and 9.98 and LOD and LOQ for Palanosetron was found to be 3.00 and 10.00. Thus, it shows that the method is stability indicating, sensitive, accurate, robust and precise. Hence, the developed HPLC method can be successfully applied to the pharmaceutical dosage form and can be used for routine analysis.&#x0D; &#x0D; &#x0D;

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Development of Nasal Mucoadhesive Microspheres of Granisetron: A Potential Drug.

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. In this research mucoadhesive microspheres were developed in order to carry out the absorption of drug through nasal mucosa with the aim to improve therapeutic efficacy, avoid hepatic first pass metabolism and increase residence time. Mucoadhesive microspheres of Granisetron using chitosan as polymer were prepared by emulsification cross-linking method to increase the residence time on the mucosa. The surface of prepared microspheres was characterized by SEM (Scanning electron microscopy) and evaluated for particle size, encapsulation efficiency, production yield, swelling ability, in-vitro mucoadhesion, in-vitro drug release and stability study. Among all the formulations F6 with drug/polymer ratio of 1:3 displayed the best result. On drug release kinetic model study, all the formulations follow Zero order. Stability studies revealed that the microspheres kept at 25±2°C and 60±5% RH showed the maximum stability. After all the evaluation parameters and result obtained it can be said that these results confirmed the suitability of Granisetron mucoadhesive chitosan microspheres for nasal delivery system.

ESTIMATION OF ONDANSETRON HYDROCHLORIDE BY RP-HPLC

A RP-HPLC method was developed for the estimation of Ondansetron Hydrochloride in Bulk drug using high performance liquid chromatography. Ondansetron was a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic drug to treat nausea and vomiting after cancer chemotherapy. The separation was achieved by Promosil C-18 (250 mm x 4.6 mm x 10 µm) column because it allows higher separation and Acetonitrile: Methanol (50:50) as mobile phase with a flow rate of 1.2 ml/min. The detection was carried out at 216 nm. The retention time of drug was found 2.64 min. The developed method was validated. The proposed method shall prove equally effective to analyze Ondansetron Hydrochloride in the corresponding drug sample and may prove to be of great importance in pharmaceutical analysis. KEYWORDS: Ondansetron, Acetonitrile, Antiemetic, Methanol.