28-Day Repeated Oral Toxicity Study of a Hypolipidemic Agent, Nk-104 in Rats

Akiba, Tomohide; Shibuta, Tetsuo; Amano, Yukinori; Okubo, Masato; Asanuma, Akimune; Koga, Teruji; Tanaka, Masahiro; Takimoto, Masayoshi

doi:10.2131/jts.23.supplementv_701

Cited by 5 publications

(2 citation statements)

References 4 publications

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“…Akiba et al (1999) observed that NK-104, a HMG CoA reductase inhibitor suppressed body weight gain or decreased body weight with dose of 50 mg/kg in rats. Chronic pravastatin plus captopril treatment decreased weight gain, improving lipid profile and insulin resistance (Villa et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Effect of Coenzyme Q10 and green tea on plasma and liver lipids, platelet aggregation, TBARS production and erythrocyte Na leak in simvastatin treated hypercholesterolmic rats

et al. 2007

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This study was conducted to investigate the hypocholesterolemic effect of simvastatin (30 mg/kg BW) and antioxidant effect of coenzyme Q10 (CoQ10, 15 mg/kg BW) or green tea (5%) on erythrocyte Na leak, platelet aggregation and TBARS production in hypercholesterolemic rats treated with statin. Food efficiency ratio (FER, ADG/ADFI) was decreased in statin group and increased in green tea group, and the difference between these two groups was significant (p<0.05). Plasma total cholesterol was somewhat increased in all groups with statin compared with control. Plasma triglyceride was decreased in statin group and increased in groups of CoQ10 and green tea, and the difference between groups of statin and green tea was significant (p<0.05). Liver total cholesterol was not different between the control and statin group, but was significantly decreased in the group with green tea compared with other groups (p<0.05). Liver triglyceride was decreased in groups of statin and green tea compared with the control, and the difference between groups of the control and green tea was significant (p<0.05). Platelet aggregation of both the initial slope and the maximum was not significantly different, but the group with green tea tended to be higher in initial slope and lower in the maximum. Intracellular Na of group with green tea was significantly higher than the control or statin group (p<0.05). Na leak in intact cells was significantly decreased in the statin group compared with the control (p<0.05). Na leak in AAPH treated cells was also significantly reduced in the statin group compared with groups of the control and CoQ10 (p<0.05). TBARS production in platelet rich plasma was significantly decreased in the groups with CoQ10 and green tea compared with the control and statin groups (p<0.05). TBARS of liver was significantly decreased in the group with green tea compared with the statin group (p<0.05). In the present study, even a high dose of statin did not show a cholesterol lowering effect, therefore depletion of CoQ10 following statin treatment in rats is not clear. More clinical studies are needed for therapeutic use of CoQ10 as an antioxidant in prevention of degenerative diseases independent of statin therapy.

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Section: Discussionmentioning

confidence: 99%

Effect of Coenzyme Q10 and green tea on plasma and liver lipids, platelet aggregation, TBARS production and erythrocyte Na leak in simvastatin treated hypercholesterolmic rats

et al. 2007

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“…Although the development of rhabdomyolysis with high-dose statins usually occurs within 14 days [28][29][30], no in vivo animal study has reported the development of rhabdomyolysis with pitavastatin. The only study we found reported some skeletal muscle involvement (atrophy, vacuolation, and necrosis) in some female rats treated with 50 mg/kg/day pitavastatin in repeated toxicity studies for 28 days (31). Therefore, we determined the dose of pitavastatin as 50 mg/kg/day in this study.…”

Section: Drug Administration and Verification Of Rhabdomyolysismentioning

confidence: 99%

Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments

Negishi¹,

Oshima²,

Mutoh³

et al. 2022

Int. J. Med. Sci.

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Adverse drug events due to drug-drug interactions can be prevented by avoiding concomitant use of causative drugs; therefore, it is important to understand drug combinations that cause drug-drug interactions. Although many attempts to identify drug-drug interactions from real-world databases such as spontaneous reporting systems have been performed, little is known about drug-drug interactions caused by three or more drugs in polypharmacy, i.e., multiple drug-drug interactions. Therefore, we attempted to detect multiple drug-drug interactions using decision tree analysis using the Japanese Adverse Drug Event Report (JADER) database, a Japanese spontaneous reporting system. First, we used decision tree analysis to detect drug combinations that increase the risk of rhabdomyolysis in cases registered in the JADER database that used six statins. Next, the risk of three or more drug combinations that significantly increased the risk of rhabdomyolysis was validated with in vivo experiments in rats. The analysis identified a multiple drug-drug interaction signal only for pitavastatin. The reporting rate of rhabdomyolysis for pitavastatin in the JADER database was 0.09, and it increased to 0.16 in combination with allopurinol. Furthermore, the rate was even higher (0.40) in combination with valsartan. Additionally, necrosis of leg muscles was observed in some rats simultaneously treated with these three drugs, and their creatine kinase and myoglobin levels were elevated. The combination of pitavastatin, allopurinol, and valsartan should be treated with caution as a multiple drug-drug interaction. Since multiple drug-drug interactions were detected with decision tree analysis and the increased risk was verified in animal experiments, decision tree analysis is considered to be an effective method for detecting multiple drug-drug interactions.

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Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs

Funk

Landes

2005

Experimental and Toxicologic Pathology

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28-Day Repeated Oral Toxicity Study of a Hypolipidemic Agent, Nk-104 in Rats

Cited by 5 publications

References 4 publications

Effect of Coenzyme Q10 and green tea on plasma and liver lipids, platelet aggregation, TBARS production and erythrocyte Na leak in simvastatin treated hypercholesterolmic rats

Effect of Coenzyme Q10 and green tea on plasma and liver lipids, platelet aggregation, TBARS production and erythrocyte Na leak in simvastatin treated hypercholesterolmic rats

Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments

Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs

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