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![Effects of 5‐HT₃ receptor antagonists on cisplatin‐induced nephrotoxicity. (a–f) Representative hematoxylin and eosin staining (H&E) of the kidney section of the control mice, cisplatin (CDDP)‐injected mice with vehicle or a 5‐HT₃ receptor antagonist. (a) vehicle, (b) CDDP, (c) CDDP + ondansetron, (d) CDDP + granisetron, (e) CDDP + ramosetron, (f) CDDP + palonosetron. (g) Quantitative analysis of renal damage scores. Values are expressed as mean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 vs. vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01 versus CDDP + palonosetron mice; n = 7–9 in each group. (h), (i) The mRNA expression levels of kidney injury markers (Kim‐1 [h] and Lcn‐2 [i]) in the kidneys of mice in each group. Values are expressed as mean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 versus vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01 versus CDDP + palonosetron mice; n = 7–9 in each group](publication/351558698/figure/fig1/AS:11431281180032344@1691473256217/Effects-of-5-HT-receptor-antagonists-on-cisplatin-induced-nephrotoxicity-a-f.png)
Effects of 5‐HT₃ receptor antagonists on cisplatin‐induced nephrotoxicity. (a–f) Representative hematoxylin and eosin staining (H&E) of the kidney section of the control mice, cisplatin (CDDP)‐injected mice with vehicle or a 5‐HT₃ receptor antagonist. (a) vehicle, (b) CDDP, (c) CDDP + ondansetron, (d) CDDP + granisetron, (e) CDDP + ramosetron, (f) CDDP + palonosetron. (g) Quantitative analysis of renal damage scores. Values are expressed as mean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 vs. vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01 versus CDDP + palonosetron mice; n = 7–9 in each group. (h), (i) The mRNA expression levels of kidney injury markers (Kim‐1 [h] and Lcn‐2 [i]) in the kidneys of mice in each group. Values are expressed as mean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 versus vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01 versus CDDP + palonosetron mice; n = 7–9 in each group
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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 ef...
Citations
... To establish a mouse model of cisplatin-induced renal injury, we used C57BL/6N male mice following established protocols described previously. 18,19 Mice were randomly allocated to six groups (n = 5-8 mice/group): group 1, vehicle-injected; group 2, VPAtreated; group 3, cisplatin-injected; and groups 4-6, cisplatin-injected with add-on VPA at 10, 30, and 100 mg/kg, respectively. Mice were intraperitoneally injected with cisplatin (groups 3-6, 15 mg/kg) or vehicle (groups 1 and 2, saline) once. ...
... A previous study using a large medical information database and hospital medical records found an increased incidence of cisplatin-induced kidney injury in patients administered ondansetron and a decreased incidence in those administered palonosetron. 18 Our results are similar to those of the previous study, thus confirming the accuracy of the present analysis. VPA exhibited an ROR of less than 1, indicating reduced occurrence of cisplatin-induced renal injury (Table 1). ...
... 4 Our previous study suggested that differences in cisplatin accumulation at 4 h after cisplatin administration affect the extent of cisplatin-induced renal injury. 18 To demonstrate that VPA is not related to cisplatin levels, renal platinum concentrations were determined to examine the effect of VPA on cisplatin accumulation in the kidneys. Our findings revealed no alterations in platinum levels in the kidneys or whole blood ( Figure S1). ...
Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin‐induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin‐induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin‐induced toxicity. In the mouse model of cisplatin‐induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin‐treated and valproic acid‐treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin‐induced decrease in cell viability was significantly suppressed by co‐treatment with valproic acid. Valproic acid may inhibit cisplatin‐induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application.
... Therefore, protecting the renal function during administration is needed. However, a study indicated that the first-generation 5-HT3R antagonists (ondansetron, granisetron, tropisetron) exacerbated cisplatin-induced renal injury, whereas the second-generation 5-HT3R antagonists (palonosetron) showed greater anti-cisplatin-induced nephrotoxicity than other 5-HT3R antagonists [84,85]. A study reported ondansetron is associated with an increasing risk of AKI [86]. ...
Background:
Perioperative acute kidney injury (AKI) is common in surgical patients and is associated with high morbidity and mortality. There are currently few options for AKI prevention and treatment. Due to its complex pathophysiology, there is no efficient medication therapy to stop the onset of the injury or repair the damage already done. Certain anesthetics, however, have been demonstrated to affect the risk of perioperative AKI in some studies. The impact of anesthetics on renal function is particularly important, as it is closely related to the prognosis of patients. Some anesthetics can induce anti-inflammatory, anti-necrotic and anti-apoptotic effects. Propofol, sevoflurane, and dexmedetomidine (DEX) are a few examples of anesthetics that have protective association with AKI in the perioperative period.
Summary:
In this study, we reviewed the clinical characteristics, risk factors and pathogenesis of AKI. Subsequently, the protective effects of various anesthetic agents against perioperative AKI and the latest research are then introduced.
Key message:
This work demonstrates that a thorough understanding of the reciprocal effects of anesthetic drugs and AKI is crucial for safe perioperative care and prognosis of patients. However, more complete mechanisms and pathophysiological processes still need to be further studied.
... More than 90% of the 5-HT in the body are released in the gastrointestinal tract, and many 5-HT receptors are also distributed in the intestine, such as 5-HT1 A [41]. 5-HT in the gut produces a possibility that gut alterations may be important in the pathophysiology of MDD [42]. This may be the reason that many studies have recently found that the brain-gut axis alternation is an important cause of depression, and indeed the greatest side effect of increased 5-HT is an increase in gastrointestinal nausea and vomiting response [43]. ...
Major depressive disorder (MDD) is a common and complex mental disorder, that adversely impacts an individual’s quality of life, but its diagnosis and treatment are not accurately executed and a symptom-based approach is utilized in most cases, due to the lack of precise knowledge regarding the pathophysiology. So far, the first-line treatments are still based on monoamine neurotransmitters. Even though there is a lot of progress in this field, the mechanisms seem to get more and more confusing, and the treatment is also getting more and more controversial. In this study, we try to review the broad advances of monoamine neurotransmitters in the field of MDD, and update its effects in many advanced neuroscience studies. We still propose the monoamine hypothesis but paid special attention to their effects on the new pathways for MDD, such as inflammation, oxidative stress, neurotrophins, and neurogenesis, especially in the glial cells, which have recently been found to play an important role in many neurodegenerative disorders, including MDD. In addition, we will extend the monoamine hypothesis to basic emotions; as suggested in our previous reports, the three monoamine neurotransmitters play different roles in emotions: dopamine—joy, norepinephrine—fear (anger), serotonins—disgust (sadness). Above all, this paper tries to give a full picture of the relationship between the MDD and the monoamine neurotransmitters such as DA, NE, and 5-HT, as well as their contributions to the Three Primary Color Model of Basic Emotions (joy, fear, and disgust). This is done by explaining the contribution of the monoamine from many sides for MDD, such the digestive tract, astrocytes, microglial, and others, and very briefly addressing the potential of monoamine neurotransmitters as a therapeutic approach for MDD patients and also the reasons for its limited clinical efficacy, side effects, and delayed onset of action. We hope this review might offer new pharmacological management of MDD.
... A previous retrospective study reported that palonosetron suppressed CDDP-induced increases in serum creatinine (Scr) and blood urea nitrogen (BUN) levels from clinical data treated with CDDP and 5-HT 3 RAs [7]. Furthermore, an analysis using the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that first-generation 5-HT 3 RAs (ondansetron, granisetron, or ramosetron) significantly increased renal adverse events associated with CDDP as compared with a second-generation 5-HT 3 RA, palonosetron [8]. However, the advantage of palonosetron on CDDP-induced nephrotoxicity and CINV in comparison with other 5-HT 3 RAs remains unclear in patients with the triple antiemetic therapy. ...
... CDDP is mainly transported to renal tissues via organic cation transporter 2 (OCT2) at the renal basolateral membrane [12,13], whereas CDDP is excreted into urine through multidrug and toxin extrusion protein transporter 1 (MATE1), which is localized on the apical membrane [14], indicating that OCT2 and MATE1 should be responsible for CDDP-induced nephrotoxicity. As shown in a previous study using the mice model of CDDPinduced nephrotoxicity [8], the concomitant use of a first-generation 5-HT 3 RA (ondansetron, granisetron, or ramosetron) significantly increased CDDP 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 CDDP alone. ...
... Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of CDDP alone. An uptake study in hMATE1-expressing HEK293 cells revealed that the first-generation 5-HT 3 RAs have a lower IC 50 than palonosetron, thus, palonosetron is thought to have weaker MATE1 inhibitory activity than the firstgeneration 5-HT 3 RAs [8]. Furthermore, palonosetron was reported to interfere with OCT2 activity [15]. ...
Background
Cisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT 3 RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT 3 RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT 3 RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis.
Methods
We retrospectively analyzed the effect of 5-HT 3 RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT 3 RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database.
Results
In a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT 3 RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups ( p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169–0.472).
Conclusions
The findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT 3 RAs in patients with the triple antiemetic therapy.
... The mouse model of cisplatin-induced renal injury was generated following a previously described method. 13 The mice were randomly divided into eight groups (n = 7-9 per group): vehicle-injected, cisplatin-injected, and fenofibrate (30, 100, and 300 mg/kg) or bezafibrate (30, 100, and 300 mg/kg) administered to the cisplatin-injected group. The mice were intraperitoneally injected with cisplatin (15 mg/kg) or vehicle (saline). ...
Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin‐induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin‐induced renal injury, Library of Integrated Network‐based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin‐induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US FDA Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin‐induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin‐induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin‐induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin‐induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin‐induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.
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Drug repositioning is a drug discovery strategy in which an existing drug is utilized as a therapeutic agent for a different disease. As information regarding the safety, pharmacokinetics, and formulation of existing drugs is already available, the cost and time required for drug development is reduced. Conventional drug repositioning has been dominated by a method involving the search for candidate drugs that act on the target molecules of an organism in a diseased state through basic research. However, recently, information hosted on medical information and life science databases have been used in translational research to bridge the gap between basic research in drug repositioning and clinical application. Here, we review an example of drug repositioning wherein candidate drugs were found and their mechanisms of action against a novel therapeutic target were identified via a basic research method that combines the findings retrieved from various medical and life science databases.
