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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 -
The Journal of International Medical... Jun 2022To investigate the occurrence rate and risk factors of postoperative nausea and vomiting (PONV) in lung cancer patients following lobectomy and application of analgesic...
OBJECTIVE
To investigate the occurrence rate and risk factors of postoperative nausea and vomiting (PONV) in lung cancer patients following lobectomy and application of analgesic pumps.
METHODS
This retrospective study reviewed clinical data from patients that had undergone lobectomy for lung cancer under general anaesthesia. The risk factors of PONV were analysed using binary logistic regression models.
RESULTS
A total of 203 patients (97 females) were enrolled. The rate of PONV was 29.6% (60 of 203 patients) for all patients, 42.3% (41 of 97 patients) for female patients and 17.9% (19 of 106 patients) for male patients. Female patients undergoing thoracotomy (odds ratio [OR] 7.770, 95% confidence interval [CI] 1.747, 34.568) or having surgery durations ≥120 min (OR 4.493, 95% CI 1.502, 12.851) were significantly more susceptible to PONV. The risk of PONV in female patients that received postoperative dolasetron (100 mg, once a day) was significantly lower (OR 0.075, 95% CI 0.007, 0.834). For male patients, the risk of PONV was significantly lower in those with a body mass index ≥24 kg/m (OR 0.166; 95% CI 0.035, 0.782).
CONCLUSION
Female and male patients have different risk factors for PONV following lobectomy for lung cancer and application of analgesic pumps.
Topics: Analgesics; Antiemetics; Female; Humans; Incidence; Lung Neoplasms; Male; Postoperative Nausea and Vomiting; Retrospective Studies; Risk Factors
PubMed: 35735025
DOI: 10.1177/03000605221105343 -
Journal of Pharmacological and... 2019The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical...
INTRODUCTION
The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical tests in cynomolgus monkeys on seven QT reference drugs containing the drugs used in the IQ-CSRC clinical trial and applied exposure-response (ER) analysis to the data to investigate the potential for translational information on the QT effect.
METHODS
In each of six participating facilities in the J-ICET project, telemetered monkeys were monitored for 24 h following administration of vehicle or 3 doses of test drugs, and pharmacokinetic profiles at the same doses were evaluated separately. An individual rate-corrected QT interval (QTca) was derived and the vehicle-adjusted change in QTca from baseline (∆∆QTca) was calculated. Then the relationship of concentration to QT effect was evaluated by ER analysis.
RESULTS
For QT-positive drugs in the IQ-CSRC study (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and levofloxacin, the slope of the total concentration-QTca effect was significantly positive, and the QT-prolonging effect, taken as the upper bound of the confidence interval for predicted ∆∆QTca, was confirmed to exceed 10 ms. The ER slope of the negative drug levocetirizine was not significantly positive and the QTca effect was below 10 ms at observed peak exposure.
DISCUSSION
Preclinical QT assessment in cynomolgus monkeys combined with ER analysis could identify the small QT effect induced by several QT drugs consistently with the outcomes in humans. Thus, the ER method should be regarded as useful for translational prediction of QT effects in humans.
PubMed: 31255745
DOI: 10.1016/j.vascn.2019.106606 -
Current Medicinal Chemistry 2021An important group of antiemetic drugs used in the treatment of nausea and vomiting after chemotherapy containing an indole moiety in their structures, working as 5-...
An important group of antiemetic drugs used in the treatment of nausea and vomiting after chemotherapy containing an indole moiety in their structures, working as 5- hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This study focuses on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity, which have been successfully used as antiemetic drugs for reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, providing a general outlook towards the development of more efficient antiemetic drugs.
Topics: Antiemetics; Antineoplastic Agents; Humans; Indoles; Nausea; Pharmaceutical Preparations; Receptors, Serotonin, 5-HT3
PubMed: 34238146
DOI: 10.2174/0929867328666210708091134 -
Clinical Pharmacology and Therapeutics Jul 2024The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non-rodent QT assay...
The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non-rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure-response analysis was performed, as done in clinical practice. By-timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic C. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration-QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug-induced QTc prolongation in humans as a key pillar of the integrated risk assessment.
Topics: Dogs; Animals; Prospective Studies; Long QT Syndrome; Electrocardiography; Male; Female; Telemetry; Risk Assessment; Humans; Heart Rate
PubMed: 38709223
DOI: 10.1002/cpt.3283