Effects of pregnancy and lactation on warfarin-induced changes in blood coagulation-related parameters in rats

Ohishi, Takumi; Kitazawa, Takahiro; Suzuki, S; Nakamura, Daichi; Nishihara, Yoshito; Mochizuki, Masahiro

doi:10.2131/jts.35.189

Cited by 1 publication

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References 31 publications

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“…For example, as a classical anticoagulant and the most frequently used anticoagulant to treat various blood clot diseases (Camporese and Bernardi, 2009;Hull and Pineo, 2000), Low molecular weight heparin (LMWH) produced obvious adverse effects at the dose of 20 mg/kg in rats (Borelli and Bertoli, 1986). The acute toxic experiment of warfarin reported that its lethal dose (LD50) was 500 mg/kg for mice and 420 mg/kg body mass for rats (Manolov et al, 1993;Ohishi et al, 2010). However, there were no meaningful drug-related toxic reactions in monkeys with the EH dosages up to 1300 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

The toxicity assessment of neorudin in cynomolgus monkeys

et al. 2023

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In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

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