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水杨酸主要通过肾脏作为水杨酰胺乙酸(75%)、游离水杨酸(10%)、水杨酸苯酚(10%)、酰基葡萄糖醛酸苷(5%)、龙胆酸(< 1%)、2,3-二羟基苯甲酸排泄。
2,3-Dihydroxybenzoic acid is a product of human aspirin metabolism. Martin Grootveld and Barry Halliwell, Biochemical Pharmacology, Volume 37, Issue 2, 15 January 1988, pages 271–280, doi:10.1016/0006-2952(88)90729-0
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英国国家处方集 45. British Medical Journal and 英国皇家药师协会. 2003.
Aspirin monograph: dosages, etc. Medscape.com. [2011-05-11].
参考中国实验动物中心的给药剂量
小鼠给药量 25mg/kg x 0.02kg==0.5mg,0.5mg x 388=194mg 人的给药量,浓度194/70=2.77mg/kg。
Treatment protocol
Min/+ mice were treated for a period of 28 days either with vehicle or aspirin (25 mg/kg/day). Dose of aspirin correlates to previous work conducted by Mahmoud et al. [9], which demonstrated that 0.5 mg of aspirin per day was chemopreventive in Min/+ mice. Aspirin was initially dissolved in dimethyl sulfoxide (DMSO; 5% by final volume) and then diluted to the desired concentration (5 mg/mL) with 0.5% carboxymethylcellulose (CMC). Both aspirin and drug vehicle were orally administered via a 22-gauge feeding needle (Kent Scientific Co., Litchfield, CT) attached to a 1 cc syringe. Compounds were delivered at a rate of 5 mL/kg body weight. A diluted concentration was used to aid in drug solubility and accuracy of drug administration.
Anti-inflammatory treatment
BALB/c mice were treated with either asprin in drinking water (Aspro, Bayer Australia Ltd) (0.125 μg/ml) or water (control) beginning 36 h prior to tumor cell injection and continuing throughout the experiment. Water was changed every 12 h and liquid consumption quantified. Mice were pre-determined to drink an average of 4 ml/day resulting in an estimated dose of 25 mg/kg/day. This dose has been shown to produce a similar pharmacodynamic effect on COX-1 inhibition as a dose of 100 mg/day in humans, which is considered a low dose [35].
Oral Delivery of ASA and Clopidogrel
Age-matched C57BL/6J male mice (000664; Jackson Laboratories) weighing at least 25 g were used at 8 to 12 weeks of age. Anesthesia was initiated with an intraperitoneal injection of 125 mg/kg of ketamine (02173239; Wyeth Animal Health), 12.5 mg/kg of xylazine (02169592; Bayer), and 0.25 mg/kg of atropine (00238481; Rafter 8) and maintained with Nembutal (86665/04; Ceva Sante Animal). All mice received 100 μL of vehicle or an equal volume of ASA, clopidogrel or both by gavage using 20-gauge animal feeding needles (7910; Popper and Sons, Inc). ASA was given only once, 4 hours before study, whereas clopidogrel was given twice: 24 and 4 hours before study. ASA and clopidogrel were given at doses up to 5 mg/kg body weight.
Experimental Design for BP Recording
Twelve-week-old male C57BL/6 mice acclimatized to a 12/12-hour light/dark cycle for 1 week before radiotelemetry implantation. Although our studies were confined to male mice, the clinical reports of time-dependent hypotensive effects of low-dose aspirin are evident in both genders. The basal BP and heart rate (HR) recordings began 7 days after this operation. Mice were subjected to a high-salt diet (HSD, 8% NaCl) for 2 weeks to evoke a hypertensive response, better to clarify the phenotype, then divided randomly into 2 groups and treated with aspirin (50 μg/d in 100 μL of water) by gavage at zeitgeber time (ZT) 0 or ZT12 for 7 consecutive days followed by BP recording. Urine was collected for 24 hours using metabolic cages after each BP recording. At the end of the experiment, mice were euthanized by CO2 inhalation for tissue sample collections (Figure 1). Samples were stored at −80°C until use.