| Iptakalim hydrochloride(Ipt)is one kind of antihypertensive new drugs used in the treatment of mild to moderate hypertension.SD rats were exposed to Ipt by given drinking water continuesely for 24 months.Animals Growth performance,metabolic kinetics of drug exposure in vivo,the index changes of clinical pathology and tumor occurrence were monitored to evaluate the carinogenicity of the compound.The results of this test are then used to predict compound's potential carcinogenicity risk to humans and as reference for its clinical use.There were five groups set in 24-month test of Ipt,including 600 SD rats,half male and half female.These groups were solvent control group land 2(0 mg·L-1),Ipt low dose(5mg·L-1)group,middle dose(15mg·L-1)group and high dose(45mg·L-1)group,60 rats per dose level per gender.All animals were exposed to compound via drinking water for 104 weeks.The test detection indexes included observation of animals survival status(survival rate,average survival weeks),body weight,food and water consumption,clinical abnormal symptoms etc.The results showed,after SD rats exposed to Ipt via water for 24 months,at the terminal of the dosing,the survival rate of animals in each group range from 25 to 34 percent,with an average survival of 84.2?86.9 weeks;During the dosing each group anmimals' body weight showed a growth trend,with an average body weight range of female and male rats were 108.6?511.1g and 130.3?752.2g respectively;During the administration,the water consumption of each group was fluctuated,and the average daily water consumption of female and male rats were 13.2?55.8ml·d-1 and 21.2?65.8ml·d-1 respectively;The feeding amount of each experiment was not obvious,and the average daily average intake of female and male rats were 5.0?21.0g·d-1 and 19.0?30.5g·d-1 respectively;Compared to the solvent control group,the survival status,body weight,food and water consumption,clinical abnormalities etc.of the administration of each group of animals,showed no significant differences;water consumption were decreased in males of middle group and all of high group.So that the SD rats administered by drinking Ipt for 24 months were no effected on the growth,but can reduce the water intake due to changes of palatability of drinking water.There were three groups set in 24-month test of Ipt,including 30 SD rats,half male and half female.These groups were Ipt low dose(5mg·L-1)group,middle dose(15mg·L-1)group and high dose(45mg·L-1)group,5 rats per dose level per gender.They were blooded on day 7th,28th,week 54th and 104th throug orbital plexus vein tap.The samples were used to measure Ipt concentration of SD rat plasma with LC-MS/MS assay by using statistical software WinNonlin pharmacokinetics(V5.2.1)and using non-compartmental model method(NCA)calculated AUC0-t,the numerus of Cmax and Tmax were readed directly from the data.The results showed that Cmax and AUC0-t of each dose group animals increase with dose increasing;the Cmax and AUC0-t,of low,middle,high dose group of female rats were up to a maximum on the 28th day;the Cmax and AUC0-t,of low.middle and high dose group of males in dosing day 28th,7th and week 54th up to a maximum,respectively;in the administration of the week 105th.the numerus of Cmax and AUC0-t,of females and males were all lower than the 7th day.So that the SD rats administered by drinking Ipt 24 months,Ipt was accumulated,and more fully exposed in animals of each dosing group.There were five groups set in 24-month carcinogenity test of Ipt,including 600 SD rats,half male and half female.These groups were solvent control group land 2(0 mg·L-1),Ipt low dose(5mg·L-1)group,middle dose(15mg·L-1)group and high dose group(45mg·L-1),60 rats per dose level per gender.All animals were exposed to compound via drinking water for 104 weeks.There were two scheduled animal anatomy after the administered for 53 weeks and 104 weeks,respectively to few interim animals and all surviving animals on the terminal;Clinical pathology examinations for moribund and scheduled anatomied animals,including the indexes of blood routine,serum biochemistry,serum electrolytes,urinalysis;For all animals,including dead,moribund and planned euthanasia of animals,gross necropsy and microscopic histopathology observations(including 45 kinds of organs and tissues);To analysis of the cause of death of animals,compare the incidence of neoplastic lesions.The results showed that at at the end of the administration,each experimental group total mortality in the range of 66?75%,females animals slightly higher than males;the most common cause of death was the occurring of pituitary tumor(female:64?72%,,male:33?50%);the major frequently spontaneous neoplasms in SD rats were pituitary tumors(female:61-77%,males 62-74%),superficial tumors(in females,mainly breast tumor with incidence range of 39?52%;in males,predominantly subcutaneous fibroma with incidence range of 2?9%),and leukemia(rate of females was 18?22%;rate of male was 10?12%;Compared to solvent control group,the incidences of frequently spontaneous tumor and occasional or rare tumors were no increased in the administered animals,the tumorigenesis latency was not shortened in each dosed group,there were no significant difference in the total and average numbers of tumor per animal.In sum,we thought that there was no carcinogenic effect on SD rats after 24 months Ipt exposure. |
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