Sam Tasia S W, Ngan Man P, Riendeau Denis, Robichaud Annette, Rudd John A
Emesis Research Group, Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
J Pharmacol Sci. 2007 Feb;103(2):189-200. doi: 10.1254/jphs.fp0061169.
Cisplatin at 5 mg/kg, i.p. induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the anti-emetic activity of the non-selective cyclooxygenase inhibitor indomethacin (3 - 30 mg/kg, i.p., three times per day) and two cyclooxygenase-2 inhibitors, DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone; 1 - 10 mg/kg, i.p. administered at 40 and 48 h] and L-745,337 [5-methanesulphonamido-6-(2,4-diflurothiophenyl)-1-indanone; 10 mg/kg, i.p., administered at 40 and 48 h]. Only indomethacin potentiated significantly cisplatin-induced retching + vomiting (P<0.05); DFU antagonized delayed emesis (P<0.05) but the action was not dose-related and L-745,337 was inactive (P>0.05). However, indomethacin alone (30 mg/kg) also induced emesis (P<0.05). The leukotriene biosynthesis inhibitor, MK-886 {3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2,2-dimethylpropanoic acid; 1 - 10 mg/kg, i.p., three times per day} had no action to modify cisplatin-induced emesis (P>0.05). The combination treatment of indomethacin (10 mg/kg, i.p., three times per day) with MK-886 (10 mg/kg, i.p., three times per day) did not antagonize cisplatin-induced acute delayed retching + vomiting and had a different profile compared to the action of dexamethasone (1 mg/kg, i.p., three times per day; P<0.05). Inhibition of the cyclooxygenase and lipoxygenase pathways does not account for the anti-emetic of dexamethasone.
腹腔注射5mg/kg顺铂可在雪貂中诱发急性（第1天）和延迟性（第2天和第3天）呕吐反应，以此来研究非选择性环氧化酶抑制剂吲哚美辛（3 - 30mg/kg，腹腔注射，每天3次）以及两种环氧化酶-2抑制剂DFU [5,5-二甲基-3-(3-氟苯基)-4-(4-甲磺酰基)苯基-2(5H)-呋喃酮；1 - 10mg/kg，在40和48小时腹腔注射] 和L-745,337 [5-甲磺酰胺基-6-(2,4-二氟噻吩基)-1-茚满酮；10mg/kg，在40和48小时腹腔注射] 的止吐活性。只有吲哚美辛能显著增强顺铂诱发的干呕 + 呕吐（P<0.05）；DFU能对抗延迟性呕吐（P<0.05），但该作用与剂量无关，而L-745,337无活性（P>0.05）。然而，单独使用吲哚美辛（30mg/kg）也会诱发呕吐（P<0.05）。白三烯生物合成抑制剂MK-886 {3-[1-(对氯苄基)-5-(异丙基)-3-叔丁基硫代吲哚-2-基]-2,2-二甲基丙酸；1 - 10mg/kg，腹腔注射，每天3次} 对顺铂诱发的呕吐没有作用（P>0.05）。吲哚美辛（10mg/kg，腹腔注射，每天3次）与MK-886（10mg/kg，腹腔注射，每天3次）联合治疗不能对抗顺铂诱发的急性延迟性干呕 + 呕吐，且与地塞米松（1mg/kg，腹腔注射，每天3次；P<0.05）的作用情况不同。环氧化酶和脂氧合酶途径的抑制不能解释地塞米松的止吐作用。
