中药注射剂致敏性研究
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摘要
目的:
通过小鼠、豚鼠、Beagle犬的类过敏(anaphylactoid reaction)反应试验,筛选一个敏感度、准确率高的类过敏反应试验方法,通过吐温80 ( Tween 80)的定性定量检测,调查中药注射剂(traditional Chinese medicine injection)中吐温80的情况,选择含有吐温80的品种进行类过敏试验,探讨吐温80对中药注射剂致敏性(sensitization)的影响,从辅料方面寻找一个解决某些中药注射剂致敏性的方法。
方法:
1、小鼠类过敏试验:小鼠一次性尾静脉注射给药致敏,给药剂量采用成人日用量的15倍(公斤体重),给药容积0.5ml/只,给药后观察小鼠的行为学取血检测血浆中组胺(Histamine)含量,以行为学评分(behavioral score)和组胺含量变化综合判定类过敏反应结果。
2、豚鼠类过敏试验:豚鼠一次性静脉推注,给药容积2ml/只,给药剂量采用人临床用量的6倍,给药后观察豚鼠的行为学变化,15min后股动脉取血检测血浆组胺含量,以行为学评分和组胺含量变化综合判定类过敏反应结果。
3、Beagle犬类过敏、过敏试验:实验开始第1、3、5及14天分别给予各组犬相应药液,前3次为致敏阶段,给药体积均为5.0ml.kg-1,给药剂量相当于临床成人用药的等效剂量,第4次为激发阶段,给药体积为第一次的2倍,前肢静脉恒速注射。连续观察给药前及后3h内每组犬的行为学变化,记录症状出现及消失时间,并根据症状的轻重进行行为学评分;首次给药前后及末次药后10min抽取4ml静脉血检测组胺、IgE、IgG和IgM。
4、吐温80的定性定量测定方法
4.1吐温80的定性测定
4.1.1硫氰酸钴铵显色法(Cobalt thiocyanate ammonium color-developing method):供试液加硫氰酸钴铵溶液2ml,摇匀,加1ml氯仿摇匀,静置1.5h,观察氯仿层颜色。结果判断:氯仿层出现蓝色为阳性(++),浅蓝色为弱阳(+),绿色为可疑(±),其他颜色均记为阴性(-)。
4.1.2薄层层析法(Silicon thin-layer chromatography method):
4.1.2.1样品分析薄层条件:以甲醇-水-甲酸为展开剂,8:5:1的比例混合,能明显分开各供试品,效果理想。
4.1.2.2点样与展开:吸取各组供试品适量,点于距离下端约0.5cm处,点样结束,吹干,将板放入展开剂饱和的碘缸中,展开8cm将板取出,吹干溶剂,约15min左右,检识各注射液中含有吐温80的情况。结果判断:在与阳性对照色谱在相应位置上有清晰的棕黄色斑点记为阳性(++),不清晰者记为弱阳(+),没有棕黄色斑点者记为阴性(-)。
4.2吐温80定量测定:比色法,进行方法学考察并测定样品。
结果:
1、一次性给药后,以行为异常和组胺含量变化综合判断临床过敏性休克排名较前的5种中药注射剂对小鼠的类过敏反应,双黄连和脉络宁判定为阳性,鱼腥草、黄芪、参麦为可疑,与临床报道不全相符。
2、一次性给药后,以行为异常和组胺含量变化综合判断临床过敏性休克排名较前的10种中药注射剂对豚鼠类过敏反应,双黄连判定为可疑,其他均为阴性,与临床报道不相符。
3、一次性给药后,临床报道过敏性休克排名较前的10位中药注射剂对Beagle犬进行类过敏试验,综合行为异常,组胺含量变化为主要判定指标,结果显示10种中药注射剂均出现了类过敏反应阳性或强阳性结果,未发现假阴性结果,与临床报道相符。
4、通过对43种中药注射剂中吐温80的检测,肝炎宁、醒脑静、鱼腥草、正清风痛宁、参麦、生脉、复方苦参、脉络宁、消癌平、胆木、血必净、复方丹参、鸡矢藤、得力生及康艾注射液都含有吐温80,含量从0.72±0.00～6.85±0.02 mg.ml-1不等,其他注射剂未检出吐温80。
5、说明书上标示的执行标准不含吐温80的中药注射剂而查出吐温80的有生脉、复方苦参和正清风痛宁。
6、含有吐温80的5种中药注射液首次静脉给药后出现严重的行为异常;通过对血浆中组胺检测,参麦、肝炎宁和醒脑静组组胺明显升高,综合行为异常和组胺含量变化为主要判定指标综合判断,5种中药注射剂均达到类过敏反应强阳性或阳性。
7、激发给药后的过敏试验,含有吐温80的5种注射剂出现严重的行为异常;血浆组胺检测发现,参麦、生脉、正清风痛宁和肝炎宁组明显升高,综合行为异常,组胺含量变化为主要判定指标综合判断,5种注射剂过敏试验达到阳性或强阳性。
结论:
1、类过敏反应以Beagle犬为最佳实验动物,以行为异常和组胺含量变化为主要判定指标,IgE作为辅助指标,结果准确可靠,得到结果与临床报告相符,未发现假阴性。
2、本研究采用硫氰酸钴铵显色法和薄层层析法两种方法进行中药注射剂中吐温80的鉴定,结果较为准确。
3、中药注射剂中吐温80的添加有待加强监督与规范。中药注射剂中辅料应加强检测及安全性评价,特别对部颁标准中没有标明或标明不含有吐温80的注射剂,进行吐温80的定性定量检测,为进一步研究、评价、增强中药注射剂的安全性以及临床用药提供可靠的依据。
4、含吐温80的5个中药注射剂品种发生严重不良反应与吐温80相关,今后应谨慎使用,并逐步禁用于中药注射剂,积极寻找安全、合理的适用于中药注射剂的药用辅料,全面取代吐温80。
5、大量研究及临床应用表明,134种中药注射剂有的品种存在不同程度的安全隐患,特别是排序在前的品种,问题更为严重,应尽快组织力量进行一次更新换代的全面系统研究,从根本上、源头上解决问题,提高产品质量,安全性及有效性。
OBJECTIVES:
To screen a sensitive anaphylactoid reaction experimental method with high accuracy by the anaphylactoid reaction experiment of traditional Chinese medicine injections on mice, guinea pigs and dogs, to investigate the addition of Tween80 in the traditional Chinese medicine injections by qualitative and quantitative determination of the Tween80, then study the anaphylactoid reaction of the injections containing Tween80 on the Beagle dogs and export the effect of Tween80 on the sensitization of traditional Chinese medicine injections, to find one of solutions to solve the sensitization of traditional Chinese medicine injections.
METHODS:
1. Anaphylactoid reaction experiment on mice. The mice were allergized by tail intravenously injection, the dosage was 15 times as the adult dosage, the delivery volume was 0.5ml every mouse, then behavior changes of the mice were observed and the contents of serum Histamine were detected. The result was determined according to the synthetic index of changes of behavior and the serum Histamine.
2. Anaphylactoid reaction experiment on guinea pigs. The guinea pigs were allergized by intravenously injection, the delivery volume was 2ml every guinea pig, the dosage was 6 times as the adult dosage , then behavior changes of the guinea pigs were observed and the contents of serum Histamine were detected. The result was determined according to the synthetic index of changes of behavior and the serum Histamine.
3. Anaphylactoid and allergical reaction experiments on Beagle dogs. The Beagle dogs were allergized by forelimb injecting constantly( at a speed of 5ml/min with an injection pump). On the first, third, fifth and the fourteenth day, the delivery volume was 5ml/kg, the dosage was 2 times as the adult dosage, the forme three times were allergic steps, the last time was exciting step, the dosage of the last time was 2 times as the first, behavior changes of the dogs were observed , blood was drawn before and after the drug delivery, the contents of serum Histamine, immunoglobulin E , immunoglobulin G and immunoglobulin E were detected. The result was determined according to the synthetic index of changesof the behavior and the serum Histamine.
4. The qualitative and quantitative determination methods of Tween80.
4.1 Qualitative determination of Tween80.
4.1.1 Cobalt thiocyanate ammonium color-developing method: The tested material were added in the 2ml cobalt thiocyanate ammonium color-developings in a tube, shaken up, then 1ml Chloroform was added in the tube , shaken up and standed for 1.5h, the colour of Chloroform layer were observed. Result determinning: the blue colour of Chloroform layer was determined positive, light blue was weak positive, green was susipicious, the others were negative.
4.1.2 Silicon thin-layer chromatography method.
4.1.2.1 The condition of thin-layer chromatograph. Benthing with a mixed solvent of MeoH-H2O-HCOOH(8:5:1) as the developer, the test material can be developed well.
4.1.2.2 Spotting and developing. Taking some tested material, spotting about 0.5cm from the bottom of the thin-layer plate, finished, blowing dry, putting the plate in the iodine jar, taking out when the developing length was 8cm, blowing dry the solvent, 15min later, observing the colour and position of the dots. The result was determined as positive when the dot was yellow and clear and the position was on the same line with the positive spot, weak positive when the colour was not clear, negative when there is no yellow spot in the corresponding position.
4.2 Quantitative determination of Tween80: colorimetic method was used to determine the content of Tween80. The method was studied and the sample were determined.
RESULTS:
1. Results of the anaphylactoid reaction experiment on mice. According to the synthetic index of behavior changes and the serum Histamine, Double Coptis and Mailuoning were determined as positive, the Houttuynia cordata , astragalus and shenmai were susipicious, which were not conform with the clinical export.
2. Results of the anaphylactoid reaction experiment of 10 traditonal Chinese medicine on guinea pigs. According to the synthetic index of behavior changes and the serum Histamine, Double Coptis was determined as susipicious, the others were negative, which were not conform with the clinical export.
3. Results of the anaphylactoid reaction experiment of 10 traditonal Chinese medicine injections on Beagle dogs. According to the synthetic index of changes of the behavior and serum Histamine, the 10 traditonal chinese medicine injections were determined as positive. There were no false negative, which were conform with the clinical export.
4. Forty-three traditional Chinese medicine injections were determined. Fifteen species including the Houttuynia cordata injection and so on were checked out containing Tween80, the content were from 0.72±0.00 to 6.85±0.02 mg.ml-1 respectively. The others were not checked out.
5. Among the 15 traditional Chinese medicines injections, there were 8 species which illustrating the addition of Tween80 openly, Delsheng, kang,ai and Xuebijing were not founded in the experiments. So the species which have no illustrations about the additions of Tween 80 but checked out in the experiment were Shengmai, Fufang kushen and Zhengqingfentongning.
6. Results of the anaphylactoid reaction experiment of 5 traditonal Chinese medicine injections including Tween 80 on Beagle dogs. The dogs showed serious dystrophy, according to the synthetic index of changes of the behavior and serum Histamine, the 5 injections were determined as positive or strong positive .
7. Results of the allergical reaction experiment of 5 traditonal Chinese medicine injections containing Tween 80 on Beagle dogs. The dogs showed serious dystrophy . According to the synthetic index of changes of the behavior and serum Histamine, the 5 injections containing Tween 80 were determined as positive or strong positive .
CONCLUSIONS:
1. Anaphylactoid reaction experiment of the traditional Chinese medicine injections which rank the tops in the anaphylactic shock clinical reports on the mice, guinea-pigs and Beagle dogs were carried. The results show that dog is the best experiment animal , the result determination depend on the synthetic index of changes of the behavior and serum Histamine, IgE is the assistant determination index. The experiment result are accuate , and conform with the clinical report. There are no false negative.
2. The results are accurate when the content determination of Tween 80 in the traditional chinese injections by the Cobalt thiocyanate ammonium color-developing method and silicon thin-layer chromatography.
3. The additions of Tween80 of traditional Chinese medicine injections should be supervised strongly and standarded. The detect and the security evalution of excipient in the traditional Chinese medicine injections should be enhanced, especially the species which do not illustrate the addition of the Tween80. The qualitative and quantitative determination of Tween80 should be carried to study to evaluate and enhance the security of the traditional Chinese medicine, which offer the evidence for clinic medication.
4. The serious adverse reaction of traditional Chinese medicine injections containing Tween80 is relate to the Tween80 . So Tween80 should be banned to add in the tradictional Chinese medicine injections step by step. Securial and reasonable medical excipient should be found to subsititute Tween80.
5. A lot of experimental studies and clinical useness showed that some traditional Chinese medicine injections existed some hidden danger, especially the species rank in the tops of clinical report of adverse faction. The questions of them are more sierous. A system study shoule be carried as soon as quickly to solve this problem fundamentally from the source. Only the medicine quality ,security and validity can increase by this.
通过小鼠、豚鼠、Beagle犬的类过敏(anaphylactoid reaction)反应试验,筛选一个敏感度、准确率高的类过敏反应试验方法,通过吐温80 ( Tween 80)的定性定量检测,调查中药注射剂(traditional Chinese medicine injection)中吐温80的情况,选择含有吐温80的品种进行类过敏试验,探讨吐温80对中药注射剂致敏性(sensitization)的影响,从辅料方面寻找一个解决某些中药注射剂致敏性的方法。
方法:
1、小鼠类过敏试验:小鼠一次性尾静脉注射给药致敏,给药剂量采用成人日用量的15倍(公斤体重),给药容积0.5ml/只,给药后观察小鼠的行为学取血检测血浆中组胺(Histamine)含量,以行为学评分(behavioral score)和组胺含量变化综合判定类过敏反应结果。
2、豚鼠类过敏试验:豚鼠一次性静脉推注,给药容积2ml/只,给药剂量采用人临床用量的6倍,给药后观察豚鼠的行为学变化,15min后股动脉取血检测血浆组胺含量,以行为学评分和组胺含量变化综合判定类过敏反应结果。
3、Beagle犬类过敏、过敏试验:实验开始第1、3、5及14天分别给予各组犬相应药液,前3次为致敏阶段,给药体积均为5.0ml.kg-1,给药剂量相当于临床成人用药的等效剂量,第4次为激发阶段,给药体积为第一次的2倍,前肢静脉恒速注射。连续观察给药前及后3h内每组犬的行为学变化,记录症状出现及消失时间,并根据症状的轻重进行行为学评分;首次给药前后及末次药后10min抽取4ml静脉血检测组胺、IgE、IgG和IgM。
4、吐温80的定性定量测定方法
4.1吐温80的定性测定
4.1.1硫氰酸钴铵显色法(Cobalt thiocyanate ammonium color-developing method):供试液加硫氰酸钴铵溶液2ml,摇匀,加1ml氯仿摇匀,静置1.5h,观察氯仿层颜色。结果判断:氯仿层出现蓝色为阳性(++),浅蓝色为弱阳(+),绿色为可疑(±),其他颜色均记为阴性(-)。
4.1.2薄层层析法(Silicon thin-layer chromatography method):
4.1.2.1样品分析薄层条件:以甲醇-水-甲酸为展开剂,8:5:1的比例混合,能明显分开各供试品,效果理想。
4.1.2.2点样与展开:吸取各组供试品适量,点于距离下端约0.5cm处,点样结束,吹干,将板放入展开剂饱和的碘缸中,展开8cm将板取出,吹干溶剂,约15min左右,检识各注射液中含有吐温80的情况。结果判断:在与阳性对照色谱在相应位置上有清晰的棕黄色斑点记为阳性(++),不清晰者记为弱阳(+),没有棕黄色斑点者记为阴性(-)。
4.2吐温80定量测定:比色法,进行方法学考察并测定样品。
结果:
1、一次性给药后,以行为异常和组胺含量变化综合判断临床过敏性休克排名较前的5种中药注射剂对小鼠的类过敏反应,双黄连和脉络宁判定为阳性,鱼腥草、黄芪、参麦为可疑,与临床报道不全相符。
2、一次性给药后,以行为异常和组胺含量变化综合判断临床过敏性休克排名较前的10种中药注射剂对豚鼠类过敏反应,双黄连判定为可疑,其他均为阴性,与临床报道不相符。
3、一次性给药后,临床报道过敏性休克排名较前的10位中药注射剂对Beagle犬进行类过敏试验,综合行为异常,组胺含量变化为主要判定指标,结果显示10种中药注射剂均出现了类过敏反应阳性或强阳性结果,未发现假阴性结果,与临床报道相符。
4、通过对43种中药注射剂中吐温80的检测,肝炎宁、醒脑静、鱼腥草、正清风痛宁、参麦、生脉、复方苦参、脉络宁、消癌平、胆木、血必净、复方丹参、鸡矢藤、得力生及康艾注射液都含有吐温80,含量从0.72±0.00～6.85±0.02 mg.ml-1不等,其他注射剂未检出吐温80。
5、说明书上标示的执行标准不含吐温80的中药注射剂而查出吐温80的有生脉、复方苦参和正清风痛宁。
6、含有吐温80的5种中药注射液首次静脉给药后出现严重的行为异常;通过对血浆中组胺检测,参麦、肝炎宁和醒脑静组组胺明显升高,综合行为异常和组胺含量变化为主要判定指标综合判断,5种中药注射剂均达到类过敏反应强阳性或阳性。
7、激发给药后的过敏试验,含有吐温80的5种注射剂出现严重的行为异常;血浆组胺检测发现,参麦、生脉、正清风痛宁和肝炎宁组明显升高,综合行为异常,组胺含量变化为主要判定指标综合判断,5种注射剂过敏试验达到阳性或强阳性。
结论:
1、类过敏反应以Beagle犬为最佳实验动物,以行为异常和组胺含量变化为主要判定指标,IgE作为辅助指标,结果准确可靠,得到结果与临床报告相符,未发现假阴性。
2、本研究采用硫氰酸钴铵显色法和薄层层析法两种方法进行中药注射剂中吐温80的鉴定,结果较为准确。
3、中药注射剂中吐温80的添加有待加强监督与规范。中药注射剂中辅料应加强检测及安全性评价,特别对部颁标准中没有标明或标明不含有吐温80的注射剂,进行吐温80的定性定量检测,为进一步研究、评价、增强中药注射剂的安全性以及临床用药提供可靠的依据。
4、含吐温80的5个中药注射剂品种发生严重不良反应与吐温80相关,今后应谨慎使用,并逐步禁用于中药注射剂,积极寻找安全、合理的适用于中药注射剂的药用辅料,全面取代吐温80。
5、大量研究及临床应用表明,134种中药注射剂有的品种存在不同程度的安全隐患,特别是排序在前的品种,问题更为严重,应尽快组织力量进行一次更新换代的全面系统研究,从根本上、源头上解决问题,提高产品质量,安全性及有效性。
OBJECTIVES:
To screen a sensitive anaphylactoid reaction experimental method with high accuracy by the anaphylactoid reaction experiment of traditional Chinese medicine injections on mice, guinea pigs and dogs, to investigate the addition of Tween80 in the traditional Chinese medicine injections by qualitative and quantitative determination of the Tween80, then study the anaphylactoid reaction of the injections containing Tween80 on the Beagle dogs and export the effect of Tween80 on the sensitization of traditional Chinese medicine injections, to find one of solutions to solve the sensitization of traditional Chinese medicine injections.
METHODS:
1. Anaphylactoid reaction experiment on mice. The mice were allergized by tail intravenously injection, the dosage was 15 times as the adult dosage, the delivery volume was 0.5ml every mouse, then behavior changes of the mice were observed and the contents of serum Histamine were detected. The result was determined according to the synthetic index of changes of behavior and the serum Histamine.
2. Anaphylactoid reaction experiment on guinea pigs. The guinea pigs were allergized by intravenously injection, the delivery volume was 2ml every guinea pig, the dosage was 6 times as the adult dosage , then behavior changes of the guinea pigs were observed and the contents of serum Histamine were detected. The result was determined according to the synthetic index of changes of behavior and the serum Histamine.
3. Anaphylactoid and allergical reaction experiments on Beagle dogs. The Beagle dogs were allergized by forelimb injecting constantly( at a speed of 5ml/min with an injection pump). On the first, third, fifth and the fourteenth day, the delivery volume was 5ml/kg, the dosage was 2 times as the adult dosage, the forme three times were allergic steps, the last time was exciting step, the dosage of the last time was 2 times as the first, behavior changes of the dogs were observed , blood was drawn before and after the drug delivery, the contents of serum Histamine, immunoglobulin E , immunoglobulin G and immunoglobulin E were detected. The result was determined according to the synthetic index of changesof the behavior and the serum Histamine.
4. The qualitative and quantitative determination methods of Tween80.
4.1 Qualitative determination of Tween80.
4.1.1 Cobalt thiocyanate ammonium color-developing method: The tested material were added in the 2ml cobalt thiocyanate ammonium color-developings in a tube, shaken up, then 1ml Chloroform was added in the tube , shaken up and standed for 1.5h, the colour of Chloroform layer were observed. Result determinning: the blue colour of Chloroform layer was determined positive, light blue was weak positive, green was susipicious, the others were negative.
4.1.2 Silicon thin-layer chromatography method.
4.1.2.1 The condition of thin-layer chromatograph. Benthing with a mixed solvent of MeoH-H2O-HCOOH(8:5:1) as the developer, the test material can be developed well.
4.1.2.2 Spotting and developing. Taking some tested material, spotting about 0.5cm from the bottom of the thin-layer plate, finished, blowing dry, putting the plate in the iodine jar, taking out when the developing length was 8cm, blowing dry the solvent, 15min later, observing the colour and position of the dots. The result was determined as positive when the dot was yellow and clear and the position was on the same line with the positive spot, weak positive when the colour was not clear, negative when there is no yellow spot in the corresponding position.
4.2 Quantitative determination of Tween80: colorimetic method was used to determine the content of Tween80. The method was studied and the sample were determined.
RESULTS:
1. Results of the anaphylactoid reaction experiment on mice. According to the synthetic index of behavior changes and the serum Histamine, Double Coptis and Mailuoning were determined as positive, the Houttuynia cordata , astragalus and shenmai were susipicious, which were not conform with the clinical export.
2. Results of the anaphylactoid reaction experiment of 10 traditonal Chinese medicine on guinea pigs. According to the synthetic index of behavior changes and the serum Histamine, Double Coptis was determined as susipicious, the others were negative, which were not conform with the clinical export.
3. Results of the anaphylactoid reaction experiment of 10 traditonal Chinese medicine injections on Beagle dogs. According to the synthetic index of changes of the behavior and serum Histamine, the 10 traditonal chinese medicine injections were determined as positive. There were no false negative, which were conform with the clinical export.
4. Forty-three traditional Chinese medicine injections were determined. Fifteen species including the Houttuynia cordata injection and so on were checked out containing Tween80, the content were from 0.72±0.00 to 6.85±0.02 mg.ml-1 respectively. The others were not checked out.
5. Among the 15 traditional Chinese medicines injections, there were 8 species which illustrating the addition of Tween80 openly, Delsheng, kang,ai and Xuebijing were not founded in the experiments. So the species which have no illustrations about the additions of Tween 80 but checked out in the experiment were Shengmai, Fufang kushen and Zhengqingfentongning.
6. Results of the anaphylactoid reaction experiment of 5 traditonal Chinese medicine injections including Tween 80 on Beagle dogs. The dogs showed serious dystrophy, according to the synthetic index of changes of the behavior and serum Histamine, the 5 injections were determined as positive or strong positive .
7. Results of the allergical reaction experiment of 5 traditonal Chinese medicine injections containing Tween 80 on Beagle dogs. The dogs showed serious dystrophy . According to the synthetic index of changes of the behavior and serum Histamine, the 5 injections containing Tween 80 were determined as positive or strong positive .
CONCLUSIONS:
1. Anaphylactoid reaction experiment of the traditional Chinese medicine injections which rank the tops in the anaphylactic shock clinical reports on the mice, guinea-pigs and Beagle dogs were carried. The results show that dog is the best experiment animal , the result determination depend on the synthetic index of changes of the behavior and serum Histamine, IgE is the assistant determination index. The experiment result are accuate , and conform with the clinical report. There are no false negative.
2. The results are accurate when the content determination of Tween 80 in the traditional chinese injections by the Cobalt thiocyanate ammonium color-developing method and silicon thin-layer chromatography.
3. The additions of Tween80 of traditional Chinese medicine injections should be supervised strongly and standarded. The detect and the security evalution of excipient in the traditional Chinese medicine injections should be enhanced, especially the species which do not illustrate the addition of the Tween80. The qualitative and quantitative determination of Tween80 should be carried to study to evaluate and enhance the security of the traditional Chinese medicine, which offer the evidence for clinic medication.
4. The serious adverse reaction of traditional Chinese medicine injections containing Tween80 is relate to the Tween80 . So Tween80 should be banned to add in the tradictional Chinese medicine injections step by step. Securial and reasonable medical excipient should be found to subsititute Tween80.
5. A lot of experimental studies and clinical useness showed that some traditional Chinese medicine injections existed some hidden danger, especially the species rank in the tops of clinical report of adverse faction. The questions of them are more sierous. A system study shoule be carried as soon as quickly to solve this problem fundamentally from the source. Only the medicine quality ,security and validity can increase by this.
引文
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