| Summary: | 博士 === 中國醫藥學院 === 藥物化學研究所 === 88 === In studies of a series of anthraquinone derivatives for usage in the relief or prophylaxis of allergic condition, it was found that 9,10-anthraquinone-2-carboxylic acid (AQCA) had an excellent activity in our laboratory. The purpose of this study was to investigate the pharmacology and pharmacokinetics of AQCA in animals. Two-week oral toxicity study of AQCA was also evaluated in male and female rats. The following results were obtained.
AQCA potently inhibited type I allergic reactions as passive cutaneous anaphylaxis (PCA) in rats by both intravenous and oral dosing. Histamine release by antigen and IgE antibody in rat peritoneal cavity was inhibited by the oral administration of AQCA. AQCA reduced the bronchoconstriction induced by i.v. ovalbumin in anesthetized IgE sensitized rats. Bronchoconstriction by platelet-activating factor, but not by histamine, was also inhibited by AQCA in guinea pigs. AQCA also had inhibitory effects on inflammation of carrageenin paw edema and adjuvant arthritis.
At the oral dose of 20 mg/kg, AQCA decreased the body temperature and gastric acid secretion in rats. AQCA also showed a diuretic effect in rats. Increased gastric and intestinal motility were observed in mice treated with AQCA 20 mg/kg.
A simple and sensitive high-performance liquid chromatographic (HPLC) method involving UV detection was developed for the determination of AQCA in serum. A reverse-phase column (Lichrosherâ100 RP-18) was eluted with a mobile phase of 0.4% phosphoric acid: acetonitrile (7:3) / methanol = 45 / 55 at a flow rate of 1.2 mL/min. The UV absorbance was monitored at 256 nm. After a simple clean-up procedure, the limit of quantitation achieved was 0.6 mg/mL and the standard curve was found to be linear over the serum concentration of 0.6 mg/mL ~ 18 mg/mL. The intraday-assay and interday-assay coefficient of variance in serum was less than 2%, and the recovery was 96.98%.
The established HPLC method was applied to the study of pharmacokinetics and bioavailability of AQCA. The inhibitory activity of AQCA (20 mg/kg) on PCA lasted more than 12 hr after oral administration. The oral bioavailability decreased with the increment of the dose, from 96 % (5 mg/kg) to 81 % (10 and 20 mg/kg). The absorption after oral administration was prolonged with Tmax values ranging from 1 to 6 h; while t1/2 (4.8 - 16 h) values appeared to be comparable. These results suggest that AQCA has a potent and long acting anti-PCA activity; it is likely to be therapeutically useful in the treatment of asthma.
The 2-week repeated oral dose toxicity study of AQCA was evaluated in both male and female rats. In hematology, increased of erythrocytes and hematocrit, but decreases of MCH and MCHC were observed in male rats of the 50 mg/kg dose group were investigated. In blood chemistry, an increased level of total cholesterol, triglyceride, albumin, globulin and creatinine in male rats of 50 mg/kg dose group. Male and female rats given 50 mg/kg showed an increase in liver weight.
In conclusion, AQCA has potent and long acting anti-PCA reaction. In addition, the toxicological non-observed levels in rats were thought to be 20 mg/kg below. So, AQCA might be a good candidate to be developed for clinical use. To establish a newly dose form of AQCA for clinical testing will be the subject of future research.
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