Quantification of Structurally Alert Mutagenic Impurities in Meropenem Trihydrate Drug Substance by Liquid Chromatography with High Resolution Mass Spectrometer (LC-HRMS)

Potential mutagenic impurities in Active Pharmaceutical Ingredient, Meropenem Trihydrate were assessed and a novel analytical method for their quantification was developed and validated. This Liquid Chromatographic method using High Resolution Mass Spectrometer (LC-HRMS) technique is proved to be suitable for simultaneous quantification of all ten identified impurities with required specificity, sensitivity, resolution, precision, accuracy, and other method characteristics as per ICH Guidelines. The acceptable limit of less than 2.9 μg/g was considered for evaluations, based on drug substance dosage and duration of treatment. The method stands most sensitive with a Limit of Detection of 0.35 μg/g, considering the challenge full acceptance criteria as per current regulatory standards.

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

MUTAGENICITY AND CARCINOGENICITY OF FISH SAUCE FROM A COUNTY WITH THE HIGH RISK FOR GASTRIC CANCER IN CHINA

The mutagenicity and carcinogenicity of fish sauce (FS) sample from Changle County, a high gastric cancer mortality (113.20/105) area, were investigated with the biologic short-term tests and laboratory animal experiment. The results showed that the extract of FS was markedly direct mutagenic toward S. typhimurium TA100, induced high sister chromatid exchanges (SCE) and micronucleus (MN) in V79 cells after nitrosation with sodium nitrite. But the non-nitrosated FS did not. The nitrosated fish sauce (NFS) also induced SOS in E. coli PQ37 and alkylation of calfthymus DNA. The potency of NFS to induce unscheduled DNA synthesis (UDS) in human normal gastric mucosal cells was increased about fivefold compared with FS. When the NFS extract was given to newborn rats by gavage, dys-plasia and adenocaroinoma were induced in the glandular stomach in the 4th and 16th experimental week, respectively. N-nitrosamides were also found in NFS, which may account for the mutagenicity and carcinogenicity of NFS. It is indicated that FS, a traditional daily eaten seasoning, may contribute to the causes of the high gastric cancer mortality for the local residents.

Studies on the Mutagenicity and Teratogenicity of Kuianchun and Its Potential Carcinogenicity Prediction

Kuianchun is a newly synthesized antibacterial and growth-promoting drug. This paper selected a battery of three short-term tests, including Ames test, micronucleus test and sperm abnormality test, to detect the mutagenicity of Kuianchun. The carcinogenicity prediction and battery selection method (CPBS method) was used to determine the probability of carcinogenicity of Kuianchun based upon the results of short-term tests mentioned above. In addition, traditional teratogenic test was selected to study teratogenicity of Kuianchun. In Ames test, Kuianchun showed mutagenic for Salmonella typhimurium strains TA98 and TA100 in the absence and presence of microsomal metabolic activation system (S9-mix). However, the mutagenicity was reduced by the addition of S9-mix. In micronucleus test, Kuianchun was administered intra-peritoneally to male mouse 30 hours and 6 hours before they were killed respectively. The result indicated that there was no significant difference on the number of micronucleated polychromatic erythrocytes (PCEs) in the mouse bone marrow induced by Kuianchun compared with the negative contrast (50% DMSO) (P>0.05). In sperm abnormality test, Kuianchun was administered through a gastric incubation to male mouse as a suspension in 2% Tween-80. The dosage levels were 450, 750, 1000 and 1500mg/kg per day for 5 days. The result indicated that the percentage of abnormal sperms induced by Kuianchun was not significant compared with the negative contrast (P > 0.05). In traditional teratogenic test, Kuianchun was given orally to pregnant mouse at 1730, 1/20 and 1/15 LD50 during 6 - 15days of pregnancy period (the LD50 = 9000mg/kg). No toxicity was found either on mother and embryo in mouse, and teratogenic effects were also not observed at all tested dosages.The probability of carcinogenicity of Kuianchun is 23.8%(6 = 0.238). The result demonstrated that Kuianchun is a non-carcinogen.

CHEMICAL“CARCINOGENS”,AS MODULATORS OF INTER-CELLULAR COMMUNICATION,ARE MITOGENS,NOT MUTAGENS.

Although mutations clearly play a role in themulti-stage process of carcinogenesis,a challengewll be made to the paradigm that most chemical"carcinogens" act via mutagenic activity("carcinogens as mutagens").Control ofproliferation and differentiation within andbetween tissues is mediated by

The transcriptome analysis of cleft lip/palate-related PTCH1 variants in GMSM-K cells show carcinogenic potential

Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.

苜蓿抗寒突变体生理生化及性状指标分析

为选育在黑龙江省可越冬的理想紫花苜蓿品种。以‘龙牧806’零磁空间诱变处理后二代群体中获得的lm1609、lm1625、lm1704三个抗寒突变体为实验材料,通过测定发芽指标、越冬率、产量特性指标及根系生理生化指标,进行抗寒性能鉴定。3个突变体发芽指数与对照差异不显著;发芽势、简化活力指数lm1609显著高于lm1625、lm1704,分别为82.05%、469.82(P<0.05);3个突变体的越冬率都显著低于对照组;突变体和对照6月6日起始株高差异不显著,随着植株生长,7月6日和8月6日lm1609、lm1704显著高于lm1625和对照;突变体lm1609、lm1625、lm1704三者鲜草产量差异不显著,但显著高于对照(P<0.05);三个苜蓿突变体植株根系过氧化物酶、超氧化物歧化酶均显著高于对照,并且突变体lm1609 POD、SOD最高,分别达到304.85 OD470/(min·g)、208.41 U/g(P<0.05)。lm1609突变体具有较高的抗寒特性及产量特性,是为理想的抗寒突变体材料。

建立我国自主知识产权的致癌性小鼠模型

致癌性试验是药物非临床安全性评价的重要内容之一。当前国内外普遍采用并认可基于ICH S1B指南建立的药物非临床致癌性试验替代方案。遗传修饰致癌性小鼠模型是替代方案中“卡脖子”的关键技术问题。从1997年ICH S1B指南发布至今,我国制药行业主要依赖进口获得小鼠模型,其价格高昂、进口周期长、条件严苛,且由于模型资源唯一,制药行业承受着成本高昂和供应链不稳的双重压力。本文概述了国内外致癌性试验相关指导原则,介绍了国内外主要的致癌性小鼠模型,包括Tg.rasH2、KI.C57-ras、p53^(+/-)小鼠等的构建、验证与应用历程,并展望了建立我国自主知识产权的致癌性小鼠模型以及标准化生产供应的途径。

^(60)Co-γ辐射对2种锦带幼苗生长及生理指标的影响

为了探究辐射诱变对“白花锦带花”和“锦带花”形态及生理特性的影响,采用不同剂量(0~300 Gy)的^(60)Co-γ射线辐射“白花锦带花”与“锦带花”休眠期种子,观测辐射对锦带花生长的影响,测定其生长量及幼苗叶片的叶绿素含量、叶绿素荧光指标、光合作用参数、SOD、POD、MDA和可溶性蛋白含量。研究结果显示,由于辐射剂量的增大,苗高、叶长、叶宽、节间距、叶绿素荧光、光合作用参数、SOD活性、POD活性出现了明显的先升高后降低的趋势,在50 Gy时到达了峰值。同时,随着辐射剂量的增加,叶绿素含量和可溶性蛋白含量呈现出下降的趋势,MDA含量明显升高。综上所述,在(2 Gy/min)剂量率的辐射条件下“白花锦带花”种子较适宜的诱变剂量为50 Gy,而“锦带花”以50~100 Gy最合适。

Preliminary Study on the Mutagenic Effects of Space Flight on Alfalfa Seeds

[Objective] The study aimed to understand the mutagenic effects of space flight on alfalfa seeds.[Method] Seeds of three lines of alfalfa were carried into orbit by the satellite 'Shijian-8' for space fight,the indices including seed germination rate,plant height and growth rate,were measured after the seeds been retrieved.[Result] Remarkable mutagenic effects occurred on the flight seeds,which were mainly presented by abnormal cotyledon,extended variation range of plant height and growth rate.Nineteen plants with increased plant height were preliminarily screened from the T0 progenies,but whether the mutated trait could inherit should be confirmed in further study.Three flight lines of alfalfa are different in the percentages of abnormal cotyledon(10%-18%),variation range of plant height(increased 30%-150% compared to control),selected plant number with increased plant height(5-7 plants),suggesting that differences exits between the three lines in mutation efficiency.[Conclusion] Valuable mutated materials could be obtained by space flight and applied in modern agriculture.

低误差第二代测序技术应用于肿瘤研究和药物致突变性风险评价的进展

目的:探讨低误差第二代测序(next-generation sequencing,NGS)技术在肿瘤研究和药物致突变性评价领域的进展。方法:通过查阅文献、收集资料等方法,汇总近年来低误差NGS技术进展、优缺点以及在肿瘤研究和药物致突变性/致癌性评价的应用。结果:传统的NGS技术的背景误差率较高,限制其在低频率突变检测方面的应用。近年开发的多种低误差NGS技术(即校正测序错误的NGS,errorcorrected next-generation sequencing,ecNGS)可将NGS的检测误差率降低至10^(-7)~10^(-4)或甚至更低,满足肿瘤临床监测和指导用药的需求。此外,HiFi-Seq和PECC-Seq等技术的最低误差率可降低至10^(-8),可检出药物短期暴露导致的细胞/组织的超低频突变,有助于在药物研发早期评估其致癌性风险。结论:ecNGS技术目前处于开发阶段,尚未标准化,且未在临床、毒理学、风险评估领域推广应用。然而,该方法可直接检出肿瘤早期病变组织中的突变和药物诱导的组织/细胞突变,有望取代或补充现有的致突变性试验方法,纳入相关指导原则,成为药物早期遗传毒性、致癌性筛查的金标准。

渭河陕西段干支流多环芳烃分布特征及潜在生态风险研究

【目的】为研究渭河陕西段干支流多环芳烃的时空分布特征,分析其来源与潜在的生态风险,【方法】采用气相色谱-质谱法(GC-MS)连续2 a对研究区内30个采样点水体的15种多环芳烃进行了定量检测分析,使用异构体比值法解析其来源种类及贡献程度,并运用苯并(a)芘毒性当量生态风险评价(TEQBap)和终生致癌风险评价(ILCR)分析其潜在风险。【结果】结果显示:渭河陕西段水体中ΣPAHs范围为0~93.00 ng·L^(-1),检出平均值为9.67 ng·L^(-1);单体浓度范围为0~30.50 ng·L^(-1),其中苯并蒽和芴的检出浓度最高,检出平均值分别为3.25 ng·L^(-1)、2.83 ng·L^(-1);在环数占比上,多环芳烃主要以三环、四环和五环的中高环形态存在。【结论】结论表明:渭河陕西段平水期各多环芳烃浓度相比丰水期有所增加,丰水期各多环芳烃种类分布相比平水期较为单一;各采样点处多环芳烃小于轻污染水平,与国内外其他河流相比处于较低水平;多环芳烃主要来源为煤等化石燃料及生物质的燃烧,并具有一定的生态风险,致癌风险不容忽视。

Study on Mutagenic Effect of Cobalt-60 Irradiation on Potato

[Objective] This study aimed to investigate the mutagenic effect of cobalt- 60 irradiation on potato. [Method] Potato tubers of Favorita and Zhongshu No.3 were irradiated with 5, 10, 20, 30, 50 and 70 Gy of cobalt-60 γ-ray respectively, to explore the mutagenic effect of different doses of γ-ray heavy ion irradiation on potato. [Result] The results showed that the emergence rate, seedling rate, plant growth, yield and commodity of potato varied after irradiated with different doses of cobalt-60 γ-ray; 10Gy of cobalt-60 irradiation played a positive effect on the growth and development of potato, while high doses played a negative effect on the growth and development of potato. After cobalt-60 irradiation, the botanical traits of M1 gen- eration varied greatly, resulting in a number of beneficial mutation traits; some traits of M2 and M3 generations became stably inherited. [Conclusion] Cobalt-60 irradiation breeding is conducive to the variety improvement and germplasm innovation as an effective means of genetic improvement for potato.

Study on Mutagenic Effect of Space Flight in Two-line Sterile Rice

Seeds of two-line sterile rice cultivars Zhu 1S and Lu 18S were carried into space by ＂Shijian 8＂ breeding recoverable satellite, then planted in ground. Mutagenic effects from space induction were compared with those from y-irradiation and complex processing of space induction and y-irradiation. The results showed that agronomic effect was stimulated in Mo progenies of the two-line sterile rice varieties treated by space flight, and their radiosensitivities to the irradiation of space flight performed non-sensitive. The order of mutation frequency was determined to be SP ＋ γ 〉 γ 〉 SP in M2 generation. And a series of mutated elites（individuals） were screened. Physiological indices of mutants screened like the activity of protective enzymes were measured to explore the physiological and biochemical basis of biological effect in space environment to two-line sterile rice. The results of this study show that space mutation breeding is an effective novel mean for breeding.

Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications,root causes and risk assessment:A systematic review

The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

雷火灸治疗癌因性疲乏临床疗效与安全性的Meta分析

目的:采用Meta分析系统评价雷火灸治疗癌因性疲乏(CRF)的有效性与安全性。方法:计算机检索数据库知网、万方、维普、PubMed、Embase、Cochrane Library、Web of Science等中与雷火灸治疗CRF相关的临床随机对照研究,由2名研究者通过纳排标准对所纳文献进行筛选,对照组采用常规治疗方案,试验组采用雷火灸或雷火灸配合其他疗治方案,结局指标含中医症状积分、体力功能状态评分(KPS)、生活质量评分、疲乏症状评分、总有效率、不良反应发生率、睡眠质量评分(PSQI),检索时间从建库至2022年12月。结果:最终纳入文献13篇,共957例患者。选择RevMan 5.3软件进行Meta分析,结果显示,在体力功能状态评分(KPS)[MD=10.46,95%CI(4.97,15.94),Z=3.74,P=0.0002],生活质量评分[SMD=0.91,95%CI(0.24,1.58),Z=2.65,P=0.008],疲乏症状评分[SMD=-3.42,95%CI(-4.96,-1.88),Z=4.36,P<0.0001],总有效率[RR=1.73,95%CI(1.30,2.31),Z=3.78,P=0.0002]方面,试验组优于对照组,差异有统计学意义(P<0.05)。结论:雷火灸能够减轻癌症患者的疲劳程度,改善患者生活与睡眠质量,且比常规疗法更具优势。但由于所纳文献质量一般、样本量有限,今后仍需大样本的高质量RCT研究进一步验证。

乳双歧杆菌MN-Gup在发酵乳中的应用及其对血糖的改善作用

以分离自我国巴马长寿老人肠道菌群,且具有益生特性的乳双歧杆菌Bifidobacterium. animalis. subsp. Lactis. MN-Gup为研究对象,探究了该菌株在发酵乳中的发酵特性及MN-Gup发酵乳在贮藏期内的理化性质,同时采用高脂肪饮食和链脲佐菌素诱导二型糖尿病大鼠模型考察MN-Gup益生菌酸奶对血糖的调节作用。结果显示,MN-Gup益生菌酸奶在4℃冷藏条件下贮藏期内(28 d)可以保持较好的乳酸菌活菌数(>10^(8)CFU/g)及理化指标,且与普通酸奶相比,益生菌酸奶具有更优的感官评价喜好度,说明乳双歧杆菌MNGup具有良好发酵性能的同时可赋予发酵乳良好的特征风味。进而通过动物实验证实,MN-Gup益生菌酸奶可以显著降低二型糖尿病大鼠的空腹血糖和胰岛素抵抗水平,并促进体内胰高血糖素样肽-1的分泌,调节脂代谢,具有改善二型糖尿病临床症状的功效。

1960—2020年黄河、长江、珠江入海水沙通量演变特征

[目的]基于动态更新数据综合对比中国三大河流入海水沙通量的特征,为流域开发和管理提供依据。[方法]收集黄河(利津站)、长江(大通站)、珠江(高要站、石角站、博罗站)5个水文控制站1960—2020年实测数据,采用滑动平均法、Pettitt检验法、双累积曲线法以及小波变换分别对水沙通量的趋势性、变异性、周期性特征进行分析,采用交叉小波变换和小波相干谱探究径流量和泥沙量的共振周期与相干性。[结果]近60a黄河、长江、珠江入海水沙通量均发生了明显变化,黄河径流量和泥沙量在1986年突变减少,泥沙量在1997年二次突变减少;长江和珠江入海径流量未发生变异,泥沙量分别于1992,1999年突变减少。这三大河流入海水沙具有显著的年际和年代际周期特征,年代际共同演化周期分别集中于1980年以前、1990年以前和2000年以前。年际共同演化周期为5a,“丰—枯”转换频繁。交叉小波分析结果显示,黄河、长江和珠江的入海径流量和泥沙量在1965—1975年具有显著的1~3a的共振周期,以正相位演变为主。[结论]中国三大河流入海水沙具有显著的趋势性、变异性和周期性特征,可以据此进行的流域开发和管理更有效。

2018—2022年苏州市生活饮用水中三氯甲烷浓度分析及健康风险评估

目的分析苏州市生活饮用水中三氯甲烷浓度水平,评估其健康风险。方法于2018—2022年对苏州市集中式供水出厂水、末梢水和二次供水采样,收集三氯甲烷监测数据,采用《化学物质环境健康风险评估技术指南》(WS/T 777-2021)推荐的模型评估人群饮用水中三氯甲烷暴露的健康风险。结果共收集2610份水样,三氯甲烷浓度范围为ND~57.00μg/L,浓度中位数为8.00μg/L,达标率为100%。研究期间丰水期三氯甲烷浓度高于枯水期(P<0.01),末梢水中三氯甲烷浓度高于出厂水和二次供水(P<0.01),使用一氯胺消毒的饮用水中三氯甲烷浓度低于使用液氯和次氯酸钠消毒的浓度(P<0.01),以江河为水源的饮用水中三氯甲烷浓度高于以湖泊为水源的浓度(P<0.01)。人群饮水三氯甲烷暴露的致癌风险男性为0.45×10^(-5)~3.02×10^(-5),女性为0.46×10^(-5)~3.03×10^(-5)。结论苏州市集中式供水生活饮用水中三氯甲烷浓度均合格,人群经饮水途径暴露三氯甲烷的健康风险水平低。

N-亚硝基布美他尼SD大鼠体内致突变性风险研究

目的评价布美他尼杂质N-亚硝基布美他尼的体内致突变风险和肝细胞DNA损伤风险。方法SD大鼠随机分为6组,分别为:溶媒对照组(溶媒为0.5%羧甲基纤维素钠),N-亚硝胺布美他尼100、300、1000 mg·kg^(-1)剂量组,阳性对照组1[N-乙基-N-亚硝基脲(ENU),40 mg·kg^(-1)]、阳性对照组2[甲磺酸乙酯(EMS),200 mg·kg^(-1)]。2个阳性对照组均为每组6只动物,其余每组12只动物。大鼠连续14 d经口灌胃给予受试物N-亚硝胺布美他尼。首次给药后约14 d和约28 d后采集外周血用于Pig-a基因突变率检测,末次给药后约3 h取肝细胞开展彗星试验。结果试验期间给予N-亚硝基布美他尼未导致异常临床症状和动物体重及摄食量改变。100、300、1000 mg·kg^(-1)剂量组动物肝细胞平均tail%DNA值(平均数/中位数)分别为2.90±0.38/2.34±0.46、3.58±0.27/2.87±0.51、3.45±0.59/2.21±1.44,与溶媒对照组相应数值相比未见差异,且无明显剂量效应相关性。首次给药后14 d,100、300、1000 mg·kg^(-1)剂量组动物平均RBC^(CD59-)和RET^(CD59-)百万分之发生率(RBC^(CD59-)百万分之发生率/RET^(CD59-)百万分之发生率)分别为2.9±1.6/1.2±0.8、2.8±2.4/1.3±1.5、2.4±1.0/1.3±1.5;首次给药后28 d,100、300、1000 mg·kg^(-1)剂量组动物RBC^(CD59-)百万分之发生率/RET^(CD59-)百万分之发生率分别为5.1±1.5/2.2±0.6、4.3±1.5/3.5±3.6、4.8±2.4/2.5±2.7。上述数值与相同时间点溶媒对照组相比均未见差异,且经统计学分析未见剂量效应相关性。结论连续经口给予N-亚硝基布美他尼14 d,SD大鼠的最大耐受量高于1000 mg·kg^(-1),未检出外周血基因突变风险和肝细胞DNA损伤风险。研究数据可为药品中遗传毒性杂质的合理监管和含N-亚硝基杂质药物的安全使用提供数据支持。