Acute, subchronic oral toxicity, and genotoxicity evaluations of LPM570065, a new potent triple reuptake inhibitor

被引:13
作者
Li, Chunmei [1 ]
Jiang, Wanglin [2 ]
Gao, Yonglin [3 ]
Lin, Fei [4 ]
Zhu, Haibo [5 ]
Wang, Hongbo [1 ]
Ye, Liang [5 ]
Qi, Jia Grace [1 ]
Tian, Jingwei [1 ]
机构
[1] Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm,Minist Educ, Yantai 264005, Peoples R China
[2] Binzhou Med Univ, Sch Pharm, Yantai 264003, Peoples R China
[3] Yantai Univ, Sch Life Sci, Yantai 264005, Peoples R China
[4] Luye Pharma Grp Ltd, State Key Lab Long Acting Targeting Drug Delivery, Yantai 264003, Peoples R China
[5] Binzhou Med Univ, Sch Publ Hlth & Management, Yantai 264003, Peoples R China
基金
中国国家自然科学基金;
关键词
LPM570065; Triple reuptake inhibitor (TRI); Toxicity; INDUCED HYPERPROLACTINEMIA; ANTIDEPRESSANT; DESIGN; SAFETY;
D O I
10.1016/j.yrtph.2018.07.011
中图分类号
DF [法律]; D9 [法律]; R [医药、卫生];
学科分类号
0301 ; 10 ;
摘要
In the current study, to support the safety of LPM570065 as a new potent triple reuptake inhibitors (TRIs), LPM570065 was investigated through a single- and 13-week repeated-dose oral toxicity evaluation and mutagenicity assays. In an acute toxicity evaluation, Sprague-Dawley (SD) rats were single administration at dose of 500, 1000 and 2000 mg/kg. The results suggested that two (2/20) and seven (7/20) animals were died in the 1000 and 2000 mg/kg group, respectively. In contrast, there were no treatment-related effects at a dose of 500 mg/kg. In a 13-week toxicity evaluation, SD rats were given 30, 100, or 300 mg/kg LPM570065 for 13 successive weeks and then allowed a 4-week recovery period. Impermanent salivation was found at each of the doses, and an impermanent minor body weight decrease was noted in the 300 mg/kg males (P < 0.05). Notably, serum prolactin levels were lowered by 43.25% and 78.65% in the male rats in 100 and 300 mg/kg groups, respectively (P < 0.05). Further, the serum testosterone was elevated by 37% in the 30 and 100 mg/kg males. In conclusion, the maximum tolerated dose (MTD) was 500 mg/kg and the lethal dose was 1000 mg/kg in SD rats after a single administration of LPM570065. In 13-week repeated-dose oral toxicity, the no-observed adverse-effect level (NOAEL) of LPM570065 was greater than 300 mg/kg for rats. Moreover, LPM570065 was not mutagenic or clastogenic. According to this result it can be concluded that the MTD of LMP570065 is approximately up to 3000 mg/person/day in clinic, and the effects of LMP570065 on sexual function also should be considered.
引用
收藏
页码:129 / 139
页数:11
相关论文
共 25 条
[1]   Cognitive performance in antidepressant-free recurrent major depressive disorder [J].
Albert, Kimberly M. ;
Potter, Guy G. ;
McQuoid, Douglas R. ;
Taylor, Warren D. .
DEPRESSION AND ANXIETY, 2018, 35 (08) :694-699
[2]  
[Anonymous], 2009, Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3
[3]  
Bagheri Seyyed Majid, 2015, J Ayurveda Integr Med, V6, P175, DOI 10.4103/0975-9476.146552
[4]   A Generalist's Guide to Treating Patients With Depression With an Emphasis on Using Side Effects to Tailor Antidepressant Therapy [J].
Bostwick, J. Michael .
MAYO CLINIC PROCEEDINGS, 2010, 85 (06) :538-550
[5]   The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects [J].
Breuer, M. E. ;
Chan, J. S. W. ;
Oosting, R. S. ;
Groenink, L. ;
Korte, S. M. ;
Campbell, U. ;
Schreiber, R. ;
Hanania, T. ;
Snoeren, E. M. S. ;
Waldinger, M. ;
Olivier, B. .
EUROPEAN NEUROPSYCHOPHARMACOLOGY, 2008, 18 (12) :908-916
[6]   Sexual Dysfunction Due to Psychotropic Medications [J].
Clayton, Anita H. ;
Alkis, Andrew R. ;
Parikh, Nishant B. ;
Votta, Jennifer G. .
PSYCHIATRIC CLINICS OF NORTH AMERICA, 2016, 39 (03) :427-+
[7]   Testosterone Replacement Therapy: Long-Term Safety and Efficacy [J].
Corona, Giovanni ;
Sforza, Alessandra ;
Maggi, Mario .
WORLD JOURNAL OF MENS HEALTH, 2017, 35 (02) :65-76
[8]  
Erdemir F, 2014, INT BRAZ J UROL, V40, P100
[9]   Acute and a 28-day repeated-dose toxicity study of total flavonoids from Clinopodium chinense (Benth.) O. Ktze in mice and rats [J].
Gao, Yonglin ;
Wang, Yunzhi ;
Wang, Kezhou ;
Zhu, Jing ;
Li, Guisheng ;
Tian, Jingwei ;
Li, Chunmei ;
Wang, Zhenhua ;
Li, Ji ;
Lee, Albert W. ;
Guo, Chenghua .
REGULATORY TOXICOLOGY AND PHARMACOLOGY, 2017, 91 :117-123
[10]   Nonclinical safety of astilbin: A 4-week oral toxicity study in rats with genotoxicity, chromosomal aberration, and mammalian micronucleus tests [J].
Gao, Yonglin ;
Li, Chunmei ;
Wang, Yunzhi ;
Liu, Yunguo ;
Li, Guisheng ;
Fan, Xiaochen ;
Li, Yanshen ;
Tian, Jingwei ;
Lee, Albert W. .
FOOD AND CHEMICAL TOXICOLOGY, 2017, 107 :1-9