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HE Jing, AN Ye, ZHANG Chaoshen. Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404009
Citation: HE Jing, AN Ye, ZHANG Chaoshen. Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404009

Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills

doi: 10.12206/j.issn.2097-2024.202404009
  • Received Date: 2024-04-02
  • Rev Recd Date: 2024-10-17
  • Objection: To study and compare the pharmacodynamics in the treatment of chronic pharyngitis between Compound Heishen pills and Compound Heishen Drop pills.   Methods  Sixty healthy Wistar rats were randomly divided into blank group, positive control group and treatment group. The foot swelling thickness of each rat was measured at 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 h after inflammation, and the foot swelling rate of each rat was calculated. Through the experimental model of rat toe swelling, the inhibition of foot swelling induced by carrageenan was observed by two dosage forms: drop pill and pill. Sixty healthy Kunming mice were randomly divided into the blank group, positive control group and treatment group. After 4 days of continuous intragastric administration, the mice were intraperitoneally injected with 0.5% phenol red solution. After 30min, the mice were sacrificed, their trachea was dissected and washed with 0.5%NaHCO3 solution. The washing solution was put into ultraviolet spectrophotometer, and the absorbance was measured at 546 nm to calculate the corresponding concentration of phenolic red. Through the expectorant experiment of phenol red in mice, the effects of dropping pill and pill on the secretion of phenol red in experimental mice respiratory tract were compared.   Results  The experimental results of toes swelling in rats showed that compared with the blank experimental group, the five groups all had significant inhibition effect on acute foot swelling induced by carrageenan in rats. Compared with traditional form group, improved form had significant difference. The results of phenol red sputum removing experiment in mice showed that compared with the blank group the amount of phenol red secretion in mice was increased in 5 test groups could . There was no significant difference between improved form and traditional form on the amount of phenol red secretion in mice.   Conclusion  Both preparations had the function of anti-inflammatory and eliminating phlegm. There were no remarkable differences between the two preparations on pharmacologic actions.
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Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills

doi: 10.12206/j.issn.2097-2024.202404009

Abstract: Objection: To study and compare the pharmacodynamics in the treatment of chronic pharyngitis between Compound Heishen pills and Compound Heishen Drop pills.   Methods  Sixty healthy Wistar rats were randomly divided into blank group, positive control group and treatment group. The foot swelling thickness of each rat was measured at 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 h after inflammation, and the foot swelling rate of each rat was calculated. Through the experimental model of rat toe swelling, the inhibition of foot swelling induced by carrageenan was observed by two dosage forms: drop pill and pill. Sixty healthy Kunming mice were randomly divided into the blank group, positive control group and treatment group. After 4 days of continuous intragastric administration, the mice were intraperitoneally injected with 0.5% phenol red solution. After 30min, the mice were sacrificed, their trachea was dissected and washed with 0.5%NaHCO3 solution. The washing solution was put into ultraviolet spectrophotometer, and the absorbance was measured at 546 nm to calculate the corresponding concentration of phenolic red. Through the expectorant experiment of phenol red in mice, the effects of dropping pill and pill on the secretion of phenol red in experimental mice respiratory tract were compared.   Results  The experimental results of toes swelling in rats showed that compared with the blank experimental group, the five groups all had significant inhibition effect on acute foot swelling induced by carrageenan in rats. Compared with traditional form group, improved form had significant difference. The results of phenol red sputum removing experiment in mice showed that compared with the blank group the amount of phenol red secretion in mice was increased in 5 test groups could . There was no significant difference between improved form and traditional form on the amount of phenol red secretion in mice.   Conclusion  Both preparations had the function of anti-inflammatory and eliminating phlegm. There were no remarkable differences between the two preparations on pharmacologic actions.

HE Jing, AN Ye, ZHANG Chaoshen. Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404009
Citation: HE Jing, AN Ye, ZHANG Chaoshen. Comparative study of pharmacodynamic experiments on compound Heishen drop pills and compound Heishen pills[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404009
  • 慢性咽炎为咽部黏膜、黏膜下及淋巴组织的慢性炎症[1],中医属 “慢喉痹”、“虚火喉痹”范围,主要病因病机是脏腑之阴阳气血津液失调,咽喉失养,气血痰浊郁滞[2,3],治法为:清热解毒、养阴清肺、生津润燥、理气化痰。北方地区气候寒冷、空气干燥,工业化污染较为严重,近年来慢性咽炎发病率逐年升高,影响患者的生活质量[4-6]。慢性咽炎为局部炎症,同时伴有局部痰液的刺激,因此治疗本病的关键是祛痰、抗炎[7]。复方黑参丸由玄参、北豆根、天冬、麦冬、射干五味中药组成,是解放军北部战区总医院治疗慢性咽炎的有效中药制剂,在我院临床应用多年,疗效确切。复方黑参滴丸为我院制剂室在传统中药剂型复方黑参丸的基础上进行改进的新型制剂[8]。本实验通过建立动物模型观察两种剂型的的抗炎、祛痰作用,并对改进剂型复方黑参滴丸与传统剂型复方黑参丸进行动物实验比较研究[9,10],为该剂型开发提供药理学实验基础。

    • UV2800型紫外可见分光光度计(上海舜宇恒平),KQ-400DB型超声清洗仪(昆

      山市超声仪器有限公司);FA2004A型电子分析天平(上海精天电子仪器有限公司);XMTD-4000电热恒温水浴锅(北京永光明仪器有限公司),游标卡尺。

    • 复方黑参滴丸(批号20190501):由北部战区总医院制剂室配制、复方黑参丸(批号20191015):由北部战区总医院制剂室配制、咽炎片(批号170301):长春人民药业集团有限公司、角叉菜胶(Sigma,批号142k14144)、苯酚红(分析纯,批号20140526,天津科密欧化学试剂有限公司)、碳酸氢钠(分析纯,批号20180820,天津科密欧化学试剂有限公司)[5]

    • SPF(清洁)级昆明种小鼠60只,雌雄各半,体重18~22 g。SPF级Wistar大鼠60只,体重180~220 g,雌雄各半,实验动物购自于辽宁长生生物技术有限公司,实验动物生产许可证号SCXK(辽)2010-0001,自由饮水饮食,室温(22±2)℃。

    • 取实验用复方黑参滴丸、复方黑参丸、咽炎片适量,分别研匀,加入适量蒸馏水研磨成糊状,再加入适量蒸馏水,边加边搅拌,分别使成适当浓度的混悬液,配制浓度如下:

      (1)滴丸低剂量组:配制成浓度为0.09 g生药/ml的混悬液;

      (2)滴丸中剂量组:配制成浓度为0.27 g生药/ml的混悬液;

      (3)滴丸高剂量组:配制成浓度为0.81 g生药/ml的混悬液;

      (4)复方黑参丸供试液:配制成浓度为0.09 g生药/ml的混悬液;

      (5)阳性对照药咽炎片供试液:配制成浓度为0.09 g/ml的混悬液。

    • 选取体重范围在180~220 g的健康Wistar大鼠60只,随机分为6组,每组10只,分别灌胃给药,给药量如下:

      (1)复方黑参滴丸低剂量组:0.9 g生药/kg;

      (2)复方黑参滴丸中剂量组:2.7 g生药/kg;

      (3)复方黑参滴丸高剂量组:8.1 g生药/kg;

      (4)复方黑参丸组:0.9 g生药/kg;

      (5)阳性对照药咽炎片组:0.9 g/kg;

      (6)空白对照组:给予相同容积的蒸馏水。

      所有实验大鼠连续灌胃给药4 d,每天2次。于最末一次给药1 h后,将实验的大鼠后腿拉直,于每只大鼠的右后足爪皮下注入1%角叉菜胶溶液,0.1 ml/只,分别于致炎前(0 h)及致炎后的 1、2、3、4、5、6 h测定大鼠足跖肿胀厚度,以致炎前后每只大鼠足跖肿胀率作为肿胀评价指标。足跖肿胀率按以下公式进行计算:

      分别比较各时间点给药组与对照组、改进剂型组与传统剂型组的足跖肿胀程度,进行统计学处理。结果见表1

      组别 剂量(g/kg) 致炎后不同时间的肿胀率(%)
      1 h 2 h 3 h 4 h 5 h 6 h
      空白组 / 0.574±0.10 0.676±0.10 0.809±0.18 0.860±0.19 1.035±0.19 0.941±0.16
      咽炎片 0.9 0.533±0.06 0.648±0.05 0.773±0.03 0.822±0.05* 0.808±0.10* 0.770±0.08*
      复方黑参丸 0.9 0.418±0.08** 0.510±0.12* 0.693±0.17 0.830±0.13 0.796±0.18* 0.758±0.17
      低剂量 0.9 0.469±0.13 0.634±0.19 0.769±0.16 0.853±0.13 0.819±0.13* 0.752±0.12*
      中剂量 2.7 0.509±0.08 0.555±0.13 0.804±0.08 0.862±0.11 0.802±0.10** 0.784±0.10*
      高剂量 8.1 0.406±0.10** 0.502±0.13* 0.565±0.16* 0.750±0.16*# 0.699±0.17** 0.637±0.15**
      * P<0.05,** P<0.01,与阳性对照咽炎片组比较;#P<0.05,与复方黑参丸组比较。

      统计学处理结果表明:与空白实验组相比较,5个供试品液组(复方黑参滴丸低、中、高3个剂量组、复方黑参丸组、阳性对照药咽炎片组)对角叉菜胶所引起的大鼠急性足跖肿胀均有显著的抑制作用。并且通过实验结果可以看出:与复方黑参丸(传统剂型)组比较,复方黑参滴丸(改进剂型)高剂量组有显著差异(P<0.05)。

    • 取实验用复方黑参滴丸、复方黑参丸、咽炎片适量,分别研匀,加入适量蒸馏水研磨成糊状,再加入适量蒸馏水,边加边搅拌,分别使成适当浓度的混悬液,配制浓度如下:

      (1)滴丸低剂量组:配制成浓度为0.05g生药/ml的混悬液;

      (2)滴丸中剂量组:配制成浓度为0.15g生药/ml的混悬液;

      (3)滴丸高剂量组:配制成浓度为0.45g生药/ml的混悬液;

      (4)复方黑参丸供试液:配制成浓度为0.05g生药/ml的混悬液;

      (5)阳性对照药咽炎片供试液:配制成浓度为0.05g/ml的混悬液。

    • 酚红标准曲线的绘制:精密称取苯酚红10 mg,置100 ml容量瓶中,加入5%NaHCO3溶液溶解并稀释至刻度,摇匀,配制成浓度为100 µg/ml的酚红溶液,备用。精密吸取酚红溶液0.1、0.3、0.5、0.7、1.0、3.0、5.0、10.0 ml,分别置于100 ml容量瓶中,加入5%NaHCO3溶液稀释至刻度,摇匀备用。以5%NaHCO3溶液为空白,照紫外-可见分光光度法(中国药典2020年版四部通则0401),在546 nm波长处测定上述稀释后8个浓度酚红溶液的吸光度,以吸光度(A)值为纵坐标,酚红溶液浓度为横坐标,绘制酚红标准曲线,方程为Y=0.129 7 X+0.001 3,r=0.999 8。

      选取体重范围在18~22 g的健康昆明种小鼠60只,随机分为6组,每组10只,分别灌胃给药:给药剂量如下:

      (1)复方黑参滴丸低剂量组:1.3 g生药/kg;

      (2)复方黑参滴丸中剂量组:3.9 g生药/kg;

      (3)复方黑参滴丸高剂量组:11.7 g生药/kg;

      (4)复方黑参丸组:1.3 g生药/kg;

      (5)阳性对照药咽炎片组:1.3 g/kg;

      (6)空白对照组:给予相同容积的蒸馏水。

      所有实验小鼠灌胃给药每日2次,每只小鼠给药量为0.5 ml/20 g。连续灌胃给药3 d后,禁食8 h,禁食过程中不禁水。于第4天灌胃给药30 min后,小鼠腹腔注射0.5%酚红溶液,每只注射给药0.6 ml。注射酚红30 min后处死小鼠,小鼠仰位固定,剪开颈前部皮肤,剥离出气管,用注射器抽取5%NaHCO3溶液冲洗气管,每次1 ml,反复冲洗3次,合并3次冲洗液,离心,备用。取离心后的红色澄明上清液,置于紫外分光光度计中,在546 nm波长处测定吸光度(A546)值,从绘制的酚红标准曲线算出每个吸光度(A546)值相对应的酚红浓度。结果见表2

      组别 给药剂量(g/kg) 动物数(只) 酚红分泌量(µg/ml)
      空白组 / 10 1.299±0.312
      咽炎片组 1.3 10 1.759±0.445 *
      复方黑参丸组 1.3 10 1.913±0.632 *
      低剂量组 1.3 10 1.697±0.381 *
      中剂量组 3.9 10 1.525±0.370
      高剂量组 11.7 10 1.809±0.406 **
      *P<0.05,**P<0.01,与空白组比较。

      实验结果表明:与空白组比较,5个供试品液组(复方黑参滴丸低、中、高3个剂量组、复方黑参丸组、阳性对照药咽炎片组)均能增加小鼠酚红分泌量。其中,复方黑参滴丸低、高2个剂量组、复方黑参丸组、阳性对照药咽炎片组能够显著增加小鼠酚红分泌量(P<0.05),虽然复方黑参滴丸中剂量组与空白组相比无显著差异,但从实验结果可以看出,复方黑参滴丸中剂量组有增加小鼠酚红排出量的趋势。改进剂型(复方黑参滴丸)与传统剂型(复方黑参丸)对小鼠酚红分泌量的影响无显著性差异。

    • 取实验用复方黑参滴丸适量,分别研匀,加入适量蒸馏水研磨成糊状,再加入适量蒸馏水,边加边搅拌,使成浓度为每ml含2 g生药的混悬液。

    • 选取体重范围在18~22 g的健康昆明种小鼠40只,雌雄各半。于试验前禁食不禁水12 h。考虑复方黑参滴丸药液浓度以不堵塞灌胃针,小鼠易于灌胃给药为原则,复方黑参滴丸以浓度2 g生药/ml,容积0.4 ml,进行灌胃给药。(此浓度为该制剂能够小鼠灌胃给药的最大浓度,浓度再高无法灌胃给药。),每只小鼠1 d内灌胃给药2次,上、下午各一次。小鼠灌胃给药后进行观察7 d,所有实验小鼠均未出现死亡情况和明显的毒性反应。计算小鼠的最大耐受量倍数为267倍[8]

    • 复方黑参滴丸是在复方黑参丸原处方基础上,通过提取、浓缩、制丸工艺而制成的新剂型,既保留了方中五味中药的有效成分,又克服了中药丸剂服用不便、卫生标准难以达标的缺点。开发改进剂型复方黑参滴丸可以增加患者用药的依从性,便于临床治疗应用。本实验以抗炎、祛痰作用为评价的指标,对新改进剂型复方黑参滴丸与传统剂型复方黑参丸进行了系统的药效学实验对比研究,为应用该药物剂型提供药效学依据。

      本实验采用1%角叉菜胶溶液作为致炎剂,空白组给药后1 h足跖肿胀即与给药前有显著差异,4~5 h肿胀达到峰值,形成的炎症模型与文献报道相似。选取小鼠酚红祛痰实验对复方黑参滴丸和复方黑参丸的祛痰作用进行对比研究。小鼠腹腔注射酚红后经吸收循环,可部分由支气管黏液腺分泌入气道。有祛痰作用的药物在使支气管分泌液增加的同时,呼吸道黏膜排出的酚红量也随之增加。经由气道冲洗收集,用紫外-可见分光光度法测定酚红的排泌量,从而判断药物祛痰作用强弱。实验结果表明:复方黑参滴丸3个剂量组及复方黑参丸均有明显的抗炎、排痰、祛痰作用。改进剂型复方黑参滴丸与传统剂型复方黑参丸比较无显著性差异,表明药物剂型改变并未影响药物的疗效。

      复方黑参滴丸由玄参、北豆根、天冬、麦冬、射干五味中药组成,具有清热解毒、养阴润肺、利咽消肿的功效。方中玄参主要含有环烯醚萜类、苯丙素苷类、黄酮类等化学成分,其中,哈帕酯苷、哈帕苷、苯丙素苷有抗炎药理作用[24];北豆根含多种生物碱,其中,北豆根总碱、蝙蝠葛碱、蝙蝠葛酚性碱对呼吸道、肠道致病菌及条件致病菌均有抑菌作用[25]。天冬主要含有天冬酰胺、黏液质、甾体皂苷等化学成分,所含天冬酰胺有镇咳、祛痰作用。处方中药味均为《中国药典》收载的常用中药,毒性小。因此,本实验通过小鼠的最大耐受量试验,观察实验动物对复方黑参滴丸的耐受程度。通过实验,给小鼠灌胃复方黑参滴丸混悬液的剂量,达到成人日服剂量(15 g)的267倍后小鼠仍不引起死亡,实验动物完全能够耐受。结果表明,新改进剂型复方黑参滴丸毒性相当小,安全性高。口服安全可靠,可以为临床应用提供实验依据。

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