本所在一系列■■酮衍生物質的抗過敏活性研究中發現，9,10-■■酮-2-羧酸(AQCA)具有相當優越的活性，隨即有將之開發為臨床上試驗用之動機。本研究的主題在於臨床前試驗，配合動物，完成AQCA之藥理學及藥動學試驗，亦完成十四日毒性試驗，獲得下列結果。 AQCA靜脈注射或口服給藥，對皮膚被動過敏反應(PCA)的抑制作用有相當明顯的效果，使用大鼠腹腔被動過敏反應的活體實驗，同時測定大鼠犧牲時的血中濃度，也發現AQCA 能抑制histamine的釋出，證實了AQCA 能抑制第一型過敏反應的皮膚發炎。卵白蛋白誘發呼吸道阻力上升試驗，證實AQCA明顯降低呼吸道阻力，顯示AQCA 可用於預防氣喘的發作。AQCA對天竺鼠直接以histamine誘發的呼吸道阻力上升沒有預防效果，本實驗也發現AQCA 於較高劑量時可以部分阻斷PAF 所誘發的呼吸道阻力，AQCA降低呼吸道的阻力部分應與拮抗PAF 的作用有關。AQCA亦能抑制足蹠浮腫及佐劑型關節炎。 以大鼠試驗，口服劑量20 mg/kg，AQCA具降體溫、減少胃酸分泌、利尿之效果。並具有增加胃排空、及腸蠕動之能力。 本研究開發出一簡單、高感度和精確之高效液相層析法，用以檢測血清中AQCA濃度。本分析法以Lichrosherâ100 RP-18， 5mm,250 x 4 mm endcapped層析管柱，0.4%磷酸:乙氰(7:3) / 甲醇 = 45:55為移動相，流速為1.2 mL / min，紫外光檢測器之檢測波長為256 nm，對甲基苯甲酸為內標準品。檢品經簡單處理後，注入管柱分析。血清中最低檢測值為0.6 mg/mL ，於0.6 ~ 18 mg/mL濃度間具有良好的線性檢量關係，確效試驗顯示，精密度佳(RSD少於2%)，回收率為96.98%。 繼以此分析法應用於AQCA藥品動力分析及絕對生體可用率研究之探討。AQCA 高劑量（20 mg / kg）時，於口服12小時後仍能抑制大鼠皮膚被動過敏反應，顯示AQCA是作用強且長之抗過敏活性藥物。大鼠口服AQCA之生體可用率( F )因劑量增加而降低，5 mg / kg的生體可用率為96%；10和20 mg / kg的生體可用率降至81%。口服AQCA之吸收狀況均慢且長，到達血漿中尖峰濃度之時間（Tmax）介於1~6小時,平均滯留時間 (MRT)和半衰期 (T1/2) 因劑量增加而增長。AQCA口服給藥之吸收期間長(Tmax 1-6 h)，且具高生體可用率，顯示其進入血中之前被代謝的很少。AQCA是一活性強且作用時間長之抗過敏性化合物，具有開發為氣喘藥的潛力。 在雌雄鼠十四日毒性試驗結果顯示，血液學檢驗結果顯示僅對雄鼠有影響。AQCA高劑量（50 mg/Kg）時增加紅血球數目、血球容積，但降低平均紅血球血紅素量、平均紅血球血紅素濃度，但白蛋白、膽固醇、肌肝酸及三酸甘油脂明顯增加。AQCA高劑量（50 mg/Kg）時明顯增加雌雄鼠肝臟重量。 綜合以上結果，AQCA是一活性強且具長期間性之抗PCA反應之化物，加上其不高的毒性，可建議開發為臨床上治療氣喘和關節炎之藥物。嘗試開發一新長效劑型以適用於臨床上試驗，將是續接的研究主題。; 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 asthm
