国产与进口托烷司琼胶囊的人体生物等效性

目的:评价国产和进口托烷司琼胶囊的生物等效性。方法:采用双周期两制剂交叉试验设计,用LC-MS/MS法对国产和进口托烷司琼胶囊在20名中国健康男性受试者中的血药浓度进行测定。药动学参数用ANOVA处理。结果:国产与进口托烷司琼胶囊的AUC0-→t分别为:(543.61±415.55),(547.04±455.59)μg·h·L-1;AUC0→∞分别为(573.30±439.11),(591.77±513.15)μg·h·L-1;cmax为分别(39.13±14.45),(37.44±14.30)μg·L-1;tmax分别为(1.61±0.71),(1.85±0.79)h;T1／2分别为(9.69±4.81),(9.77±5.51)h。国产托烷司琼胶囊的相对生物利用度为(106.47±24.07)％(n=20)。2组参数cmax,AUC0→t经对数转换后,行方差分析和双单侧t检验,均未见统计学意义。结论:托烷司琼国产的制剂与进口制剂具有生物等效性。     

Tropisetron ameliorates early diabetic nephropathy in streptozotocin‐induced diabetic rats

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti‐inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin‐induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor‐α were also determined. Streptozotocin‐treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor‐α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor‐α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti‐oxidative and anti‐inflammatory mechanisms that appear to be independent of the 5‐HT₃ receptor.     

有限采样法估算口服托烷司琼药时曲线下面积模型的建立和验证

目的建立有限采样法估算口服托烷司琼药时曲线下面积(AUC0-t)的模型,并对该模型进行验证。方法采用2周期双交叉的试验设计,20名健康志愿者口服托烷司琼参比制剂和受试制剂20mg,LC-MS/MS法测定各采样时间点托烷司琼的血药浓度。以参比制剂血药浓度数据作为建模数据,以稀疏血药浓度数据点建立多元回归数学模型,估算AUC0-t。采用内部、外部数据结合Monte Carlo模拟技术对模型进行验证和模型敏感度和稳定性评价。结果给药后8h和24h血药浓度(c8、c24)数据点预测AUC0-t的回归模型的线性关系最佳(r2=0.99,平均预测误差<1%、平均绝对误差<5%)。验证结果表明:c8,c24估算AUC0-t的准确性较好(平均预测误差<8%、平均绝对误差<7%),AUC0-t预测误差超过±20%的样本数<5%。结论有限采样法估算口服托烷司琼AUC0-t准确性好,适用于该药的药动学和药效学研究。     

托烷司琼对七氟烷激活小鼠 5- 羟色胺 3 受体的抑制作用

目的探讨托烷司琼对七氟烷激活小鼠5-羟色胺3(5-HT3)受体的抑制作用及其机制。方法将120只成年C57BL/6J小鼠随机分为对照组、七氟烷组和托烷司琼组,每组40只。对照组小鼠不做任何处理,七氟烷组和托烷司琼组小鼠给予七氟烷刺激,托烷司琼组小鼠同时给予托烷司琼处理。给药2周后,以酶联免疫吸附法测定小鼠外周血5-羟色胺(5-HT)水平;Western blot检测脑组织中5-HT3受体水平变化。结果七氟烷组小鼠外周血血清中5-HT水平显著高于对照组(P<0.05);托烷司琼组小鼠外周血血清中5-HT水平与对照组比较差异无统计学意义(P>0.05);托烷司琼组小鼠外周血血清中5-HT水平显著低于七氟烷组(P<0.05)。七氟烷组小鼠脑组织中5-HT3受体水平显著高于对照组(P<0.05);托烷司琼组小鼠脑组织中5-HT3受体水平与对照组比较差异无统计学意义(P>0.05);托烷司琼组小鼠脑组织中5-HT3受体水平显著低于七氟烷组(P<0.05)。结论托烷司琼能显著抑制七氟烷引起的小鼠脑组织中5-HT3受体水平增高,其机制可能与托烷司琼阻断七氟烷引起的小鼠体内5-HT水平升高导致的5-HT3受体反应性增高有关。     

Tropisetron versus metoclopramide for the treatment of nausea and vomiting in the emergency department: A randomized,double‐blinded,clinical trial

Aim: We aimed to compare the relative efficacy of tropisetron and metoclopramide in treating nausea/vomiting in undifferentiated ED patients. Methods: We undertook a randomized, double‐blinded, clinical trial. Adult patients requiring treatment for nausea/vomiting were randomly assigned to either tropisetron (5 mg) or metoclopramide (10 mg), by i.v. bolus. The primary end‐point was incidence of vomiting. Secondary end‐points were decrease in nausea score from baseline (0–100 VAS), the requirement of ‘rescue’ anti‐emetics, ongoing nausea over 48 h and side‐effects. Results: Fifty patients were enrolled in each group. The demographic variables, presenting complaints and nausea scores at baseline did not differ (P > 0.05). By 180 min, two (4.0%) and nine (18.0%) patients had vomited in the tropisetron and metoclopramide groups respectively (difference 14.0%, 95% CI 0.1–28.0, P= 0.05). Also, there were two and 20 episodes of vomiting respectively. Vomiting rates were 0.02 and 0.16 episodes/person‐hour (difference 0.14 episodes/person‐hour, 95% CI 0.07–0.21, P < 0.001) respectively. By 60 min and thereafter, the decrease in nausea score from baseline was greater (although not significantly so) in the tropisetron group. At 180 min, the decreases were 47.9 mm and 37.0 mm respectively (difference 10.9 mm, 95% CI ?0.7–22.6). Five (10.0%) and 13 (26.0%) patients required a rescue anti‐emetic respectively (difference 16.0%, 95% CI ?0.7–32.7, P= 0.07). Of patients followed up, 13/47 (27.7%) and 20/49 (40.8%) had ongoing nausea respectively (difference 13.2%, 95% CI ?7.7–34.0, P= 0.25). The tropisetron group had less akathisia. Conclusions: Tropisetron was associated with a significantly lower vomiting rate and shows promise as an alternative anti‐emetic in the ED.     

Serotonin receptor blockade increases food intake and body weight after total gastrectomy in rats

BACKGROUND: Total gastrectomy often results in early satiety and loss of body weight. Serotonin inhibits food intake, and postprandial serotonin release is increased after total gastrectomy. Serotonin might contribute to early satiety and loss of body weight after total gastrectomy. METHODS AND MATERIALS: Food intake and body weight were investigated with an automated recording system in gastrectomized rats 1-12 months postoperatively. Rats were treated with metergoline, a 5-hydroxytryptamine (5-HT)(1/2) receptor antagonist, two different 5-HT(3) receptor antagonists, a combination of metergoline and devazepide, a cholecystokinin (CCK) a receptor antagonist, or vehicle. In addition, metergoline or vehicle was applied continuously by an intraperitoneal osmotic minipump for 7, 28, or 84 days after total gastrectomy. RESULTS: Metergoline treatment resulted in a dose-dependent increase in food intake in gastrectomized rats. 5-HT(3) receptor antagonist treatment had no effect, and devazepide in addition to metergoline did not further stimulate food intake. Metergoline increased food intake at 1, 3, and 6 months postoperatively by up to 45% (24-h cumulative food intake [FI], 6 months: vehicle 3.83 +/- 0.10, metergoline 5.52 +/- 0.15 g/100 g body weight (BW), P < 0.0001). Chronic metergoline treatment for 7, 28, or 84 days significantly increased food intake after total gastrectomy compared to vehicle treatment (FI 7 days: vehicle 30.83 +/- 0.71, metergoline 36.27 +/- 0.85 g/100 g BW; P < 0.0002; average weekly FI during 28 days; vehicle 31.23 +/- 0.22, metergoline 36.83 +/- 0.33 g/100 g BW, P < 0.0001; average weekly FI during 84 days: vehicle 33.02 +/- 0.59, metergoline 35.07 +/- 0.48 g/100g BW, P < 0.008), and there was a significant body weight increase compared to vehicle treatment (7 days: DeltaBW vehicle -0.7 +/- 1.2 g vs DeltaBW metergoline 9.0 +/- 2.1 g, P < 0.001; 28 days: DeltaBW vehicle 0.3 +/- 2.2 vs DeltaBW metergoline 13.0 +/- 2.3, P < 0.001; 84 days: DeltaBW vehicle 25.7 +/- 10.2 vs DeltaBW metergoline 49.5 +/- 7.2, P < 0.04). Treatment for 84 days resulted in a significant body weight gain, while vehicle treatment had no effect (vehicle: 438 +/- 11 g vs 464 +/- 12 g, P < 0.2, n.s.; metergoline: 448 +/- 9 g vs 498 +/- 10 g, P < 0.007). CONCLUSIONS: Inhibition of food intake by serotonin might contribute to early satiety and loss of body weight after total gastrectomy.     

Oral ondansetron,tropisetron or metoclopramide to prevent postoperative nausea and vomiting: a comparison in high-risk patients undergoing thyroid or parathyroid surgery

BACKGROUND: Oral antiemetic prophylaxis may be a practical alternative to intravenous administration. Intravenous ondansetron and tropisetron prevent postoperative nausea and vomiting (PONV) at least as efficiently as traditional antiemetics, droperidol and metoclopramide. We tested the hypothesis that the incidence of PONV after oral ondansetron or tropisetron prophylaxis is lower compared with metoclopramide among high-risk patients. METHODS: In a prospective, double-blind study we studied 179 high-risk patients who received either ondansetron 16 mg, tropisetron 5 mg, or metoclopramide 10 mg orally 1 h before the operation. A standard general anesthetic technique and postoperative analgesia were used. The incidence of PONV and the need for rescue antiemetic medication was recorded for 24 h. RESULTS: In the postanesthesia care unit, the incidence of PONV was lower after premedication with tropisetron compared with ondansetron and metoclopramide (15%, 32% and 39%, respectively). The incidence of PONV during 0-24 h was the same in each group (68%, 58% and 75% in the ondansetron, tropisetron and metoclopramide group, respectively), but the incidence of vomiting was significantly lower after ondansetron (34%) and tropisetron (22%) prophylaxis compared with metoclopramide (53%). The need for additional antiemetics was significantly lower after tropisetron prophylaxis compared with metoclopramide. Patient satisfaction was significantly higher after tropisetron than after metoclopramide. CONCLUSIONS: In the initial period, the incidence of PONV was lower after premedication with oral tropisetron than after ondansetron or metoclopramide. Considering the entire 24-h postoperative period, the incidence of PONV was the same after all three premedications, but the incidence of vomiting was lower after oral ondansetron and tropisetron than after metoclopramide.     

托烷司琼胶囊和片剂的药物动力学和生物等效性研究

21名男性健康受试者三交叉口服托烷司琼受试制剂(胶囊A、片剂B)和参比制剂(胶囊C),进行药物动力学及生物等效性研究。采用HPLC/MS/MS测定血浆中托烷司琼浓度。A、B和C三者的Cmax分别为(44.6±17.7)、(43.9±14.9)和(39.1±13.6)ng/ml,AUC0→48h分别为(673.9±511.3)、(668.6±479.8)和(597.1±462.3)ng·h·ml-1。A、B的相对生物利用度分别为(114.1±20.9)%、(114.8±9.0)%,三者具有生物等效性。     

Tropisetron plus dexamethasone is more effective than tropisetron alone for the prevention of postoperative nausea and vomiting in children undergoing tonsillectomy

The 5-HT3 antagonists are effective in reducing postoperative nausea and vomiting (PONV) associated with paediatric tonsillectomy. Although prophylactic tropisetron can reduce the incidence of PONV by half, the resulting level of over 40% is still unacceptably high. The aim of this study was to evaluate the effect of adding dexamethasone to tropisetron. In a blinded study, 59 children (mean age 6.1 years) were administered 0.1 mg.kg-1 up to 2 mg of tropisetron and 66 children (mean age 5.7 years) received the same dose of tropisetron plus 0.5 mg.kg-1 up to 8 mg of dexamethasone. Both drugs were given intravenously during induction of anaesthesia for tonsillectomy. During the inpatient stay of 24 h, the incidence of postoperative vomiting in the tropisetron alone group was 53% compared with 26% in the combination group (P=0.002, chi-squared). A significant reduction in nausea from 53% to 30% was also observed (P=0.02). Parents completed a daily diary for 5 days following discharge. Delayed vomiting occurred in 27% and 11% of the tropisetron and combination therapy groups, respectively (P=0.025) Sixteen percent and 9%, respectively, required medical attention (P=0.27). Tropisetron plus dexamethasone is more effective than tropisetron alone in reducing the incidence of PONV following paediatric tonsillectomy.