新舒眠宁注射液的研制、麻醉效果及药代动力学研究

发布时间：2019-01-07 19:57

【摘要】：兽医临床用于犬麻醉的药物并不多。单一的麻醉药达不到理想的麻醉效果,故临床上常将两种或两种以上的药物同时或先后使用,以达到降低剂量、提高麻醉效果和安全性目的。然而,目前已有复合麻醉剂麻醉效果不甚理想,急需研制出一种麻醉效果确实、安全性高、使用方便的犬用麻醉剂。替来他明、赛拉嗪和咪达唑仑是小动物临床常用药,能用于犬麻醉前用药、诱导以及维持麻醉,但各药单用时,难以使动物进入理想的麻醉状态,且副作用较大。本研究旨将3种药物合理配伍,以期为临床提供一种安全有效的复合麻醉剂。在预试验的基础上,确定3种药物的大致有效剂量。通过对小白鼠进行正交试验,正交决定性验证试验最终确定最佳组方值为替来他明(4 g.100 mL~(-1))、赛拉嗪(0.85 g.100 mL~(-1))和咪达唑仑(0.2 g.100 mL~(-1))。进行了急性毒性、静脉刺激性以及溶血性等安全性试验,测定半数有效量、半数致死量和治疗指数分别为108.12 mg.kg-1、27.38 mg.kg-1和3.95,对静脉具有轻度刺激性,无溶血性,命名为新舒眠宁。新舒眠宁静注比格犬后,起效迅速平稳,诱导时间为21±5.10s,麻醉过程中,镇痛、镇静和肌松效果良好,麻醉维持时间为29.36±7.21 min,苏醒过程平稳较快,苏醒时间为35.28±6.85 min。整个麻醉过程中,未见明显副作用。采用监护仪对心率、呼吸频率、体温、血氧饱和度、血压、呼气末二氧化碳分压等各项生理参数进行监测,结果表明一些时间点的生理参数虽然差异显著(P0.05)或极显著(P0.01),但均在麻醉状态下正常麻醉生理范围内,并通过手术试验验证了新舒眠宁具有良好的镇痛、镇静和肌松效果,能满足临床手术麻醉要求。新舒眠宁静注比格犬后,在不同的时间点采血,测定血药浓度,研究3种药物在体内的药代动力学。试验建立了一种可同步测定犬血浆中3种药物的LC-MS法,替来他明在100～5 000 ng范围内线性关系良好(r2=0.997 1),赛拉嗪在10～2 500 ng范围内线性关系良好(r2=0.998 7),咪达唑仑在10～2 500ng范围内线性关系良好(r2=0.9990)。3种药物的主要动力学参数为:替来他明Vc=0.81±0.106 L.kg-1 T1/2α=3.54±0.65 min,T1/2β=68.089±18.767 min,AUC=184.016±35.677 μg.min.mL~(-1),CL(s)=0.022 4±0.004 28 L.min-1.kg-1;赛拉嗪 Vc=0.837±0.154 L.kg-1,T1/2α=4.12±1.52 min,T1/2β=47.34±13.66 min,AUC=20.065±2.602 μg.min.mL~(-1),CL(s)=0.030 3±0.004 03 L.min-1.kg'1 咪达唑仑 Vc=0.3±0.039 L.kg-1,T1/2α=3.29±0.16 min,T1/2β=45.08±4.15 min,AUC=14.944±0.681 μg.min.mL~(-1),CL(s)= 0.010 5±0.000 5 L.min-1.kg-1。结论:本研究成功研制出一种复合麻醉剂,命名为新舒眠宁。通过建立3种药物液质联用测定法,初步研究了新舒眠宁药代动力学,为临床合理使用提供了依据。本复合麻醉剂可安全、有效地用于犬临床麻醉。
[Abstract]:There are few veterinary drugs used in canine anesthesia. Single anesthetic can not achieve ideal anesthetic effect, so two or more kinds of drugs are often used simultaneously or successively in clinic in order to reduce the dose and improve the anesthetic effect and safety. However, the anesthetic effect of compound anesthetic is not satisfactory, so it is urgent to develop a canine anesthetic which is effective, safe and convenient to use. Teletamine, ceprazine and midazolam are common clinical drugs for small animals. They can be used in dogs before anesthesia, induce and maintain anaesthesia, but when used alone, it is difficult for animals to enter into ideal anaesthesia state and have great side effects. The aim of this study was to provide a safe and effective compound anesthetic for clinical use. On the basis of pretest, the approximate effective doses of three drugs were determined. By orthogonal experiment in mice, the orthogonal deterministic verification test determined the best group square value as teletamine (4 g. 100 mL~ (-1),). Ceprazine (0. 85 g. 100 mL~ (-1) and midazolam (0. 2 g. 100 mL~ (-1).) The safety tests of acute toxicity, venous irritation and hemolysis were carried out. The 50% effective dose, 50% lethal dose and treatment index were 108.12 mg.kg-1,27.38 mg.kg-1 and 3.95, respectively. No hemolytic, named Xinshumianning. The induction time was 21 卤5.10 s. The analgesic, sedation and muscle relaxation effects were good during anesthesia. The maintenance time of anesthesia was 29.36 卤7.21 min,. Recovery time was 35.28 卤6.85 min.. There were no obvious side effects during the whole anesthesia. Heart rate, respiratory frequency, body temperature, blood oxygen saturation, blood pressure, end expiratory carbon dioxide partial pressure and other physiological parameters were monitored by monitor. The results showed that the physiological parameters of some time points were significantly different (P0.05) or extremely significant (P0.01), but all of them were in the range of normal anesthetic physiology under anaesthesia. Sedation and muscle relaxation can meet the requirements of clinical anesthesia. The blood samples were collected at different time points to determine the blood concentration and the pharmacokinetics of the three drugs in vivo. A LC-MS method for simultaneous determination of three drugs in canine plasma was established. The linear relationship of teletamine was good in the range of 100g / 5 000 ng (r _ 2 / 0.997 _ 1), and the linear relationship was good in the range of 10 ~ 2 500 ng (r _ (22) 0.998 ~ 7). The main kinetic parameters of midazolam were as follows: Vc=0.81 卤0.106 L.kg-1 T1 / 2 伪 = 3.54 卤0.65 min,T1/2 尾 = 68.089 卤18.767 min,. AUC=184.016 卤35.677 渭 g 路min 路mL ~ (-1), CL (s) = 0.022 4 卤0.004 28 L 路min -1 路kg -1; Vc=0.837 卤0.154 L 路kg ~ (-1) T _ 1 / 2 伪 = 4.12 卤1.52 min,T1/2 尾 = 47.34 卤13.66 min,AUC=20.065 卤2.602 渭 g 路min ~ (-1). CL (s) = 0.030 3 卤0.004 03 L.min-1.kg'1 midazolam Vc=0.3 卤0.039 L 路kg -1 T1 / 2 伪 = 3.29 卤0.16 min,T1/2 尾 = 45.08 卤4.15 min,AUC=14.944 卤0.681 渭 g 路min ~ (-1). CL (s) = 0.010 5 卤0.000 5 L.min-1.kg-1. Conclusion: a new compound anesthetic was successfully developed and named as Xinshumianning. The pharmacokinetics of Xinshuanning was preliminarily studied by establishing three methods of liquid / mass spectrometry, which provided a basis for rational clinical use. The compound anesthetic can be used safely and effectively in canine clinical anesthesia.
【学位授予单位】：南京农业大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：S859.791

【相似文献】