De Caterina R, Giannessi D, Bernini W, Lazzerini G, Lavezzari M, Stragliotto E, Biagi G, Coccheri S
CNR Institute of Clinical Physiology, Pisa, Italy.
Thromb Haemost. 1996 Mar;75(3):510-4.
Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.
吲哚布芬（(+/-)-2-[对-(1-氧代-2-异吲哚啉基)-苯基]-丁酸）是一种通过在环氧化酶水平可逆性阻断花生四烯酸代谢来抑制血小板功能的药物。由于这类药物的耐受性特征大多与血小板外的环氧化酶抑制作用有关，我们前瞻性地评估了与阿司匹林相比，体内给予吲哚布芬对血小板和血小板外环氧化酶的抑制程度。我们评估了这两种药物对全血中TXB2和6-酮-PGF1α体外生成的影响，分别作为TXA2和PGI2（前列环素）生成的指标，这两种情况分别是在37℃自发凝血1小时后（研究1）或添加2微克/毫升胶原蛋白后（研究2）。全血中6-酮-PGF1α的生成是血小板和血小板外环氧化酶活性的综合指标，来源于血小板和白细胞的花生四烯酸代谢。15名缺血性心脏病患者且基线血清TXB2水平>300纳克/毫升，被分配接受单次给予200毫克吲哚布芬（n = 6）或500毫克阿司匹林（n = 9）。在给药后0、1、2、4、6、8、12和24小时评估全血前列腺素生成情况（研究I）。10名健康男性志愿者被分配进行一项双盲、随机交叉比较，比较7天内每日两次给予200毫克吲哚布芬与每日给予300毫克阿司匹林的情况（研究2）。在每个研究周期开始和结束时（第0天和第7天）进行前列腺素生成和全血血小板聚集检测。在单次给药后的每个时间点（研究1），吲哚布芬对全血6-酮-PGF1α的抑制百分比低于对TXB2的抑制百分比。在2小时时，阿司匹林（98±4%）和吲哚布芬（97±6%）使TXB2降低到相似程度（p = 无显著性差异），而对6-酮-PGF1α的抑制明显不同（阿司匹林后>98%，吲哚布芬后81±2.5%，p<0.01）。在给予阿司匹林或吲哚布芬一周后（研究2），全血血小板聚集的最大抑制程度相似（阿司匹林从17.2±1.4欧姆降至3.6±1.3欧姆；吲哚布芬从18.3±1.0欧姆降至1.6±0.7欧姆（阿司匹林与吲哚布芬相比p = 无显著性差异）。尽管在添加胶原蛋白后全血TX生成受到同等抑制（阿司匹林从49.0±4.3纳克/毫升降至1.1±0.6纳克/毫升，吲哚布芬从49.8±1.3纳克/毫升降至1.4±0.6纳克/毫升），然而，同样，吲哚布芬对6-酮-PGF1α生成的影响小于阿司匹林（阿司匹林从409±30皮克/毫升降至37±13皮克/毫升，抑制率 = 91%；吲哚布芬从396±35降至318±40，抑制率 = 20%）。吲哚布芬和阿司匹林的这些差异效应可能导致吲哚布芬与阿司匹林相比具有更好的血小板选择性、耐受性和效益/风险特征。这些特征值得进一步评估。
