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Neuropharmacology Jun 2017Crystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use...
Crystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use of homologous proteins. Tropisetron is an orthosteric ligand at both 5-HT and α7 nACh receptors and its binding orientation has been determined in the structural homologue AChBP (pdbid: 2WNC). Co-crystallisation with a structurally-related ligand, granisetron, reveals an almost identical orientation (pdbid; 2YME). However, there is a >1000-fold difference in the affinity of tropisetron at 5-HT versus α7 nACh receptors, and α7 nACh receptors do not bind granisetron. These striking pharmacological differences prompt questions about which receptor the crystal structures most closely represent and whether the ligand orientations are correct. Here we probe the binding orientation of tropisetron and granisetron at 5-HT receptors by in silico modelling and docking, radioligand binding on cysteine-substituted 5-HT receptor mutants transiently expressed in HEK 293 cells, and synthetic modification of the ligands. For 15 of the 23 cysteine substitutions, the effects on tropisetron and granisetron were different. Structure-activity relationships on synthesised derivatives of both ligands were also consistent with different orientations, revealing that contrary to the crystallographic evidence from AChBP, the two ligands adopt different orientations in the 5-HT receptor binding site. Our results show that even quite structurally similar molecules can adopt different orientations in the same binding site, and that caution may be needed when using homologous proteins to predict ligand binding.
Topics: Binding Sites; Binding, Competitive; Crystallography, X-Ray; Granisetron; HEK293 Cells; Humans; Indoles; Ligands; Models, Molecular; Molecular Structure; Mutation; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Structure-Activity Relationship; Tritium; Tropisetron
PubMed: 28137449
DOI: 10.1016/j.neuropharm.2017.01.023 -
Zhongguo Fei Ai Za Zhi = Chinese... Oct 2018Chemotherapy is the most important method for cancer treatment. However, chemotherapy induced nausea and vomiting (CINV) has a profound effect on patients. In recent...
BACKGROUND
Chemotherapy is the most important method for cancer treatment. However, chemotherapy induced nausea and vomiting (CINV) has a profound effect on patients. In recent years, there have been new antiemetic drugs, such as aprepitant. We review the curative effect of aprepitant with tropisetron and dexamethasone for prevention of nausea and vomiting in patients receiving Cisplatin chemotherapy.
METHODS
Observation is divided into three stages. Whole study phase (0-120 h after chemotherapy administration), acute phases (0-24 h), and delayed phase (24 h-120 h). The primary endpoints were complete response (CR) and complete prevention (CP) during the three different study phase.
RESULTS
In the whole study phase, 86.02% of patients achieved CR; in acute phases and delayed phases were 89.25%, 87.1%, respectively. CP were 46.22%, 83.87%, 45.16%, respectively. Anti-CINV effect was significantly associated with age distribution (P=0.008).
CONCLUSIONS
Aprepitant with tropisetron and dexamethasone prevented effectively CNIV for patients receiving Cisplatin chemotherapy. This combination could improve the quality of life and the compliance of patient with chemotherapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aprepitant; Cisplatin; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Quality of Life; Vomiting
PubMed: 30309434
DOI: 10.3779/j.issn.1009-3419.2018.10.12 -
Saudi Journal of Anaesthesia Jan 2013Postoperative nausea and vomiting (PONV) are frequently encountered after thyroidectomy. For PONV prevention, selective serotonin 5-hydroxytryptamine type 3 (5-HT3)...
BACKGROUND
Postoperative nausea and vomiting (PONV) are frequently encountered after thyroidectomy. For PONV prevention, selective serotonin 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are considered one of the first-line therapy. We report on the efficiency of granisetron and tropisetron, with that of placebo on the prevention of PONV in patients undergoing total thyroidectomy.
METHODS
One hundred twenty-seven patients were divided into three groups and randomized to receive intravenously, prior to induction of anesthesia, tropisetron 5 mg, or granisetron 3 mg, or normal saline. All patients received additionally 0.625 mg droperidol. All episodes of postoperative PONV during the first 24 h after surgery were evaluated.
RESULTS
Nausea visual analogue scale (VAS) score was lower in tropisetron and granisetron groups than the control group at all measurements (P<0.01) except for the 8-h measurement for tropisetron (P=0.075). Moreover, granisetron performed better than tropisetron (P<0.011 at 4 h and P<0.01 at all other points of time) apart from the 2-h measurement. Vomiting occurred in 22.2%, 27.5%, and 37.5% in granisetron, tropisetron, and control groups, respectively (P=0.43).
CONCLUSIONS
The combination of the 5-HT3 antagonists with droperidol given before induction of anesthesia is well tolerated and superior to droperidol alone in preventing nausea but not vomiting after total thyroidectomy.
PubMed: 23717236
DOI: 10.4103/1658-354X.109817 -
Journal of Pain and Symptom Management Mar 1998The single-institution, prospective, randomized trial was performed to evaluate the efficacy of tropisetron and chlorpromazine in the management of nausea and vomiting... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The single-institution, prospective, randomized trial was performed to evaluate the efficacy of tropisetron and chlorpromazine in the management of nausea and vomiting of terminal cancer patients. Patients had no recent chemotherapy or radiotherapy, and emesis was not due to bowel obstruction, electrolytic or metabolic disturbances, drug intake, or intracranial disease. One hundred and sixty patients randomly received either (a) chlorpromazine (CLO) (50 mg/day) plus dexamethasone (DEX) (2 mg/day), (b) chlorpromazine (25 mg/day) plus tropisetron (TRO) (5 mg/day), (c) chlorpromazine (25 mg/day plus tropisetron (5 mg/day) plus dexamethasone (2 mg/day), or (d) tropisetron (TRO) (5 mg/day). Patients were monitored from day 1 to day 15. No nausea or vomiting was defined as "total" control. On day 15, total vomiting control was achieved in 33.3% of the patients receiving CLO + DEX, 84.6% of the patients receiving CLO + TRO, 92.5% of the patients receiving CLO + TRO + DEX, and 78.9% of the patients receiving TRO. Total control of nausea was achieved in 18.0% of the patients receiving CLO + DEX, 74.4% of the patients receiving (CLO + TRO), 85.0% of the patients receiving CLO + TRO + DEX, and 65.8% of the patients receiving TRO. Tropisetron-containing combinations produced significant control of nausea and vomiting from the third day onward. All antiemetic drugs were well tolerated. These data suggest that tropisetron-containing combinations or tropisetron as a single agent are much more effective in the control of emesis in patients with advanced cancer than the conventional antiemetic combination of chlorpromazine plus dexamethasone. Tropisetron is well tolerated and may be the best choice for controlling persistent nausea and vomiting in terminal cancer patients.
Topics: Adult; Aged; Antiemetics; Chlorpromazine; Drug Therapy, Combination; Female; Humans; Indoles; Male; Middle Aged; Nausea; Neoplasms; Serotonin Antagonists; Tropisetron; Vomiting
PubMed: 9564119
DOI: 10.1016/s0885-3924(97)00349-7 -
Cell Stress & Chaperones Sep 2022Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1...
Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Inflammation; Interleukin-1; Rats; Streptozocin; Tropisetron; Tumor Necrosis Factor-alpha; bcl-2-Associated X Protein
PubMed: 35972643
DOI: 10.1007/s12192-022-01287-9 -
Scientific Reports Dec 2016IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including...
IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spike discharge in enteric and visceral sensory neurons. Both labelling and activation of enteric neurons was prevented by preincubation with the HuD antigen. Activation of enteric neurons was inhibited by the nicotinic receptor antagonists hexamethonium and dihydro-β-erythroidine and reduced by the P2X antagonist pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid (PPADS) but not by the 5-HT antagonist tropisetron or the N-type Ca-channel blocker ω-Conotoxin GVIA. Ca imaging experiments confirmed activation of enteric neurons but not enteric glia. These findings demonstrate a direct excitatory action of ANNA-1, in particular anti-HuD, on visceral sensory and enteric neurons, which involves nicotinic and P2X receptors. The results provide evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction.
Topics: Animals; Antibodies, Neoplasm; ELAV-Like Protein 4; Enteric Nervous System; Female; Guinea Pigs; Humans; Male; Sensory Receptor Cells
PubMed: 27905561
DOI: 10.1038/srep38216 -
The International Journal of... Sep 2019The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In...
BACKGROUND
The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT3 receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing.
METHODS
Rats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task.
RESULTS
The rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration.
CONCLUSIONS
These results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT3/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking.
Topics: Animals; Cocaine; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Electroshock; Male; Rats; Reinforcement Schedule; Self Administration; Tropisetron
PubMed: 31125405
DOI: 10.1093/ijnp/pyz023 -
Medicine Nov 2016This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia.A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed.Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery.Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect.
Topics: Aged; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Intravenous; Antiemetics; Cholecystectomy, Laparoscopic; Drug Therapy, Combination; Female; Fentanyl; Humans; Indoles; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain Measurement; Pain, Postoperative; Postoperative Nausea and Vomiting; Tropisetron
PubMed: 27902584
DOI: 10.1097/MD.0000000000005074 -
BMC Anesthesiology Sep 2022To observe the effect of different antiemetic drugs for the prevention of postoperative nausea and vomiting (PONV) after gynaecological day surgery under remimazolam... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To observe the effect of different antiemetic drugs for the prevention of postoperative nausea and vomiting (PONV) after gynaecological day surgery under remimazolam general anesthesia.
METHODS
One hundred ninety-two patients were selected for gynaecological day surgery and randomly divided into three groups: droperidol group (DD group), tropisetron group (DT group) and control group (DC group). Flurbiprofen axetil 50 mg and dexamethasone 5 mg were given intravenously before induction of anesthesia, and 2 min later droperidol 1 mg was given intravenously to the DD group, tropisetron 5 mg to the DT group and saline (5 ml) to the DC group. Induction of anesthesia: remimazolam 6 mg/kg/h was continuously infused until sleep, mivacurium 0.2 mg/kg and alfentanil 20ug/kg were slowly pushed, 3 min later intubation was performed to control breathing. Maintenance of anesthesia: 40ug/kg/h of alfentanil, 1 mg/kg/h of remimazolam continuous infusion. After awakening and extubation, the patient was transferred to the PACU. PONV were recorded in the PACU and an electronic questionnaire was pushed 24 h after surgery.
RESULTS
The incidence of PONV within the PACU was significantly lower in the DD (14.5%)and DT(26.7%) groups than in the DC(50%) group (p < 0.01), there was no significantly difference between the DT and DD groups. There were no significant difference in the incidence of PONV in 24 h after surgery between the three groups(DD:DT:DC = 44.5%:45.1%:63.8%,p > 0.05).
CONCLUSIONS
Droperidol or tropisetron combined with dexamethasone is superior to dexamethasone alone for the prevention of PONV in the PACU after remimazolam combined with alfentanil anesthesia, with no significant difference in the incidence of PONV in 24 h after surgery.
Topics: Alfentanil; Ambulatory Surgical Procedures; Anesthesia, General; Antiemetics; Benzodiazepines; Dexamethasone; Droperidol; Female; Humans; Mivacurium; Postoperative Nausea and Vomiting; Tropisetron
PubMed: 36109691
DOI: 10.1186/s12871-022-01835-x -
Medicine Feb 2015Tropisetron is an adjuvant for butorphanol used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is...
Tropisetron is an adjuvant for butorphanol used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the incidence of postoperative nausea and vomiting. However, this admixture is not available commercially and stability data applicable to hospital practice are limited. This study aimed to describe the drug compounding and evaluates the long-term (up to 14 days) stability of butorphanol and tropisetron in 0.9% sodium chloride injection for PCA use.In this study, commercial solutions of butorphanol tartrate and tropisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL. The polyolefin bags and glass bottles were stored at 4°C and 25°C for up to 14 days. The drug stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography assay of drug concentrations.The data obtained for admixtures prepared and stored at temperatures of 25°C and 4°C show the drugs have maintained at least 98% of the initial concentration. All solutions remained clear and colorless over the 14-day period, and the pH value did not change significantly.The results indicate that admixtures of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL in 0.9% sodium chloride injection solution were stable for 14 days when stored in polyolefin bags or glass bottles at 4°C and 25°C and protected from light. The infusion is feasible for manufacturing in pharmacy aseptic units and can be stored for up to 14 days for routine use in PCA infusions.
Topics: Analgesia, Patient-Controlled; Analgesics, Opioid; Butorphanol; Chromatography, High Pressure Liquid; Drug Combinations; Drug Stability; Drug Storage; Humans; Indoles; Infusions, Intravenous; Sodium Chloride; Tropisetron
PubMed: 25674732
DOI: 10.1097/MD.0000000000000432