AbstractTolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S.

摘要托伐普坦相关性肝病是一种罕见但致命的不良事件；然而，确切的风险和发病时间仍不清楚。。患者数据来自日本药品不良事件报告数据库（JADER）和日本AERS数据库，该数据库由美国。

Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04).

食品和药物管理局不良事件报告系统（FAERS）由日本药品信息中心处理。肝病被分类为严重或非严重。在使用FAERS的分析中，托伐普坦的使用与肝病有关[严重肝病：报告优势比（ROR）4.93，95%置信区间（CI）4.33-5.61；信息成分（IC）2.11，95%CI 1.92-2.29；非严重肝病：ROR 6.78，95%CI 6.01-7.65；IC 2.51，95%CI 2.33-2.68]和JADER（严重肝病：ROR 4.21，95%CI 3.57-4.97；IC 1.86，95%CI 1.63-2.10；非严重肝病：ROR 4.27，95%CI 3.68-4.95；IC 1.83，95%CI 1.62-2.04）。

A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs.

发病时间分析显示，无论严重程度如何，60岁以下患者的中位发病时间明显长于60岁以上患者（FAERS：严重肝病7天vs.58天，p<0.0001；非严重肝病8天vs.52.5天，p<0.0001；JADER：严重肝病9.5 vs。

32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes..

32天，p=0.0017；非严重肝病9天比89天，p<0.0001）。无论肝病的严重程度如何，都观察到了严重的结果。应根据年龄监测患者的肝功能，以防止致命的后果。。

IntroductionTolvaptan, a vasopressin receptor 2 antagonist, is widely used to treat autosomal dominant polycystic kidney disease, syndrome of inappropriate secretion of antidiuretic hormone, and edema caused by heart failure and cirrhosis1,2. However, it is necessary to appropriately manage adverse events (AEs), which include thirst, hypernatremia, constipation, and polyuria3,4,5,6.

引言托伐普坦是一种加压素受体2拮抗剂，广泛用于治疗常染色体显性遗传性多囊肾病，抗利尿激素分泌不当综合征以及心力衰竭和肝硬化引起的水肿1,2。然而，有必要适当管理不良事件（AE），包括口渴，高钠血症，便秘和多尿3,4,5,6。

Thirst is the most frequently reported AE, and adequate hydration is necessary to avoid dehydration. In particular, elderly patients become less sensitive to thirst are require more attention7. Recently, the results of a survey using the Japanese Adverse Drug Event Report database (JADER), indicated that tolvaptan had a high association with drug‐induced liver injury8.

口渴是最常报告的AE，需要足够的水合作用以避免脱水。特别是，老年患者对口渴的敏感性降低，需要更多的关注7。最近，使用日本药物不良事件报告数据库（JADER）进行的一项调查结果表明，托伐普坦与药物引起的肝损伤高度相关8。

Hepatic disorder caused by tolvaptan is a rare, but potentially lethal AE9. There are some reports indicating that tolvaptan is associated with idiosyncratic drug-induced liver injury9,10,11,12,13,14,15, and regular hepatic monitoring is recommended to prevent liver damage10. The mechanisms underlying tolvaptan-associated hepatoxicity have been examined in vitro16,17,18,19,20, and hypersensitivity to tolvaptan has been associated with liver injury17.

托伐普坦引起的肝病是一种罕见但可能致命的AE9。有报道表明托伐普坦与特异性药物性肝损伤有关[9,10,11,12,13,14,15]，建议定期进行肝脏监测以预防肝脏损伤10。托伐普坦相关肝毒性的机制已在体外进行了研究[16,17,18,19,20]，对托伐普坦的超敏反应与肝损伤有关17。

In the clinical study, the association between female sex and hepatoxicity has been reported, but this report has not been thoroughly investigated due to the small number of cases15. Furthermore, the impact of aging on tolvaptan-associated hepatoxicity has not been thoroughly studied. In a previous research on various drugs excluding tolvaptan, aging and female sex have been identified as risk factors for drug‐induced liver injury21.

在临床研究中，已经报道了女性性别与肝毒性之间的关联，但由于病例数量少，该报告尚未得到彻底调查15。此外，尚未彻底研究衰老对托伐普坦相关肝毒性的影响。在之前对托伐普坦以外的各种药物的研究中，衰老和女性已被确定为药物性肝损伤的危险因素21。

Therefore, aging and sex may influence the onset of tolvaptan-associated hepatic disorder, though the relationship remains unclear.Pharmacovigilance .

因此，年龄和性别可能会影响托伐普坦相关性肝病的发作，尽管这种关系尚不清楚。药物警戒。

Data availability

数据可用性

The FAERS and JADER databases analyzed in this study are publicly available. Both databases can be downloaded from their websites (FAERS: https://www.fda.gov/, JADER: https://www.pmda.go.jp/index.html).

本研究中分析的FAERS和JADER数据库可公开获得。这两个数据库都可以从各自的网站下载（FAERS：https://www.fda.gov/，贾德：https://www.pmda.go.jp/index.html)。

ReferencesBlair, H. A. Tolvaptan: A review in autosomal dominant polycystic kidney disease. Drugs 79, 303–313 (2019).Article

参考文献Blair，H。A。Tolvaptan：常染色体显性多囊肾病的综述。药物79303-313（2019）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Plosker, G. L. Tolvaptan. Drugs 70, 443–454 (2010).Article

普洛斯克，G.L.托尔瓦普坦。药物70443-454（2010）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gheorghiade, M. et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA 297, 1332–1343 (2007).Article

Ghorghiade，M.等人。口服加压素拮抗剂托伐普坦对心力衰竭住院患者的短期临床效果：珠穆朗玛峰临床状态试验。JAMA 2971332–1343（2007）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Konstam, M. A. et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 297, 1319–1331 (2007).Article

Konstam，M.A.等人。口服托伐普坦对因心力衰竭恶化住院患者的影响：珠穆朗玛峰结局试验。JAMA 2971319-1331（2007）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Schrier, R. W. et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N. Engl. J. Med. 355, 2099–2112 (2006).Article

Schrier，R。W。等人，托伐普坦，一种选择性口服加压素V2受体拮抗剂，用于低钠血症。N、 英语。J、 医学3552099-2112（2006）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407–2418 (2012).Article

Torres，V.E.等人，托伐普坦治疗常染色体显性多囊肾病患者。N、 英语。J、 医学3672407-2418（2012）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kinugawa, K. et al. Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of samsca post-marketing surveillance in heart failure (SMILE study). Int. Heart J. 56, 137–143 (2015).Article

Kinugawa，K。等人。托伐普坦在80岁心力衰竭患者中的有效性和不良事件。samsca心力衰竭上市后监测的中期分析（SMILE研究）。《国际心脏杂志》56137-143（2015）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Kamimura, H. et al. Analysis of drug-induced liver-related adverse event trend reporting between 1997 and 2019. Hepatol. Res. 53, 556–568 (2023).Article

Kamimura，H.等人。1997年至2019年间药物引起的肝脏相关不良事件趋势报告分析。肝病。第53556-568号决议（2023年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Rangarajan, B., Binoy, V., Hingmire, S. S. & Noronha, V. Tolvaptan. South Asian J. Cancer 3, 182–184 (2014).Article

兰加拉詹（B.Rangarajan），比尼（Binoy），辛格米尔（Hingmire），S.S。和诺罗尼亚（Noronha），托尔瓦普坦（V.Tolvaptan）。南亚J.癌症3182-184（2014）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Alpers, D. H. et al. Clinical pattern of tolvaptan-associated liver injury in trial participants with autosomal dominant polycystic kidney disease (ADPKD): An analysis of pivotal clinical trials. Am. J. Kidney Dis. 81, 281–293 (2023).Article

Alpers，D.H.等人。常染色体显性多囊肾病（ADPKD）试验参与者托伐普坦相关性肝损伤的临床模式：关键临床试验的分析。美国肾脏病杂志。81281-293（2023）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Lu, J. et al. Efficacy and safety of tolvaptan versus placebo in the treatment of patients with autosomal dominant polycystic kidney disease: A meta-analysis. Int. Urol. Nephrol. 55, 631–640 (2023).Article

Lu，J.等人。托伐普坦与安慰剂治疗常染色体显性多囊肾病患者的疗效和安全性：荟萃分析。内部Urol。肾。55631-640（2023）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Mochizuki, T., Muto, S., Miyake, M., Tanaka, T. & Wang, W. Safety and efficacy of tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance. Clin. Exp. Nephrol. 25, 1231–1239 (2021).Article

Mochizuki，T.，Muto，S.，Miyake，M.，Tanaka，T。＆Wang，W。托伐普坦在常染色体显性多囊肾病患者中的安全性和有效性-SLOW-PKD监测的中期结果。临床。实验肾。251231-1239（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pellegrino, A. M., Annicchiarico Petruzzelli, L., Riccio, E. & Pisani, A. Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: A case report. BMC Nephrol. 20, 426 (2019).Article .

Pellegrino，A.M.，Annicchiarico Petruzzelli，L.，Riccio，E。＆Pisani，A。常染色体显性多囊肾病（ADPKD）患者联合托伐普坦和阿莫西林/克拉维酸治疗的特异性肝毒性：病例报告。BMC肾。20426（2019）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Torres, V. E. et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N. Engl. J. Med. 377, 1930–1942 (2017).Article

Torres，V.E.等人，托伐普坦治疗晚期常染色体显性多囊肾病。N、 英语。J、 医学3771930-1942（2017）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Watkins, P. B. et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: Analysis of clinical trials database. Drug Saf. 38, 1103–1113 (2015).Article

Watkins，P.B.等人。常染色体显性多囊肾病患者托伐普坦相关性肝损伤的临床模式：临床试验数据库分析。药物安全。381103-1113（2015）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mosedale, M. et al. Editor’s highlight: Candidate risk factors and mechanisms for tolvaptan-induced liver injury are identified using a collaborative cross approach. Toxicol. Sci. 156, 438–454 (2017).CAS

Mosedale，M。等人的编辑要点：使用协作交叉方法确定托伐普坦诱导的肝损伤的候选危险因素和机制。毒理学。科学。156438-454（2017）。中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mosedale, M. et al. miR-122 release in exosomes precedes overt tolvaptan-induced necrosis in a primary human hepatocyte micropatterned coculture model. Toxicol. Sci. 161, 149–158 (2018).Article

在原代人肝细胞微模式共培养模型中，外泌体中miR-122的释放先于托伐普坦诱导的明显坏死。毒理学。科学。161149-158（2018）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Slizgi, J. R. et al. Inhibition of human hepatic bile acid transporters by tolvaptan and metabolites: Contributing factors to drug-induced liver injury? Toxicol. Sci. 149, 237–250 (2016).Article

Slizgi，J.R.等人。托伐普坦及其代谢物对人肝胆汁酸转运蛋白的抑制作用：药物性肝损伤的影响因素？毒理学。科学。149237-250（2016）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Woodhead, J. L. et al. Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. Toxicol. Sci. 155, 61–74 (2017).Article

Woodhead，J.L.等人。应用机制模型评估托伐普坦药物性肝损伤的推定机制并确定患者易感因素。毒理学。科学。155,61-74（2017）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wu, Y. et al. Mechanisms of tolvaptan-induced toxicity in HepG2 cells. Biochem. Pharmacol. 95, 324–336 (2015).Article

Wu，Y。等人。托伐普坦诱导HepG2细胞毒性的机制。生物化学。药理学。95324-336（2015）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lucena, M. I. et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: The influence of age and sex. Hepatology 49, 2001–2009 (2009).Article

。肝病492001-2009（2009）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Anzai, T., Takahashi, K., Watanabe, M., Mochizuki, M. & Murashima, A. Adverse event reports in patients taking psychiatric medication during pregnancy from spontaneous reports in Japan and the United States: An approach using latent class analysis. BMC Psychiatry 20, 118 (2020).Article .

Anzai，T.，Takahashi，K.，Watanabe，M.，Mochizuki，M。＆Murashima，A。日本和美国自发报告中怀孕期间服用精神药物的患者的不良事件报告：使用潜在类别分析的方法。BMC精神病学20118（2020）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Imai, T., Hazama, K., Kosuge, Y., Suzuki, S. & Ootsuka, S. Preventive effect of rebamipide on NSAID-induced lower gastrointestinal tract injury using FAERS and JADER. Sci. Rep. 12, 2631 (2022).Article

Imai，T.，Hazama，K.，Kosuge，Y.，Suzuki，S。＆Ootsuka，S。使用FAERS和JADER预防瑞巴派特对NSAID诱导的下消化道损伤的预防作用。科学。第122631页（2022年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nagai, J. & Ishikawa, Y. Analysis of anticholinergic adverse effects using two large databases: The US food and drug administration adverse event reporting system database and the Japanese adverse drug event report database. PLoS One 16, e0260980 (2021).Article

Nagai，J。＆Ishikawa，Y。使用两个大型数据库分析抗胆碱能不良反应：美国食品和药物管理局不良事件报告系统数据库和日本不良药物事件报告数据库。PLoS One 16，e0260980（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nawa, H. et al. Evaluation of the potential complication of interstitial lung disease associated with antifibrotic drugs using data from databases reporting spontaneous adverse effects. Clin. Transl. Sci. 15, 2982–2988 (2022).Article

Nawa，H。等人。使用来自报告自发性不良反应的数据库的数据评估与抗纤维化药物相关的间质性肺病的潜在并发症。临床。翻译。科学。152982-2988（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Shimada, K. et al. Adverse reaction profiles of hemorrhagic adverse reactions caused by direct oral anticoagulants analyzed using the food and drug administration adverse event reporting system (FAERS) database and the Japanese adverse drug event report (JADER) database. Int. J. Med.

Shimada，K.等人。使用食品和药物管理局不良事件报告系统（FAERS）数据库和日本药物不良事件报告（JADER）数据库分析了直接口服抗凝剂引起的出血性不良反应的不良反应概况。国际医学杂志。

Sci. 16, 1295–1303 (2019).Article .

科学。。文章。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Beak, H. S. & Cho, M. H. Tolvaptan: A possible preemptive treatment option in children with autosomal dominant polycystic kidney disease? Child. Kidney Dis. 27, 76–81 (2023).Article

Beak，H.S.＆Cho，M.H.Tolvaptan：常染色体显性遗传多囊肾病儿童可能的先发制人治疗选择？孩子。肾脏疾病。27，76-81（2023）。文章

Google Scholar

谷歌学者

Faillie, J. L. Case-non-case studies: Principle, methods, bias and interpretation. Therapie 74, 225–232 (2019).Article

Faillie，J.L。案例非案例研究：原则，方法，偏见和解释。Therapie 74225-232（2019）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Noguchi, Y., Tachi, T. & Teramachi, H. Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source. Brief. Bioinform. 22, bbab347 (2021).Article

Noguchi，Y.，Tachi，T。＆Teramachi，H。使用自发报告系统作为临床数据源的检测算法和安全信号注意点。简介。生物信息。22，bbab347（2021）。文章

Google Scholar

谷歌学者

Bate, A. et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur. J. Clin. Pharmacol. 54, 315–321 (1998).Article

Bate，A。等人。用于药物不良反应信号产生的贝叶斯神经网络方法。欧洲临床杂志。药理学。54315-321（1998）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Lindquist, M., Ståhl, M., Bate, A., Edwards, I. R. & Meyboom, R. H. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf. 23, 533–542 (2000).Article

。药物安全。23533-542（2000）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

van Puijenbroek, E. P. et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol. Drug Saf. 11, 3–10 (2002).Article

van Puijenbroek，E.P.等人，《药物不良反应自发报告系统中信号检测不成比例度量的比较》。药物流行病学。药物安全。11，3-10（2002）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Cornelius, V. R., Sauzet, O. & Evans, S. J. A signal detection method to detect adverse drug reactions using a parametric time-to-event model in simulated cohort data. Drug Saf. 35, 599–610 (2012).Article

Cornelius，V.R.，Sauzet，O。＆Evans，S.J。一种信号检测方法，用于在模拟队列数据中使用参数时间-事件模型检测药物不良反应。药物安全。35599-610（2012）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Sauzet, O., Carvajal, A., Escudero, A., Molokhia, M. & Cornelius, V. R. Illustration of the weibull shape parameter signal detection tool using electronic healthcare record data. Drug Saf. 36, 995–1006 (2013).Article

Sauzet，O.，Carvajal，A.，Escudero，A.，Molokhia，M。＆Cornelius，V.R。使用电子医疗记录数据的weibull形状参数信号检测工具的图示。药物安全。36995-1006（2013）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Aung, T. T. et al. Autosomal dominant polycystic kidney disease prevalence among a racially diverse united states population, 2002 through 2018. Kidney360 2, 2010–2015 (2021).Article

Aung，T.T.等人，《2002年至2018年美国不同种族人群中常染色体显性多囊肾病患病率》。肾脏360 22010–2015（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Baur, B. P. & Meaney, C. J. Review of tolvaptan for autosomal dominant polycystic kidney disease. Pharmacotherapy 34, 605–616 (2014).Article

Baur，B.P。＆Meaney，C.J。托伐普坦治疗常染色体显性多囊肾病的综述。药物治疗34605-616（2014）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Muto, S. et al. Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO extension Japan trial. Drug Healthc. Patient Saf. 9, 93–104 (2017).Article

。药物健康C。患者Saf。9,93-104（2017）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hartnell, N. R. & Wilson, J. P. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States food and drug administration. Pharmacotherapy 24, 743–749 (2004).Article

Hartnell，N.R。＆Wilson，J.P。使用自愿提交给美国食品和药物管理局的上市后不良事件报告复制韦伯效应。药物治疗24743-749（2004）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Pariente, A., Gregoire, F., Fourrier-Reglat, A., Haramburu, F. & Moore, N. Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: The notoriety bias. Drug Saf. 30, 891–898 (2007).Article

Pariente，A.，Gregoire，F.，Fourier-Reglat，A.，Haramburu，F。＆Moore，N。安全警报对自发报告数据库中不成比例测量的影响：臭名昭著的偏见。药物安全。30891-898（2007）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Wang, H. W., Hochberg, A. M., Pearson, R. K. & Hauben, M. An experimental investigation of masking in the US FDA adverse event reporting system database. Drug Saf. 33, 1117–1133 (2010).Article

Wang，H.W.，Hochberg，A.M.，Pearson，R.K。＆Hauben，M。美国FDA不良事件报告系统数据库中掩蔽的实验研究。药物安全。331117-1133（2010）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Sakaida, I. et al. Real-world effectiveness and safety of tolvaptan in liver cirrhosis patients with hepatic edema: Results from a post-marketing surveillance study (START study). J. Gastroenterol. 55, 800–810 (2020).Article

Sakaida，I.等人。托伐普坦在肝硬化肝水肿患者中的实际有效性和安全性：上市后监测研究（START研究）的结果。J、 。。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bozkurt, B. et al. Heart failure epidemiology and outcomes statistics: A report of the heart failure society of America. J. Card. Fail. 29, 1412–1451 (2023).Article

Bozkurt，B。等。心力衰竭流行病学和结果统计：美国心力衰竭协会的报告。J、 卡片。失败。。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Krisanapan, P. et al. Safety and efficacy of vaptans in the treatment of hyponatremia from syndrome of inappropriate antidiuretic hormone secretion (SIADH): A systematic review and meta-analysis. J. Clin. Med. 12, 5483 (2023).Article

Krianapan，P。等人。vaptans治疗抗利尿激素分泌不适当综合征（SIADH）低钠血症的安全性和有效性：系统评价和荟萃分析。J、 临床。医学杂志125483（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sajja, K. C., Mohan, D. P. & Rockey, D. C. Age and ethnicity in cirrhosis. J. Investig. Med. 62, 920–926 (2014).Article

Sajja，K.C.，Mohan，D.P。和Rockey，D.C。肝硬化的年龄和种族。J、 调查。医学62920-926（2014）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsThis study was partially supported by the OSAKAYAKUGYO-CLUB (the fiscal year 2022, grant number 5). We thank the Japan Pharmaceutical Information Center (JAPIC: https://www.japic.or.jp) for processing FAERS data. We also thank Enago (https://www.enago.jp/) for the English language review.FundingOSAKAYAKUGYO-CLUB (the fiscal year 2022, grant number 5).Author informationAuthors and AffiliationsDivision of Drug Informatics, School of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, JapanTakaya Uno, Kouichi Hosomi & Satoshi YokoyamaAuthorsTakaya UnoView author publicationsYou can also search for this author in.

下载参考文献致谢本研究得到了OSAKAYAKUGYO-CLUB（2022财年，资助号5）的部分支持。我们感谢日本药品信息中心（日本：https://www.japic.or.jp)用于处理FAERS数据。我们也感谢Enago(https://www.enago.jp/)英语复习。FundingOSAKAYAKUGYO俱乐部（2022财政年度，拨款编号5）。作者信息作者和附属机构金台大学药学院药物信息学系，3-4-1 Kowakae，Higashi Osaka，Osaka，577-8502，JapanTakaya Uno，Kouichi Hosomi＆Satoshi YokoyamaAuthorsTakaya UnoView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarKouichi HosomiView author publicationsYou can also search for this author in

PubMed Google ScholarKouichi HosomiView作者出版物您也可以在

PubMed Google ScholarSatoshi YokoyamaView author publicationsYou can also search for this author in

PubMed Google Scholarastoshi YokoyamaView作者出版物您也可以在

PubMed Google ScholarContributionsAll authors contributed to the design of the study. Material preparation and data collection were performed by T.U. and K.H. Analysis and interpretation of the results were performed by T.U., K.H., and S.Y. The first draft of the manuscript was prepared by T.U., and all authors provided inputs on the previous versions of the manuscript.

PubMed谷歌学术贡献所有作者都为研究的设计做出了贡献。材料准备和数据收集由T.U.和K.H.进行。结果的分析和解释由T.U.，K.H.和S.Y.进行。手稿的初稿由T.U.编写，所有作者都提供了关于手稿以前版本的输入。

All authors have read and approved the final version of the manuscript.Corresponding authorCorrespondence to.

所有作者都阅读并批准了稿件的最终版本。对应作者对应。

Takaya Uno.Ethics declarations

Takaya Uno。道德宣言

Competing interests

相互竞争的利益

K.H. has received research funding from GEXVal Inc. The remaining authors declare no competing interests.

K、 H.已获得GEXVal Inc.的研究资助。其余作者声明没有利益冲突。

Ethical approval statement

道德批准声明

This study was conducted in accordance with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects established by the Ministry of Health, Labour and Welfare in Japan. It was approved by the Ethics Committee of the Kindai University School of Pharmacy on September 10, 2022 (approval number, 22-218).

这项研究是根据日本厚生劳动省制定的涉及人类受试者的医学和生物学研究伦理准则进行的。它于2022年9月10日获得金代大学药学院伦理委员会的批准（批准号22-218）。

The Ethics Committee waived the requirement for informed consent because all data were fully anonymized by the relevant regulatory authority..

道德委员会放弃了知情同意的要求，因为所有数据均由相关监管机构完全匿名。。

Additional informationPublisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary InformationSupplementary Information.Rights and permissions

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleUno, T., Hosomi, K. & Yokoyama, S. Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases.

转载和许可本文引用本文Uno，T.，Hosomi，K。＆Yokoyama，S。使用不同的国家药物警戒数据库评估托伐普坦相关性肝病。

Sci Rep 14, 25943 (2024). https://doi.org/10.1038/s41598-024-77052-yDownload citationReceived: 19 April 2024Accepted: 18 October 2024Published: 29 October 2024DOI: https://doi.org/10.1038/s41598-024-77052-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《科学报告》1425943（2024）。https://doi.org/10.1038/s41598-024-77052-yDownload引文接收日期：2024年4月19日接受日期：2024年10月18日发布日期：2024年10月29日OI：https://doi.org/10.1038/s41598-024-77052-yShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsTolvaptanHepatic disorderLiverSpontaneous reporting systemAdverse eventPharmacovigilance

关键词肝病自发性报告系统不良事件药物警戒