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International Journal of Molecular... Jun 2021The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that...
The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP uptake by OCT2 listed in order of potency was palonosetron (IC: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC: 85.4 μM) and the inhibition of ASP uptake by MATE1 in order of potency was ondansetron (IC: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC: 27.4 μM). Ondansetron (0.5-20 μM) inhibited the basolateral-to-apical transcellular transport of ASP up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP. Taken together, these data suggest that 5-HT antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.
Topics: Animals; Antiemetics; Biological Transport; Cell Line; Cells, Cultured; Dogs; Gene Expression; HEK293 Cells; Humans; Kidney; Madin Darby Canine Kidney Cells; Molecular Structure; Organic Cation Transport Proteins; Organic Cation Transporter 2; Serotonin 5-HT3 Receptor Antagonists
PubMed: 34208557
DOI: 10.3390/ijms22126439 -
Frontiers in Surgery 2022The present study is designed to study the analgesic and sedative effect of different doses of dexmedetomidine combined with butorphanol in continuous analgesia after a...
OBJECTIVE
The present study is designed to study the analgesic and sedative effect of different doses of dexmedetomidine combined with butorphanol in continuous analgesia after a cesarean section.
METHODS
A total of 60 puerperae undergoing a cesarean section recruited from a single center were divided into three groups according to the postoperative continuous analgesia protocol: control group (100 mL of normal saline containing 10 µg/kg fentanyl and 0.25 mg of palonosetron, 2 mL/h for continuous analgesia for 48 h), DB1 group (100 mL of normal saline containing 1.0 µg/kg dexmedetomidine, 4 mg of butorphanol, 10 µg/kg fentanyl, and 0.25 mg of palonosetron, 2 mL/h for continuous analgesia for 48 h), and DB2 group (100 mL normal saline containing 2.0 µg/kg dexmedetomidine, 4 mg of butorphanol, 10 µg/kg fentanyl, and 0.25 mg of palonosetron, 2 mL/h for continuous analgesia for 48 h). We compared the blood pressure, heart rate, oxygen saturation, VAS score, Ramsay score, and adverse reactions of puerperae among the three groups after surgery.
RESULTS
The baseline data all have no significant difference in the three groups ( > 0.05). Compared with those in the control group, the systolic blood pressure, diastolic blood pressure, heart rate, and VAS score of the puerperae in the DB1 group and DB2 group were significantly decreased at 6, 24, and 48 h ( < 0.05), while the Ramsay scores of the puerperae in DB1 group and DB2 group were significantly increased at 6, 24, and 48 h ( < 0.05). At the same time, the systolic blood pressure, diastolic blood pressure, heart rate, and VAS score of the puerperae in the DB2 group were significantly lower than those in the DB1 group ( < 0.05), while the Ramsay scores of the puerperae in DB2 group were significantly higher than those in the DB1 group ( < 0.05). Also, there is no significant difference in oxygen saturation and adverse reactions of puerperae among the three groups after surgery ( > 0.05).
CONCLUSION
Dexmedetomidine combined with butorphanol can improve the analgesic and sedative effects in continuous analgesia after a cesarean section, and the analgesic and sedative effects of dexmedetomidine in the high-dose group are better than those in the low-dose group.
PubMed: 35599801
DOI: 10.3389/fsurg.2022.896536 -
Pharmacoepidemiology and Drug Safety Apr 2023We explored the adverse drug reaction signals of drug-induced neutropenia (DIN) and drug-induced agranulocytosis (DIA) in hospitalized patients and evaluated the novelty...
PURPOSE
We explored the adverse drug reaction signals of drug-induced neutropenia (DIN) and drug-induced agranulocytosis (DIA) in hospitalized patients and evaluated the novelty of these correlations.
METHOD
A two-step method was established to identify the relationship between drugs and DIN or DIA using 5-year electronic medical records (EMRs) obtained from 242 000 patients at Qilu Hospital of Shandong University. First, the drugs suspected to induce DIN or DIA were selected. The associations between suspected drugs and DIN or DIA were evaluated by a retrospective cohort study using unconditional logistic regression analysis and multiple linear regression model.
RESULTS
Twelve suspected drugs (vancomycin, meropenem, voriconazole, acyclovir, ganciclovir, fluconazole, oseltamivir, linezolid, compound borax solution, palonosetron, polyene phosphatidylcholine, and sulfamethoxazole) were associated with DIN, and six suspected drugs (vancomycin, voriconazole, acyclovir, ganciclovir, fluconazole, and oseltamivir) were associated with DIA. The multivariate linear regression model revealed that nine drugs (vancomycin, meropenem, voriconazole, ganciclovir, fluconazole, oseltamivir, compound borax solution, palonosetron, and polyene phosphatidylcholine) and four drugs (vancomycin, voriconazole, ganciclovir, and fluconazole) were found to be associated with DIN and DIA, respectively. While logistic regression analysis revealed that palonosetron and ganciclovir were associated with DIN and DIA, respectively.
CONCLUSION
Palonosetron and ganciclovir were found to be correlated with drug-induced granulocytopenia. The results of this study provide an early warning of drug safety signals for drug-induced granulocytopenia, facilitating a quick and appropriate response for clinicians.
Topics: Aged; Humans; Agranulocytosis; Electronic Health Records; Neutropenia; Thrombocytopenia; Vancomycin; Meropenem; Voriconazole; Acyclovir; Ganciclovir; Palonosetron
PubMed: 36305574
DOI: 10.1002/pds.5559 -
Frontiers in Pharmacology 2022To test the hypothesis that the single use of fosaprepitant is not inferior to the use of palonosetron as antiemetic prophylaxis in the first 48 h after surgery in...
Comparative Study Between Fosaprepitant and Palonosetron in the Prophylaxis of Postoperative Nausea and Vomiting in Women Undergoing Laparoscopic Cholecystectomy: Prospective, Randomized and Double-Blind Study.
To test the hypothesis that the single use of fosaprepitant is not inferior to the use of palonosetron as antiemetic prophylaxis in the first 48 h after surgery in women undergoing laparoscopic cholecystectomy. Eighty-eight nonsmoking women (American Society of Anesthesiologists physical status I or II) aged between 18 and 60 years who underwent laparoscopic cholecystectomy received 150 mg of fosaprepitant or 75 μg of palonosetron, administered intravenously after the induction of general anesthesia. In the fosaprepitant group and in the palonosetron group, 13.6 and 18.2% of the patients, respectively, vomited in the first 48 h after surgery ( = 0.560). There were no differences between groups in the total frequency and intensity of nausea, number of complete responders, need for rescue medication, time required for the first rescue medication dose or number of adverse events. The administration of a single dose of fosaprepitant after the induction of anesthesia was as effective as the administration of a single dose of palonosetron for the prophylaxis of vomiting in the first 48 h after surgery in women undergoing laparoscopic cholecystectomy.
PubMed: 35645797
DOI: 10.3389/fphar.2022.915347 -
Cureus Mar 2022Background Incidence of postoperative nausea and vomiting (PONV) in susceptible patients can be unacceptably high (70-80% reported incidence). This study was designed to...
Background Incidence of postoperative nausea and vomiting (PONV) in susceptible patients can be unacceptably high (70-80% reported incidence). This study was designed to evaluate the effect of palonosetron and ondansetron in preventing PONV in high-risk patients undergoing gynecological laparoscopic surgery. Methodology In this randomized, controlled, double-blind trial, non-smoking females aged 18-70 years, weighing 40-90 kg, and posted for elective laparoscopic gynecological surgeries were enrolled into ondansetron (Group A, n = 65) and palonosetron (Group B, n = 65) groups. Palonosetron (1 mcg/kg IV) or ondansetron (0.1 mg/kg IV) were administered just before induction. Postoperatively, the incidence of nausea, vomiting, PONV (scored on a scale of 0-3), need for rescue antiemetic, complete response, patient satisfaction, and adverse effects were evaluated up to 48 h following surgery. Normally distributed continuous variables were compared using Student's t-test. In addition, the Chi-squared test or Fisher's exact test were used to compare nominal categorical data as deemed appropriate. P-value <0.05 was observed as statistically significant. Results The overall PONV scores and postoperative nausea scores during 0-2 and 24-48 hours were comparable, but PONV scores (p = 0.023) and postoperative nausea scores (p = 0.010) during 2-24 hours were significantly lesser in Group B compared to Group A. There was no statistically significant difference in the postoperative vomiting score or retching during 0-48 hours. The amount of first-line rescue antiemetic used during 2-24 hours was significantly higher in Group A (56%) than in Group B (31%) (p = 0.012; p <0.05). A complete response to the drug during 2-24 hours was significantly higher (p = 0.023) in Group B (63%) compared to Group A (40%), whereas response was comparable during 0-2 and 24-48 hours. Both groups had a comparable incidence of adverse effects and patient satisfaction scores. Conclusion Palonosetron has a superior anti-nausea effect, less need for rescue antiemetics, and lesser incidence of total PONV compared to ondansetron during 2-24h and comparable effect to ondansetron during 0-2h and 24-48h postoperative period in high-risk patients undergoing gynecological laparoscopic surgery.
PubMed: 35505760
DOI: 10.7759/cureus.23615 -
Structure (London, England : 1993) Oct 2020Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3...
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.
Topics: Animals; Antiemetics; Binding Sites; Cryoelectron Microscopy; Hydrogen Bonding; Mice; Molecular Dynamics Simulation; Palonosetron; Protein Conformation; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Antagonists
PubMed: 32726573
DOI: 10.1016/j.str.2020.07.004 -
Supportive Care in Cancer : Official... Jul 2020There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication...
PURPOSE
There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication to be used is still not established. This study aimed to examine the effect of palonosetron and dexamethasone on the prevention of gastrointestinal symptoms induced by TACE.
METHODS
Patients with hepatocellular carcinoma who were treated with TACE with epirubicin were retrospectively evaluated. The complete response rate of antiemetic drugs and incidence and severity of gastrointestinal symptoms were compared between the antiemetic group (AE group), which includes 51 patients prophylactically administered with palonosetron 0.75 mg and dexamethasone 9.9 mg intravenously before TACE on day 1 and dexamethasone 6.6 mg intravenously on days 2 and 3, and control group with 101 patients without antiemetic premedication.
RESULTS
Complete response rate in the entire evaluation period was significantly higher in the AE group compared with that in the control group. In the acute phase, the incidence and severity of nausea, vomiting, and anorexia significantly decreased in the AE group, but only anorexia improved in the delay phase. Additionally, postembolization syndromes, such as abdominal pain and fever, were significantly attenuated in the AE group; however, constipation worsened in this group.
CONCLUSIONS
Premedication of palonosetron and dexamethasone significantly prevents the incidence and reduces the severity of gastrointestinal symptoms especially in the acute phase. Further studies will be needed to determine the most recommended 5-HT antagonist or dosage of dexamethasone in establishing the optimal antiemetic regimen.
Topics: Abdominal Pain; Adult; Aged; Antibiotics, Antineoplastic; Antiemetics; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Dexamethasone; Epirubicin; Female; Gastrointestinal Diseases; Humans; Liver Neoplasms; Male; Middle Aged; Nausea; Palonosetron; Retrospective Studies; Vomiting
PubMed: 31732854
DOI: 10.1007/s00520-019-05178-1 -
ELife Oct 2020Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists,...
Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HTR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HTR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.
Topics: Animals; Binding Sites; Binding, Competitive; Cryoelectron Microscopy; Female; Humans; Ligands; Mice; Molecular Dynamics Simulation; Oocytes; Protein Binding; Protein Conformation; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Xenopus laevis
PubMed: 33063666
DOI: 10.7554/eLife.57870 -
Clinical and Translational Science Sep 2021Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE)...
Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.
Topics: Acute Kidney Injury; Aged; Animals; Benzimidazoles; Cisplatin; Disease Models, Animal; Female; Granisetron; Humans; Kidney; Male; Mice; Middle Aged; Nausea; Ondansetron; Organic Cation Transport Proteins; Palonosetron; Renal Elimination; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 33982438
DOI: 10.1111/cts.13045 -
Brazilian Journal of Anesthesiology... 2020Postoperative nausea and vomiting is the second most common complaint in the postoperative period after pain. The incidence of postoperative nausea and vomiting was... (Comparative Study)
Comparative Study Randomized Controlled Trial
[Comparison of palonosetron-dexamethasone and ondansetron-dexamethasone for prevention of postoperative nausea and vomiting in middle ear surgery: a randomized clinical trial].
BACKGROUND
Postoperative nausea and vomiting is the second most common complaint in the postoperative period after pain. The incidence of postoperative nausea and vomiting was 60–80% in middle ear surgeries in the absence of antiemetic prophylaxis. Because of this high incidence of postoperative nausea and vomiting, we aimed to assess the effect of palonosetron-dexamethasone and ondansetron-dexamethasone combination for the prevention of postoperative nausea and vomiting in patients of middle ear surgery.
METHODS
Sixty-four patients, scheduled for middle ear surgery, were randomized into two groups to receive the palonosetron-dexamethasone and ondansetron-dexamethasone combination intravenously before induction of anesthesia. Anesthesia technique was standardized in all patients. Postoperatively, the incidences and severity of nausea and vomiting, the requirement of rescue antiemetic, side effects and patient satisfaction score were recorded.
RESULTS
Demographics were similar in the study groups. The incidence difference of nausea was statistically significant between groups O and P at a time interval of 2–6 hours only ( = 0.026). The incidence and severity of vomiting were not statistically significant between groups O and P during the whole study period. The overall incidence of postoperative nausea and vomiting (0–24 hours postoperatively) was 37.5% in group O and 9.4% in group P ( = 0.016). Absolute risk reduction with palonosetron–dexamethasone was 28%, the relative risk reduction was 75%, and the number-needed-to-treat was 4. The patient’s satisfaction score was higher in group P than group O ( = 0.016). The frequency of rescue medication was more common in group O than in group P patients ( = 0.026).
CONCLUSION
The combination of palonosetron-dexamethasone is superior to ondansetron-dexamethasone for the prevention of postoperative nausea and vomiting after middle ear surgeries.
Topics: Adult; Antiemetics; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Ear, Middle; Female; Humans; Incidence; Male; Middle Aged; Ondansetron; Palonosetron; Patient Satisfaction; Postoperative Nausea and Vomiting; Prospective Studies; Young Adult
PubMed: 32988625
DOI: 10.1016/j.bjan.2020.04.016