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Objective: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy., Design: Open-label, prospective, multi-center phase II trial., Setting: Three institutions., Participants: Fifty-four patients scheduled to receive CapeOX chemotherapy., Interventions: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone., Main Outcome Measures: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life., Results: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported., Conclusion: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX., Trial Registration: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021., (© 2024. The Author(s).)

Background: Mirtazapine blocks 5-hydroxytryptamine type (5-HT) 2A , 5-HT 2C , 5-HT 3 and histamine H 1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers., Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h)., Results: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0., Conclusions: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute., Competing Interests: Declaration of competing interest Dr. Iihara has received personal fees from Taiho, Chugai, Yakult, Astellas, Eli Lilly, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Ono, and Nippon Boehringer Ingelheim and consulting fees for their institution from Taiho and Eisai outside the submitted work. Dr. Morita has received personal fees from AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Amgen, Eli Lilly, Takeda, Taiho, Thermo Fisher, Nihon Kayaku, MSD, Novartis, Pfizer outside the submitted work. Ms. Hirose has received personal fees from Eli Lilly, Eisai, Merck, Chugai, and Nippon Kayaku outside the submitted work. Dr. Kawazoe has received grants for their institution from Eli Lilly outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Suzuki has received personal fees from Toa Eiyo, Asahi Kasei, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka, Sandoz, Tsumura, Nipro, Taiho, Kyowa-Kirin, Nippon Chemiphar, Japan Blood Products Organization, Takeda, and Nippon Boehringer Ingelheim and grants for their institution from Nippon Kayaku, Asahi Kasei, Chugai, Taiho, Daiichi Sankyo, Japan Blood Products Organization, Mochida, and Sun Pharma outside the submitted work. Other authors do not have conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 3 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 3 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 3 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 3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT 3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT 3 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., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)