中药注射液剂I型变态反应试验方法学研究
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摘要
目的:在分析中药注射剂不良反应率高发的原因中发现,现行中药注射剂Ⅰ型变态反应试验方法可能存在灵敏度不高和预测准确性不高等问题,因此对影响中药注射剂Ⅰ型变态反应试验的因素进行研究,同时对部分中药注射剂的免疫毒性(Ⅰ型变态反应)进行了研究,为选择敏感的试验条件和提高中药注射剂Ⅰ型变态反应试验预测的准确性提供试验依据,为临床安全用药提供参考依据。
方法:以阳性抗原卵白蛋白和部分中药注射剂为受试物,按照被动皮肤过敏试验(PCA)和主动全身过敏试验(ASA)操作方法进行。
1.被动皮肤过敏试验方法:取抗原对实验动物免疫致敏,12～14天后,取血制备抗血清,另取实验动物,注射此抗血清于皮内进行被动致敏,一定时间后注射混有生物染料的同样抗原攻击,根据皮肤是否出现蓝染和蓝染程度判断此抗血清是否存在抗体及抗体滴度,进而判断抗原的免疫原性。
2.主动全身过敏试验方法:取抗原对实验动物免疫致敏,12～14天后,注射同样的抗原激发,根据动物出现的反应症状对照评价标准判断是否为过敏反应及过敏反应程度,进而判断抗原的免疫反应性。
结果:①卵白蛋白致敏剂量分别为1mg/只、2.5mg/只和5mg/只时,SD大鼠PCA试验阴性。
②卵白蛋白致敏剂量为0.1mg/只和0.2 mg/只时,豚鼠PCA试验阴性,卵白蛋白致敏剂量为0.3 mg、0.4 mg、0.5 mg和1mg/只时,豚鼠PCA试验阳性。
③卵白蛋白致敏剂量为0.2 mg/只时,不同致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)下豚鼠PCA试验均为阴性,卵白蛋白致敏剂量为0.3 mg/只时,不同致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)下豚鼠PCA试验均为阳性,组间阳性率无显著性差异。
④卵白蛋白致敏剂量为0.2 mg/只,同时加用吸附百白破疫苗,豚鼠PCA试验阳性。
⑤卵白蛋白致敏剂量为1 mg/只,同时加用吸附百白破疫苗, SD大鼠PCA试验阳性。
⑥卵白蛋白致敏剂量为0.2 mg/只,豚鼠PCA试验免疫3次组试验为阴性,免疫4次和5次试验组试验阳性。
⑦试验批次鱼腥草注射液在三个剂量下(1/2临床用量、2倍临床用量临床用量)豚鼠PCA试验阴性;豚鼠ASA试验出现类过敏反应。
⑧试验批次参附粉针三个剂量下(1/2临床用量、2倍临床用量和临床用量)豚鼠PCA试验阴性;豚鼠ASA试验出现类过敏反应。
结论:①豚鼠PCA试验免疫应答敏感性明显强于SD大鼠。
②采用SD大鼠进行PCA试验不加用佐剂(吸附百白破疫苗)的情况下不能反映阳性抗原的免疫原性。
③豚鼠PCA反应在一定抗原致敏剂量范围内反应强弱呈现出剂量依赖性,抗原致敏剂量低于一定量时,试验不能反映。
④不同注射致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)对豚鼠PCA试验没有影响。
⑤加用佐剂(吸附百白破疫苗)能够显著增强豚鼠和SD大鼠的PCA试验敏感性。
⑥在抗原致敏剂量处于临界状态时,增加免疫次数能够增强PCA试验敏感性。
⑦试验批次鱼腥草注射液不具有免疫原性;有引起类过敏反应的可能;有免疫佐剂效应趋势。
⑧试验批次参附粉针不具有免疫原性,有引起类过敏反应的可能。
Objective: The current study focus on the factors that affect the type I immediate hypersensitivity in TCM injection, which aims to provide experimental foundations for enhancing the sensitivity of the experimental conditions the accuracy of the experiment.
Methods: Using active antigen ovalbumin as the detected substance, the study was carried out by following the procedures of passive cutaneous anaphylaxis test and active systemic anaphylaxis test.
1.The methods of passive cutaneous anaphylaxis test: First, some experimental animals were immunized with antigen and their blood was acquired to prepare for the antiserum after 12 to 14 days. Second, the antiserum was intradermally injected into other experimental animals in order to create passive sensitization. Third, the same antigen mixed with biological stain was injected into the passively sensitized animals after a certain time period. We could judge the existence of antibody, the titer of the antibody, and so forth the immunogenicity of the antigen by whether the skin was blue-stained and the degree of it.
2.The method of active systemic anaphylaxis test: The experimental animals were immunized with antigen and then injected with the same antigen for provocation after 12 to 14 days. We could judge whether the experimental animals had hypersensitive reaction, the degree of the reaction and the immunoreactivity of the antigen by comparing their reactive symptoms with the evaluation criterion.
Results:①The PCA test of SD rats was negative when the sensitizing dose of active antigen ovalbumin were 1.0, 2.5 and 5.0mg per rat.
②The PCA test of Guine-pig was negative when the sensitizing doses of active antigen ovalbumin were 0.1 and 0.2 mg per rat. When the dosage of the active antigen ovalbumin increased to 0.3, 0.4, 0.5 and 1.0mg per rat, however, the PCA test of Guine-pig became positive.
③In PCA test of Guine-pig, the active antigen ovalbumin was selected as the detected substance, and each Guine-pig received 0.2 mg or 0.3 mg ovalbumin using different allergizing administrations (i.e., hypodermic injection, intramuscular injection, abdominal cavity injection and intravenous injection). The tests showed that all allergizing administrations with the dosage of 0.2 mg had negative results while those of 0.3 mg had positive results. There were no significant differences in positive rate within each dosage group.
④The PCA test of Guine-pig was positive when each Guine-pig received 0.2 mg active antigen ovalbumin and immunoadjuvant adsorbed DPT vaccine at the same time. It suggested that adsorbed DPT vaccine played a role in enhancing sensitization of Guine-pig in PCA test.
⑤The PCA test of SD rats was positive when each SD rat received 1.0 mg active antigen ovalbumin and immunoadjuvant adsorbed DPT vaccine. It suggested that adsorbed DPT vaccine played a role in enhancing sensitization of SD rat in PCA test
⑥In PCA test of Guine-pig, each Guine-pig received 0.2 mg active antigen ovalbumin but different sensitizing times across groups in order to compare the effects of immunizing times. The test suggested that the group which had 3 immunizations had negative result while the groups which had 4 and 5 immunizations had positive results.
⑦In PCA test of Guine-pig, When using Yuxingcao injection as the detected substance, the result was negative.However, in ASA test, Guine-pig showed anaphylactoid reaction.
⑧In PCA test of Guine-pig , When using Shenfu powder injection as the detected substance, the result was negative. In ASA test , Guine-pig showed anaphylactoid reaction.
Conclusions:①A obvious different exists between Guine-pigs and SD rats as experimental subject, and Guine-pigs tend to have a higher sensitivity than SD rats.
②The PCA experimental results of SD rats could not reflect the immunogenicity of active antigen correctly in the absence of the immunoadjuvant (adsorbed DPT vaccine).
③The reaction of Guine-pig in PCA test exhibits dosage dependence within a certain range of sensitizing dose. The test can’t got active result could not get it while the dosage was below a certain degree.
④Different sensitizing administrations had no effect on PCA test of Guine-pig.
⑤The sensitivity of immune response could be enhanced significantly when added with adjuvant.
⑥The sensitivity of immune response could be enhanced by increasing sensitizing times when the antigen was of microdosis.
⑦Yuxingcao injection had no immunogenicity; however, anaphylactoid reactions were observed. Yuxingcao injection has the tendency of being an immunoadjuvant.
⑧Shenfu powder injection had no immunogenicity, however anaphylactoid reactions were also observed.
方法:以阳性抗原卵白蛋白和部分中药注射剂为受试物,按照被动皮肤过敏试验(PCA)和主动全身过敏试验(ASA)操作方法进行。
1.被动皮肤过敏试验方法:取抗原对实验动物免疫致敏,12～14天后,取血制备抗血清,另取实验动物,注射此抗血清于皮内进行被动致敏,一定时间后注射混有生物染料的同样抗原攻击,根据皮肤是否出现蓝染和蓝染程度判断此抗血清是否存在抗体及抗体滴度,进而判断抗原的免疫原性。
2.主动全身过敏试验方法:取抗原对实验动物免疫致敏,12～14天后,注射同样的抗原激发,根据动物出现的反应症状对照评价标准判断是否为过敏反应及过敏反应程度,进而判断抗原的免疫反应性。
结果:①卵白蛋白致敏剂量分别为1mg/只、2.5mg/只和5mg/只时,SD大鼠PCA试验阴性。
②卵白蛋白致敏剂量为0.1mg/只和0.2 mg/只时,豚鼠PCA试验阴性,卵白蛋白致敏剂量为0.3 mg、0.4 mg、0.5 mg和1mg/只时,豚鼠PCA试验阳性。
③卵白蛋白致敏剂量为0.2 mg/只时,不同致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)下豚鼠PCA试验均为阴性,卵白蛋白致敏剂量为0.3 mg/只时,不同致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)下豚鼠PCA试验均为阳性,组间阳性率无显著性差异。
④卵白蛋白致敏剂量为0.2 mg/只,同时加用吸附百白破疫苗,豚鼠PCA试验阳性。
⑤卵白蛋白致敏剂量为1 mg/只,同时加用吸附百白破疫苗, SD大鼠PCA试验阳性。
⑥卵白蛋白致敏剂量为0.2 mg/只,豚鼠PCA试验免疫3次组试验为阴性,免疫4次和5次试验组试验阳性。
⑦试验批次鱼腥草注射液在三个剂量下(1/2临床用量、2倍临床用量临床用量)豚鼠PCA试验阴性;豚鼠ASA试验出现类过敏反应。
⑧试验批次参附粉针三个剂量下(1/2临床用量、2倍临床用量和临床用量)豚鼠PCA试验阴性;豚鼠ASA试验出现类过敏反应。
结论:①豚鼠PCA试验免疫应答敏感性明显强于SD大鼠。
②采用SD大鼠进行PCA试验不加用佐剂(吸附百白破疫苗)的情况下不能反映阳性抗原的免疫原性。
③豚鼠PCA反应在一定抗原致敏剂量范围内反应强弱呈现出剂量依赖性,抗原致敏剂量低于一定量时,试验不能反映。
④不同注射致敏途径(皮下注射、肌肉注射、腹腔注射、静脉注射)对豚鼠PCA试验没有影响。
⑤加用佐剂(吸附百白破疫苗)能够显著增强豚鼠和SD大鼠的PCA试验敏感性。
⑥在抗原致敏剂量处于临界状态时,增加免疫次数能够增强PCA试验敏感性。
⑦试验批次鱼腥草注射液不具有免疫原性;有引起类过敏反应的可能;有免疫佐剂效应趋势。
⑧试验批次参附粉针不具有免疫原性,有引起类过敏反应的可能。
Objective: The current study focus on the factors that affect the type I immediate hypersensitivity in TCM injection, which aims to provide experimental foundations for enhancing the sensitivity of the experimental conditions the accuracy of the experiment.
Methods: Using active antigen ovalbumin as the detected substance, the study was carried out by following the procedures of passive cutaneous anaphylaxis test and active systemic anaphylaxis test.
1.The methods of passive cutaneous anaphylaxis test: First, some experimental animals were immunized with antigen and their blood was acquired to prepare for the antiserum after 12 to 14 days. Second, the antiserum was intradermally injected into other experimental animals in order to create passive sensitization. Third, the same antigen mixed with biological stain was injected into the passively sensitized animals after a certain time period. We could judge the existence of antibody, the titer of the antibody, and so forth the immunogenicity of the antigen by whether the skin was blue-stained and the degree of it.
2.The method of active systemic anaphylaxis test: The experimental animals were immunized with antigen and then injected with the same antigen for provocation after 12 to 14 days. We could judge whether the experimental animals had hypersensitive reaction, the degree of the reaction and the immunoreactivity of the antigen by comparing their reactive symptoms with the evaluation criterion.
Results:①The PCA test of SD rats was negative when the sensitizing dose of active antigen ovalbumin were 1.0, 2.5 and 5.0mg per rat.
②The PCA test of Guine-pig was negative when the sensitizing doses of active antigen ovalbumin were 0.1 and 0.2 mg per rat. When the dosage of the active antigen ovalbumin increased to 0.3, 0.4, 0.5 and 1.0mg per rat, however, the PCA test of Guine-pig became positive.
③In PCA test of Guine-pig, the active antigen ovalbumin was selected as the detected substance, and each Guine-pig received 0.2 mg or 0.3 mg ovalbumin using different allergizing administrations (i.e., hypodermic injection, intramuscular injection, abdominal cavity injection and intravenous injection). The tests showed that all allergizing administrations with the dosage of 0.2 mg had negative results while those of 0.3 mg had positive results. There were no significant differences in positive rate within each dosage group.
④The PCA test of Guine-pig was positive when each Guine-pig received 0.2 mg active antigen ovalbumin and immunoadjuvant adsorbed DPT vaccine at the same time. It suggested that adsorbed DPT vaccine played a role in enhancing sensitization of Guine-pig in PCA test.
⑤The PCA test of SD rats was positive when each SD rat received 1.0 mg active antigen ovalbumin and immunoadjuvant adsorbed DPT vaccine. It suggested that adsorbed DPT vaccine played a role in enhancing sensitization of SD rat in PCA test
⑥In PCA test of Guine-pig, each Guine-pig received 0.2 mg active antigen ovalbumin but different sensitizing times across groups in order to compare the effects of immunizing times. The test suggested that the group which had 3 immunizations had negative result while the groups which had 4 and 5 immunizations had positive results.
⑦In PCA test of Guine-pig, When using Yuxingcao injection as the detected substance, the result was negative.However, in ASA test, Guine-pig showed anaphylactoid reaction.
⑧In PCA test of Guine-pig , When using Shenfu powder injection as the detected substance, the result was negative. In ASA test , Guine-pig showed anaphylactoid reaction.
Conclusions:①A obvious different exists between Guine-pigs and SD rats as experimental subject, and Guine-pigs tend to have a higher sensitivity than SD rats.
②The PCA experimental results of SD rats could not reflect the immunogenicity of active antigen correctly in the absence of the immunoadjuvant (adsorbed DPT vaccine).
③The reaction of Guine-pig in PCA test exhibits dosage dependence within a certain range of sensitizing dose. The test can’t got active result could not get it while the dosage was below a certain degree.
④Different sensitizing administrations had no effect on PCA test of Guine-pig.
⑤The sensitivity of immune response could be enhanced significantly when added with adjuvant.
⑥The sensitivity of immune response could be enhanced by increasing sensitizing times when the antigen was of microdosis.
⑦Yuxingcao injection had no immunogenicity; however, anaphylactoid reactions were observed. Yuxingcao injection has the tendency of being an immunoadjuvant.
⑧Shenfu powder injection had no immunogenicity, however anaphylactoid reactions were also observed.
引文
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