黄芩茎叶总黄酮胶囊治疗急性咽炎风热证临床与实验研究
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摘要
急性咽炎(acute pharyngitis)是咽粘膜、粘膜下组织及淋巴组织的急性炎症，常为上呼吸道感染的一部分。可单独发生，亦可继发于急性鼻炎。多发生于秋冬及冬春季节。为临床常见病、多发病。急性咽炎的发病原因主要以病毒感染(柯萨奇病毒、腺病毒、副流感病毒，鼻病毒及流感病毒)和细菌感染(链球菌、葡萄球菌和肺炎双球菌)，治疗主要选用抗病毒药、抗生素，中医中药有较好的疗效。
黄芩为临床常用中药，主要含黄酮类成分，包括黄芩素、汉黄芩素、汉黄芩甙、千层纸A等，味苦，性寒，归肺、胆、脾、大肠、小肠经。具有清热燥湿，泻火解毒之功能，广泛应用于临床处方中，亦为治疗急性咽炎的常用药物。
由于大量的临床应用带来的过渡采挖，造成药材资源的枯竭。传统的黄芩用药部位为植物根部，而其茎叶部分被长期废弃，造成极大的浪费，本次研究旨在利用和开发黄芩茎叶，从中提取总黄酮成份，扩大了黄芩的药用部分，提高其利用价值，具有重要的社会和经济意义。实验证明：从黄芩茎叶中提取总黄酮，具有高效低毒的药理活性，具有抗病毒、抗菌、抗炎、解热、镇痛、免疫调节等作用。
通过体外抗病毒实验结果表明，黄芩茎叶总黄酮对COXB3、COXB4、COXB5、流感病毒、副流感病毒等10种病毒所致的细胞病变有明显的抑制作用。动物体内实验性治疗，对流感病毒引起的小鼠肺炎有明显的抑制作用，肺指数和肺病变等级低于病毒对照组，并呈良好的量效相关性。对流感病毒所致的小鼠死亡均有不同程度的抑制作用。
体外实验结果表明：对金黄色葡萄球菌、卡它布郎汉姆氏菌、绿脓假单胞菌、葡萄球菌、甲型溶血性琏球菌、乙型溶血性琏球菌等31个菌株表现了不同的杀菌或抑菌作用。动物体内实验表明：对金黄色葡萄球菌感染所致的小鼠死亡均有一定的保护作用，并呈一定的剂量相关性，以大、中剂量组作用明显。
抗炎作用实验表明对二甲苯所致的小鼠耳廓急性炎症反应有不同程度的抑制作用；对蛋清致大鼠足跖急性炎症反应有不同程度的抑制作用，大、中剂量作用显著，剂量相关性明显。
解热作用实验表明：可不同程度的抑制大肠杆菌内毒素所致的家兔的发热反应，并呈一定的剂量相关性。
镇痛作用实验结果表明能抑制醋酸所致的小鼠扭体疼痛反应，并呈一定的剂量相关性。
对免疫功能的影响：对小鼠特异性体液免疫功能、细胞免疫功能有不同程度的影响。大、中剂量组可促进小鼠绵羊红细胞溶血素抗体生成。前期动物试验为临床研究打下了良好的基础。在此基础上，进行了临床人体耐受性试验和有效性及安全性试验。
临床人体耐受性试验目的：选择健康人为受试者，从安全的初始剂量开始，考察人体对黄芩茎叶总黄酮胶囊制剂的耐受性和安全性，为制定后期临床试验给药方案提供依据。
根据Beagle狗长期毒性试验中引起中毒症状的或脏器出现可逆性变化剂量(有效成分)1000 mg／kg／d的1／10的方法，并根据临床实际可操作性及推荐临床剂量，初步确定最大剂量为1575 mg(有效成分)／日／人(临床实际服用胶囊剂量为3550 mg，约10粒胶囊)。试验结果提示：本试验中未发生不良反应的剂量：单次给药170～1520mg。试验药物的最大耐受量1520mg(约4粒胶囊)。
在临床人体耐受性试验的基础上，我们又进行了有效性及安全性试验。主要目的：通过观察治疗前后咽痛、咽干灼热、咽粘膜悬雍垂红肿的变化情况，评价黄芩茎叶总黄酮胶囊治疗急性咽炎风热证的临床疗效；
次要目的：同时观察次症、血白细胞总数及分类的变化。
通过观察三大常规，心、肝、肾功能及出现的不良事件，对其安全性作出评价。
有效性及安全性试验入组460例，脱落8例，剔除8例，脱落、剔除率3.48％。纳入符合方案集统计445例，纳入全分析集统计456例，纳入安全集456例。经过统计学处理证明：符合方案集试验组总有效率57.78％，对照组总有效率54.05％；非劣性的95％CI的CL为-8.36％。试验组与对照组的非劣性检验比较有统计学意义。总有效率相差的95％CI(-10.68，18.14)。全分析集试验组总有效率57.18％，对照组总有效率53.91％，非劣性的95％CI的CL为-8.66％。试验组与对照组的非劣性检验比较有统计学意义。总有效率相差的95％CI(-10.95，17.49)。非劣效性检验假设成立。在此基础上进行各项指标的优效性检验，治疗后试验组和对照组之间有高度统计学意义的指标如下：咽痛记分下降值(3.88、3.19 P＜0.01)；咽粘膜、悬雍垂红肿记分(3.11、2.62 P＜0.05)；总积分下降值(11.93 10.14 P＜0.01)。
试验组出现1例轻度ALT、AST升高，(ALT28／59、AST34／49，复查正常)，未加任何处理，未破盲；研究者判断与试验药物的关系为可疑；1例轻度尿素增高(尿素8.7)未加任何处理，未破盲；研究者判断与试验药物的关系为不可能。对照组出现1例腹泻、便溏，两组安全性评价的差别无统计学意义。
通过本研究临床人体耐受性试验和有效性及安全性试验，证明黄芩茎叶总黄酮胶囊治疗急性咽炎风热证有效、安全，疗效优于银黄胶囊。本研究对于开发和利用黄芩茎叶的药用资源，具有重要的社会意义。
Acute pharyngitis, frequently encountered in clinic and usually presented as one composingpart of upper respiratory tract infection, refers to the acute infection involving pharyngealmucosa, submucosa and surrounding lymphatic tissue, which may happen alone orsecondary to acute rhinitis, in autumn or winter mostly. Acute pharyngitis is mainly causedby virus, such as coxsackievirus, adenovirus, parainfluenza virus, rhinovirus, influenzavirus, or bacteria, streptococcus, staphylococcus, streptococcus pneumoniae, for instance.As a result, antiviral agents or antibiotics are mainly used in clinic for this condition,Traditional Chinese Medicine has good effect as well.
Scutellaria, or Scutellaria baicalensis Georgi, is one herbal medicine commonly used inclinic, with chromocor total as it's main ingredients composed of baicalein, wogonin,wogoain-7-o-glucuronide, oxoxylin, etc. Scutellaria, bitter in flavor, cold in property, actingon the lung, gall bladder, spleen, large intestine and small intestine channels, has the effectof clearing away heat and fire, removing dampness and toxic material, thus is widely usedin clinic and commonly used for acute pharyngitis as well.
Excessive clinical use has resulted in immoderacy culling and digging of the herb;exhaustion of herbal resource has emerged. Traditionally, the medicinal part of scutellaria isthe root of the herb, with the stack and leaf discarded which is actually an enormouswasting. The purpose of the research is to exploit the usage of stack and leaf of scutellaria,extend its medicinal part, and thus increase its use value, which is of great social andeconomic importance. Experimental study has proven that, chromocor total extracted fromscutellaria is a high-effective and low-toxicity material, possesses the effect of anti-virus,anti-bacteria, anti-inflammation, antipyretic, analgesic and regulating immune system.
One in vitro anti-virus experiment shows that chromocor total from scutellaria stack andleaf could evidently inhibit cytopathic effect caused by over 10 kinds of viruses, such asCOXB3, COXB4, COXB5, influenza virus, parainfluenza virus, etc. One in vivoexperiment shows that this herbal substance has markable inhibitory effect to viralpneumonia in mice, with lung index and the grade of lung disease in research group lowerthan that in control group, dosage-dependent related, this herbal substance has variableinhibitory effect to mice death caused virus as well.
Another in vitro experiment shows that this herbal substance presents variablebacteria-killing or bacteriostatic effect to 31 kinds of bacteria, such as staphylacoccusaureus, pseudomonas aelugmosa, staphylococcus, streptococcus,α-hemolytic streptococcusorβ-hemolytic streptococcus, etc. Another in vivo experiment indicates it has certainprotecting effect to mice death caused by staphylacoccus aureus infection, which isdosage-dependent to some extent, more evident in large or moderate dose group.
Anti-inflammation experiment shows, this herbal substance has certain anti-imflammationeffect to acute inflammatory reaction of mice auricle caused by dimethylbenzene, and couldinhibit acute inflammatory reaction of mice toes caused by egg white, dosage-dependentevidently.
Anti-pyretic experiment shows, this herbal substance could inhibit pyretic reaction of rabbitcaused by E.COIi Endotoxin to different extent, dosage-dependent as well.
Analgesic experiment shows that this herbal substance has some influence on pain reactionin mice caused by vinegar, dosage-dependent to some extent as well.
Experiment of influence on immune system shows, this herbal substance has effects on thehumoral immune function or cellular immune function in mice to a different degree, largeor moderate dose could promote the production of hemolysin antibody in mice or sheep.Non-clinical studies mentioned above have established well-founded basis for clinicalresearch, human tolerance clinical trial and efficacy and safety assessment clinical trial were conducted afterwards.
Purpose of human tolerance clinical trial is to investigate the tolerance and safety of capsuleof chromocor total from scutellaria stack and leaf in human being with healthy volunteers,providing basis for phase 2 medication regimen.
Based on the result of dog Beagle long-term toxicity experiment, 1000 mg/kg/d has causedtoxic symptoms and reversible change of internal organs, considering the clinical feasibilityand dose recommended by sponsor as well, maximum dose of Phase 1 trial waspreliminarily suggested to be 3550 mg, about 10 capsules. Research result suggests, thenon-side effect dose for single dose is 170mg to 1520mg, the maximum tolerated dose is1520mg, about 4 capsules.
Founded by human tolerance clinical research, phase 3 clinical trial of efficacy and safetywas conducted with the main purpose of evaluating clinical efficacy of the capsule intreating acute pharyngitis of wind-heat type through observing the transformation of mainsymptoms before and after treatment such as pharyngalgia, dryness and burning sensationin throat, swelling in pharyngeal mucosa and uvula. One of the secondary purposes is toobserve the change of subordinate symptoms and that of peripheral white blood cell count,differential count of white blood cell, the other is to evaluate it's safety through observeblood routine, urine routine, stool routine, the function of heart, liver or kidney and therelated adverse events.
460 subjects were enrolled in phase 3 clinical trial, 8 withdrawals, 8 protocol deviation case,both accounts for 3.48％. Finally, data were analyzed on the basis of FAS and PP analysis.By PP analysis, the overall effective rates of trial and control group were 57.78％and54.05％, the CL of 95％CI for non-inferiority test is -8.36％, there is significance betweentrial and control group by non-inferiority test. 95％CI for the discrepancy of overalleffective rates is between -10.68 and 18.14. By FAS analysis, the overall effective rates oftrial and control group were 57.18％and 53.91％, CL of 95％CI for non-inferiority test is-8.66％, there is significance between trial and control group by non-inferiority test. 95％CIfor the discrepancy of overall effective rates is between -10.95 and 17.49. These data proved the null hypothesis is true. Statistical analysis with test of superiority on symptomsafter treatment was done after that, it shows indicators of significance are as follow, scorereduce of pharyngalgia in research and control group are 3.88 and 3.19, P＜0.01; scorereduce of swelling in pharyngeal mucosa and uvula are 3.11, 2.62 respectively, P＜0.05;overall score reduce are 11.93, 10.14 respectively, P＜0.05.
One subject in research group had got slight increase in ALT and AST which returned tonormal in following up examination with neither intervention nor unblinding, ALT is 28U/L before study, 59 U/L after, AST is 34 U/L before, 49 U/L after, investigator judged therelationship with the research drug to be suspicious; one subject in the same group hadslight increase in BUN, 8.7mmol/L, returned to normal with no intervention nor unblinding,investigator judged to be impossible. One subject in control group had diarrhea, statisticalanalysis shows there is no significance between the two groups.
Human tolerance clinical trial and clinical tiral on it's efficacy and safety has proved thatcapsule of chromocor total from scutellaria stack and leaf is effective and safe in treatingacute pharyngitis of wind-heat type, superior to Yinhuang capsule. The overall research isfundamental to the exploitation and making use of medicinal resource of scutellaria stackand leaf, which bears significant social value.
黄芩为临床常用中药，主要含黄酮类成分，包括黄芩素、汉黄芩素、汉黄芩甙、千层纸A等，味苦，性寒，归肺、胆、脾、大肠、小肠经。具有清热燥湿，泻火解毒之功能，广泛应用于临床处方中，亦为治疗急性咽炎的常用药物。
由于大量的临床应用带来的过渡采挖，造成药材资源的枯竭。传统的黄芩用药部位为植物根部，而其茎叶部分被长期废弃，造成极大的浪费，本次研究旨在利用和开发黄芩茎叶，从中提取总黄酮成份，扩大了黄芩的药用部分，提高其利用价值，具有重要的社会和经济意义。实验证明：从黄芩茎叶中提取总黄酮，具有高效低毒的药理活性，具有抗病毒、抗菌、抗炎、解热、镇痛、免疫调节等作用。
通过体外抗病毒实验结果表明，黄芩茎叶总黄酮对COXB3、COXB4、COXB5、流感病毒、副流感病毒等10种病毒所致的细胞病变有明显的抑制作用。动物体内实验性治疗，对流感病毒引起的小鼠肺炎有明显的抑制作用，肺指数和肺病变等级低于病毒对照组，并呈良好的量效相关性。对流感病毒所致的小鼠死亡均有不同程度的抑制作用。
体外实验结果表明：对金黄色葡萄球菌、卡它布郎汉姆氏菌、绿脓假单胞菌、葡萄球菌、甲型溶血性琏球菌、乙型溶血性琏球菌等31个菌株表现了不同的杀菌或抑菌作用。动物体内实验表明：对金黄色葡萄球菌感染所致的小鼠死亡均有一定的保护作用，并呈一定的剂量相关性，以大、中剂量组作用明显。
抗炎作用实验表明对二甲苯所致的小鼠耳廓急性炎症反应有不同程度的抑制作用；对蛋清致大鼠足跖急性炎症反应有不同程度的抑制作用，大、中剂量作用显著，剂量相关性明显。
解热作用实验表明：可不同程度的抑制大肠杆菌内毒素所致的家兔的发热反应，并呈一定的剂量相关性。
镇痛作用实验结果表明能抑制醋酸所致的小鼠扭体疼痛反应，并呈一定的剂量相关性。
对免疫功能的影响：对小鼠特异性体液免疫功能、细胞免疫功能有不同程度的影响。大、中剂量组可促进小鼠绵羊红细胞溶血素抗体生成。前期动物试验为临床研究打下了良好的基础。在此基础上，进行了临床人体耐受性试验和有效性及安全性试验。
临床人体耐受性试验目的：选择健康人为受试者，从安全的初始剂量开始，考察人体对黄芩茎叶总黄酮胶囊制剂的耐受性和安全性，为制定后期临床试验给药方案提供依据。
根据Beagle狗长期毒性试验中引起中毒症状的或脏器出现可逆性变化剂量(有效成分)1000 mg／kg／d的1／10的方法，并根据临床实际可操作性及推荐临床剂量，初步确定最大剂量为1575 mg(有效成分)／日／人(临床实际服用胶囊剂量为3550 mg，约10粒胶囊)。试验结果提示：本试验中未发生不良反应的剂量：单次给药170～1520mg。试验药物的最大耐受量1520mg(约4粒胶囊)。
在临床人体耐受性试验的基础上，我们又进行了有效性及安全性试验。主要目的：通过观察治疗前后咽痛、咽干灼热、咽粘膜悬雍垂红肿的变化情况，评价黄芩茎叶总黄酮胶囊治疗急性咽炎风热证的临床疗效；
次要目的：同时观察次症、血白细胞总数及分类的变化。
通过观察三大常规，心、肝、肾功能及出现的不良事件，对其安全性作出评价。
有效性及安全性试验入组460例，脱落8例，剔除8例，脱落、剔除率3.48％。纳入符合方案集统计445例，纳入全分析集统计456例，纳入安全集456例。经过统计学处理证明：符合方案集试验组总有效率57.78％，对照组总有效率54.05％；非劣性的95％CI的CL为-8.36％。试验组与对照组的非劣性检验比较有统计学意义。总有效率相差的95％CI(-10.68，18.14)。全分析集试验组总有效率57.18％，对照组总有效率53.91％，非劣性的95％CI的CL为-8.66％。试验组与对照组的非劣性检验比较有统计学意义。总有效率相差的95％CI(-10.95，17.49)。非劣效性检验假设成立。在此基础上进行各项指标的优效性检验，治疗后试验组和对照组之间有高度统计学意义的指标如下：咽痛记分下降值(3.88、3.19 P＜0.01)；咽粘膜、悬雍垂红肿记分(3.11、2.62 P＜0.05)；总积分下降值(11.93 10.14 P＜0.01)。
试验组出现1例轻度ALT、AST升高，(ALT28／59、AST34／49，复查正常)，未加任何处理，未破盲；研究者判断与试验药物的关系为可疑；1例轻度尿素增高(尿素8.7)未加任何处理，未破盲；研究者判断与试验药物的关系为不可能。对照组出现1例腹泻、便溏，两组安全性评价的差别无统计学意义。
通过本研究临床人体耐受性试验和有效性及安全性试验，证明黄芩茎叶总黄酮胶囊治疗急性咽炎风热证有效、安全，疗效优于银黄胶囊。本研究对于开发和利用黄芩茎叶的药用资源，具有重要的社会意义。
Acute pharyngitis, frequently encountered in clinic and usually presented as one composingpart of upper respiratory tract infection, refers to the acute infection involving pharyngealmucosa, submucosa and surrounding lymphatic tissue, which may happen alone orsecondary to acute rhinitis, in autumn or winter mostly. Acute pharyngitis is mainly causedby virus, such as coxsackievirus, adenovirus, parainfluenza virus, rhinovirus, influenzavirus, or bacteria, streptococcus, staphylococcus, streptococcus pneumoniae, for instance.As a result, antiviral agents or antibiotics are mainly used in clinic for this condition,Traditional Chinese Medicine has good effect as well.
Scutellaria, or Scutellaria baicalensis Georgi, is one herbal medicine commonly used inclinic, with chromocor total as it's main ingredients composed of baicalein, wogonin,wogoain-7-o-glucuronide, oxoxylin, etc. Scutellaria, bitter in flavor, cold in property, actingon the lung, gall bladder, spleen, large intestine and small intestine channels, has the effectof clearing away heat and fire, removing dampness and toxic material, thus is widely usedin clinic and commonly used for acute pharyngitis as well.
Excessive clinical use has resulted in immoderacy culling and digging of the herb;exhaustion of herbal resource has emerged. Traditionally, the medicinal part of scutellaria isthe root of the herb, with the stack and leaf discarded which is actually an enormouswasting. The purpose of the research is to exploit the usage of stack and leaf of scutellaria,extend its medicinal part, and thus increase its use value, which is of great social andeconomic importance. Experimental study has proven that, chromocor total extracted fromscutellaria is a high-effective and low-toxicity material, possesses the effect of anti-virus,anti-bacteria, anti-inflammation, antipyretic, analgesic and regulating immune system.
One in vitro anti-virus experiment shows that chromocor total from scutellaria stack andleaf could evidently inhibit cytopathic effect caused by over 10 kinds of viruses, such asCOXB3, COXB4, COXB5, influenza virus, parainfluenza virus, etc. One in vivoexperiment shows that this herbal substance has markable inhibitory effect to viralpneumonia in mice, with lung index and the grade of lung disease in research group lowerthan that in control group, dosage-dependent related, this herbal substance has variableinhibitory effect to mice death caused virus as well.
Another in vitro experiment shows that this herbal substance presents variablebacteria-killing or bacteriostatic effect to 31 kinds of bacteria, such as staphylacoccusaureus, pseudomonas aelugmosa, staphylococcus, streptococcus,α-hemolytic streptococcusorβ-hemolytic streptococcus, etc. Another in vivo experiment indicates it has certainprotecting effect to mice death caused by staphylacoccus aureus infection, which isdosage-dependent to some extent, more evident in large or moderate dose group.
Anti-inflammation experiment shows, this herbal substance has certain anti-imflammationeffect to acute inflammatory reaction of mice auricle caused by dimethylbenzene, and couldinhibit acute inflammatory reaction of mice toes caused by egg white, dosage-dependentevidently.
Anti-pyretic experiment shows, this herbal substance could inhibit pyretic reaction of rabbitcaused by E.COIi Endotoxin to different extent, dosage-dependent as well.
Analgesic experiment shows that this herbal substance has some influence on pain reactionin mice caused by vinegar, dosage-dependent to some extent as well.
Experiment of influence on immune system shows, this herbal substance has effects on thehumoral immune function or cellular immune function in mice to a different degree, largeor moderate dose could promote the production of hemolysin antibody in mice or sheep.Non-clinical studies mentioned above have established well-founded basis for clinicalresearch, human tolerance clinical trial and efficacy and safety assessment clinical trial were conducted afterwards.
Purpose of human tolerance clinical trial is to investigate the tolerance and safety of capsuleof chromocor total from scutellaria stack and leaf in human being with healthy volunteers,providing basis for phase 2 medication regimen.
Based on the result of dog Beagle long-term toxicity experiment, 1000 mg/kg/d has causedtoxic symptoms and reversible change of internal organs, considering the clinical feasibilityand dose recommended by sponsor as well, maximum dose of Phase 1 trial waspreliminarily suggested to be 3550 mg, about 10 capsules. Research result suggests, thenon-side effect dose for single dose is 170mg to 1520mg, the maximum tolerated dose is1520mg, about 4 capsules.
Founded by human tolerance clinical research, phase 3 clinical trial of efficacy and safetywas conducted with the main purpose of evaluating clinical efficacy of the capsule intreating acute pharyngitis of wind-heat type through observing the transformation of mainsymptoms before and after treatment such as pharyngalgia, dryness and burning sensationin throat, swelling in pharyngeal mucosa and uvula. One of the secondary purposes is toobserve the change of subordinate symptoms and that of peripheral white blood cell count,differential count of white blood cell, the other is to evaluate it's safety through observeblood routine, urine routine, stool routine, the function of heart, liver or kidney and therelated adverse events.
460 subjects were enrolled in phase 3 clinical trial, 8 withdrawals, 8 protocol deviation case,both accounts for 3.48％. Finally, data were analyzed on the basis of FAS and PP analysis.By PP analysis, the overall effective rates of trial and control group were 57.78％and54.05％, the CL of 95％CI for non-inferiority test is -8.36％, there is significance betweentrial and control group by non-inferiority test. 95％CI for the discrepancy of overalleffective rates is between -10.68 and 18.14. By FAS analysis, the overall effective rates oftrial and control group were 57.18％and 53.91％, CL of 95％CI for non-inferiority test is-8.66％, there is significance between trial and control group by non-inferiority test. 95％CIfor the discrepancy of overall effective rates is between -10.95 and 17.49. These data proved the null hypothesis is true. Statistical analysis with test of superiority on symptomsafter treatment was done after that, it shows indicators of significance are as follow, scorereduce of pharyngalgia in research and control group are 3.88 and 3.19, P＜0.01; scorereduce of swelling in pharyngeal mucosa and uvula are 3.11, 2.62 respectively, P＜0.05;overall score reduce are 11.93, 10.14 respectively, P＜0.05.
One subject in research group had got slight increase in ALT and AST which returned tonormal in following up examination with neither intervention nor unblinding, ALT is 28U/L before study, 59 U/L after, AST is 34 U/L before, 49 U/L after, investigator judged therelationship with the research drug to be suspicious; one subject in the same group hadslight increase in BUN, 8.7mmol/L, returned to normal with no intervention nor unblinding,investigator judged to be impossible. One subject in control group had diarrhea, statisticalanalysis shows there is no significance between the two groups.
Human tolerance clinical trial and clinical tiral on it's efficacy and safety has proved thatcapsule of chromocor total from scutellaria stack and leaf is effective and safe in treatingacute pharyngitis of wind-heat type, superior to Yinhuang capsule. The overall research isfundamental to the exploitation and making use of medicinal resource of scutellaria stackand leaf, which bears significant social value.
引文
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