白头翁治疗日本血吸虫病的物质基础及制剂学的初步研究
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摘要
血吸虫病是一种流行于热带和亚热带地区、危害严重的人畜共患寄生虫病,但临床上仅有吡喹酮一种有效的治疗药物,这与繁重的血吸虫病防治需求不相适应。本文前期研究表明白头翁对血吸虫有一定的杀灭作用,但物质基础,作用机制不明,严重限制其作为抗血吸虫病新药的开发和利用。因此本文探索用“组分中药”理论指导白头翁皂苷提取物治疗血吸虫病的中药新药研究,通过对白头翁皂苷抗血吸虫的构效、毒效关系研究,筛选出抗血吸虫的物质基础及各组分间的优化配比。并通过皂苷的吸收情况及吸收机理研究,以提高生物利用度为目标,研制出治疗血吸虫病安全有效的中药制剂。本文的具体研究内容和结果如下：
1.白头翁皂苷类成分初步构效关系的研究
在初步总结皂苷类成分苷元的结构类型、取代基的种类及位置、糖链长度、组成、苷化位置、糖与苷元及糖的连接方式及顺序等的基础上,通过药物体外抗血吸虫效应及对哺乳动物细胞毒性的研究,分析总结皂苷结构与杀虫效应、细胞毒性之间的关系。
结果显示,①白头翁皂苷苷元C-28位的羧基游离对于皂苷的抗血吸虫活性至关重要。②苷元C-3位所连糖链的糖基个数以及连接顺序对皂苷的抗血吸虫活性有一定的影响。③具有相同糖链的皂苷其活性顺序为：齐墩果酸苷元>常春藤皂苷元。
通过体外筛选出BP-SJ-7、BP-SJ-3、BP-SJ-9、BP-SJ-10四个皂苷对血吸虫有较强的杀灭作用,作用后虫体肿胀僵硬、体表透明度下降,表皮溃烂,肠腔破损。
经等辐射分析法得出,其他成分与BP-SJ-9配合作用后显示出较强的协同作用。
2.白头翁皂苷提取物体内外抗血吸虫作用的研究
在明确提取物物质基础的前提下,以体内外杀虫活性为指标,筛选不同配比组成的白头翁皂苷提取物,结果BTW3提取物与其他提取物相比对血吸虫活性有显著差异。
并通过BTW3提取物体外对血吸虫成虫、童虫及吡喹酮压力下的虫体的作用以及体内研究,明确其杀虫作用及特点。
结果显示药物体内外对血吸虫的杀灭作用具有浓度依赖性。体外临界杀虫浓度分别为：雄性成虫24μg/mL,雌性成虫32μg/mL,童虫32μg/mL,吡喹酮压力下的虫体48μg/mL。在40倍镜下观察,虫体明显收缩、扭曲,体表肿胀,100倍镜下体表肿胀明显,组织分布疏松,肠管明显肿胀弯曲且分布混乱；超微结构显示皮层褶嵴消失,融合成条索或片块状,其上感觉乳突肿大、变形、破溃而丢失,抱雌沟内壁体棘、凹陷等基本结构破坏消失,融合皱缩形成条索状物或模糊一片,乳突肿大、变形、破溃而丢失
体内最佳有效杀虫剂量：成虫、童虫均为为400mg/kg。
以400mg/kg口服给药,对1、3、7、14、21、28、35天虫龄的减虫率达到65%以上,但对不同发育期虫体的减虫率没有显著性差异。
以400mg/kg口服给药,药物对不同时间虫体的体表组织及抱雌沟损伤作用较明显,第1d观察发现：皮层褶嵴消失,融合成条索或片块状,其上感觉乳突肿大、变形、破溃而丢失,抱雌沟内壁,体棘、凹陷等基本结构破坏消失,融合皱缩形成条索状物或模糊一片,乳突肿大、变形、破溃而丢失,随着时间的延长(第3d、7d观察)虫体体表及抱雌沟变化不明显。
3.白头翁皂苷在体肠吸收特性的研究
以白头翁皂苷抗血吸虫活性成分为指标,建立了白头翁皂苷在体肠吸收模型。通过比较研究2种白头翁皂苷组成的吸收情况,不同剂量组、不同小肠区段的的吸收参数,以及P-糖蛋白抑制剂对其吸收的影响,结果2种白头翁皂苷提取物各成分的吸收存在明显差异,各成分间或提取物中其他成分可能存在促吸收的物质；白头翁皂苷5种抗血吸虫活性成分吸收情况中等,在各肠段的吸收没有显著性差异;白头翁皂苷B3、B10、B11具有吸收饱和的现象,白头翁皂苷BD、B7为被动扩散;加入P-糖蛋白抑制剂维拉帕米及P-糖蛋白底物地高辛后,各成分的吸收速率有显著提高,预测白头翁皂苷五种主要成分可能是P-糖蛋白底物。
4.白头翁皂苷提取物制剂的初步筛选
提取物原料的基本物理化学性决定制剂的剂型设计,本义对白头翁皂苷提取物的理化性质进行研究,结果显示白头翁皂苷提取物显弱酸性,在弱碱性环境中溶解能力最强;在各溶媒中各成分溶解能力的大小依次为：B7(?)B3(?)B10(?)B11(?)BD；油水分配系数很小,亲脂性较弱,亲水性强；在12h内胃酶、胰酶环境中稳定,在高温、强光照射下稳定,吸湿性较强。
根据肠吸收特性及理化性质结果初步设计为环糊精包含物、乳剂、微粉硅胶吸附剂,以对童虫、成虫的作用为指标进行筛选,结果微粉硅胶吸附剂毒性较低,且在300mg/kg口服给药对血吸虫的减虫率达到70%左右。
5.白头翁皂苷微粉硅胶吸附剂的药效学研究
对白头翁皂苷微硅胶吸附剂进行药效学实验,结果300mg/kg口服给药对不同发育期的血吸虫体内减虫率达到65%,但不同发育期间的减虫率没有显著性差异；不同技术联合使用后对血吸虫的减虫率也没有显著提高,说明白头翁皂苷微粉硅胶吸附剂对血吸虫病有一定的治疗作用,但仍需进一步研究提高其抗血吸虫药效。
Schistosomiasis is a serious damage parasitic diseases, which is epidemic in tropical and subtropical zone. But praziquantel is the only effective drug in clinic, which can not accommodate with the Schistosomiasis control. In our prophase research, Pulsatilla chinensis has an effictive drug against Schistosomiasis, but the material basis and the mechanism of action are not clear. The exploitation of antischistosomal drugs have been restrained. So the text is about the new drug againt Schistosome based on the components of traditional Chinese medicine. Through the study on structure-activity and toxic-activity relationship, the material basis of Pulsatilla chinensis againt Schistosomiasis could be screened. And on the aim of improving the bioavailability, we could get the effective and safe drug againt Schistosomiasis through the stuty on the absorption of pulchinenoside. The dissertation is summarized as follows:
1. the study on the structure-activity relationship about pulchinenoside
On the base of the understood of pulchinenoside, the structure-activity relationship can be summarized through the study on the drug against Schistosomiasis in vitro.
The results are①It is vital for anti-schistomiasis activity to the C-28Carboxyl free of the P. chinensis.②It makes a difference for antischistomiasis activity to the C-3of sugar chain and connection order of the P. chinensis.③The type of aglycone also affect the anti-schistomiasis activity, found that the Oleanolic acid has the more activity than hederagenin.
The four pulchinenosides BP-SJ-7、 BP-SJ-3、BP-SJ-9、 BP-SJ-10have been screened in vitro. Polypide is becoming swell and inflexible, the clarity descend, epidermis inflamed and epidermis damaged after exproused in drug.
BP-SJ-9together with other components have the concurrency action through isobolographic analysis
2. The study on the extract of pulchinenoside against schistosome in vitro and in vivo Based On the material basis of the extract, the extract of pulchinenoside have been screened according to the activity against schistosome, the result is BTW3has difference with the others. The effecitve and characteristic have been identified through the extrace against imago, schistosomula and the schistosomes of decreased parziquantel sensitivity in virto and in vivo.
The results are the drug have concentration dependent against schistosome in virto and in vivo. The criticality anthelminthic concentration is male schistosome24μg/mL, femal schistosome32μg/mL, schistosomula32μg/mL, and the schistosomes of decreased parziquantel sensitivity48μg/mL。 Criticality is shrinking, retortion, and epidermis is swelling on the40times mirror. On the100times mirror, epidermis is swelling, Tissue is porosity, intestinal tract is swelling, bending and distribution is confusion. Under the ultrastructural organization, the pleat of tegument is disappeared, becoming the trabs or lump, and mastoid is intumescing and transfiguring. The intine spine and hollow of gynecophoral canal is disappeared.
The effective dosage is400mg/kg in vivo. And the ratio is above65%to1、3、7、14、21、28、35day-old schistosomes, but they are not significant difference. Under the ultrastructural organization, the pleat of tegument is disappeared, becoming the trabs or lump, and mastoid is intumescing and transfiguring. The intine spine and hollow of gynecophoral canal is disappeared. But the change of tegument and gynecophoral canal are not obvious.
3. The study on the absorption characteristic of pulchinenoside
Establishing the absorption model of pulchinenoside based on the active constitutent of pulchinenoside against the schistosome. Through comparing the study on the absorption characteristic of the2pulchinenoside, they have differences in absorption. They could have other sorbefacient constitutent.The absorption of constitutents is moderately, and they are not significant difference. The absorption of pulchinenoside B3、B10, B11are saturated, but the pulchinenoside BD、 B7are passive diffusion. The absorption rate is increasing after adding P-glucoprotein inhibitor. So pulchinenoside could be P-glucoprotein inhibitor.
4. The screening on the preparation of pulchinenoside
The physico-chemical property of the extract determine the dosage form design. Pulchinenoside is subacidity, and the dissolution ability is the best in subalkaline environment. The ability is B7(?)B3(?)B10(?)B11(?)BD in all solvent. They are all stabilization in gastric enzyme and trypsogen in12h. And they are all stabilization in high temperature and glare, but the hygroscopicity is powerful. According to the absorption characteristic and physico-chemical property, we design three different type preparation. Gum Acacia design is low toxicity, and the ratio is above70%after Oral Drug Administration.
5. the pharmacodynamics study on the Gum Acacia design of pulchinenoside
Studying the potency on the Gum Acacia design of pulchinenoside, the result is the ratio of decreasing worms is above65%to different stages after300mg/kg Oral Drug Administration. But they are not significant difference. The usage of different designs is still increasing the ratio of decreasing worms.
1.白头翁皂苷类成分初步构效关系的研究
在初步总结皂苷类成分苷元的结构类型、取代基的种类及位置、糖链长度、组成、苷化位置、糖与苷元及糖的连接方式及顺序等的基础上,通过药物体外抗血吸虫效应及对哺乳动物细胞毒性的研究,分析总结皂苷结构与杀虫效应、细胞毒性之间的关系。
结果显示,①白头翁皂苷苷元C-28位的羧基游离对于皂苷的抗血吸虫活性至关重要。②苷元C-3位所连糖链的糖基个数以及连接顺序对皂苷的抗血吸虫活性有一定的影响。③具有相同糖链的皂苷其活性顺序为：齐墩果酸苷元>常春藤皂苷元。
通过体外筛选出BP-SJ-7、BP-SJ-3、BP-SJ-9、BP-SJ-10四个皂苷对血吸虫有较强的杀灭作用,作用后虫体肿胀僵硬、体表透明度下降,表皮溃烂,肠腔破损。
经等辐射分析法得出,其他成分与BP-SJ-9配合作用后显示出较强的协同作用。
2.白头翁皂苷提取物体内外抗血吸虫作用的研究
在明确提取物物质基础的前提下,以体内外杀虫活性为指标,筛选不同配比组成的白头翁皂苷提取物,结果BTW3提取物与其他提取物相比对血吸虫活性有显著差异。
并通过BTW3提取物体外对血吸虫成虫、童虫及吡喹酮压力下的虫体的作用以及体内研究,明确其杀虫作用及特点。
结果显示药物体内外对血吸虫的杀灭作用具有浓度依赖性。体外临界杀虫浓度分别为：雄性成虫24μg/mL,雌性成虫32μg/mL,童虫32μg/mL,吡喹酮压力下的虫体48μg/mL。在40倍镜下观察,虫体明显收缩、扭曲,体表肿胀,100倍镜下体表肿胀明显,组织分布疏松,肠管明显肿胀弯曲且分布混乱；超微结构显示皮层褶嵴消失,融合成条索或片块状,其上感觉乳突肿大、变形、破溃而丢失,抱雌沟内壁体棘、凹陷等基本结构破坏消失,融合皱缩形成条索状物或模糊一片,乳突肿大、变形、破溃而丢失
体内最佳有效杀虫剂量：成虫、童虫均为为400mg/kg。
以400mg/kg口服给药,对1、3、7、14、21、28、35天虫龄的减虫率达到65%以上,但对不同发育期虫体的减虫率没有显著性差异。
以400mg/kg口服给药,药物对不同时间虫体的体表组织及抱雌沟损伤作用较明显,第1d观察发现：皮层褶嵴消失,融合成条索或片块状,其上感觉乳突肿大、变形、破溃而丢失,抱雌沟内壁,体棘、凹陷等基本结构破坏消失,融合皱缩形成条索状物或模糊一片,乳突肿大、变形、破溃而丢失,随着时间的延长(第3d、7d观察)虫体体表及抱雌沟变化不明显。
3.白头翁皂苷在体肠吸收特性的研究
以白头翁皂苷抗血吸虫活性成分为指标,建立了白头翁皂苷在体肠吸收模型。通过比较研究2种白头翁皂苷组成的吸收情况,不同剂量组、不同小肠区段的的吸收参数,以及P-糖蛋白抑制剂对其吸收的影响,结果2种白头翁皂苷提取物各成分的吸收存在明显差异,各成分间或提取物中其他成分可能存在促吸收的物质；白头翁皂苷5种抗血吸虫活性成分吸收情况中等,在各肠段的吸收没有显著性差异;白头翁皂苷B3、B10、B11具有吸收饱和的现象,白头翁皂苷BD、B7为被动扩散;加入P-糖蛋白抑制剂维拉帕米及P-糖蛋白底物地高辛后,各成分的吸收速率有显著提高,预测白头翁皂苷五种主要成分可能是P-糖蛋白底物。
4.白头翁皂苷提取物制剂的初步筛选
提取物原料的基本物理化学性决定制剂的剂型设计,本义对白头翁皂苷提取物的理化性质进行研究,结果显示白头翁皂苷提取物显弱酸性,在弱碱性环境中溶解能力最强;在各溶媒中各成分溶解能力的大小依次为：B7(?)B3(?)B10(?)B11(?)BD；油水分配系数很小,亲脂性较弱,亲水性强；在12h内胃酶、胰酶环境中稳定,在高温、强光照射下稳定,吸湿性较强。
根据肠吸收特性及理化性质结果初步设计为环糊精包含物、乳剂、微粉硅胶吸附剂,以对童虫、成虫的作用为指标进行筛选,结果微粉硅胶吸附剂毒性较低,且在300mg/kg口服给药对血吸虫的减虫率达到70%左右。
5.白头翁皂苷微粉硅胶吸附剂的药效学研究
对白头翁皂苷微硅胶吸附剂进行药效学实验,结果300mg/kg口服给药对不同发育期的血吸虫体内减虫率达到65%,但不同发育期间的减虫率没有显著性差异；不同技术联合使用后对血吸虫的减虫率也没有显著提高,说明白头翁皂苷微粉硅胶吸附剂对血吸虫病有一定的治疗作用,但仍需进一步研究提高其抗血吸虫药效。
Schistosomiasis is a serious damage parasitic diseases, which is epidemic in tropical and subtropical zone. But praziquantel is the only effective drug in clinic, which can not accommodate with the Schistosomiasis control. In our prophase research, Pulsatilla chinensis has an effictive drug against Schistosomiasis, but the material basis and the mechanism of action are not clear. The exploitation of antischistosomal drugs have been restrained. So the text is about the new drug againt Schistosome based on the components of traditional Chinese medicine. Through the study on structure-activity and toxic-activity relationship, the material basis of Pulsatilla chinensis againt Schistosomiasis could be screened. And on the aim of improving the bioavailability, we could get the effective and safe drug againt Schistosomiasis through the stuty on the absorption of pulchinenoside. The dissertation is summarized as follows:
1. the study on the structure-activity relationship about pulchinenoside
On the base of the understood of pulchinenoside, the structure-activity relationship can be summarized through the study on the drug against Schistosomiasis in vitro.
The results are①It is vital for anti-schistomiasis activity to the C-28Carboxyl free of the P. chinensis.②It makes a difference for antischistomiasis activity to the C-3of sugar chain and connection order of the P. chinensis.③The type of aglycone also affect the anti-schistomiasis activity, found that the Oleanolic acid has the more activity than hederagenin.
The four pulchinenosides BP-SJ-7、 BP-SJ-3、BP-SJ-9、 BP-SJ-10have been screened in vitro. Polypide is becoming swell and inflexible, the clarity descend, epidermis inflamed and epidermis damaged after exproused in drug.
BP-SJ-9together with other components have the concurrency action through isobolographic analysis
2. The study on the extract of pulchinenoside against schistosome in vitro and in vivo Based On the material basis of the extract, the extract of pulchinenoside have been screened according to the activity against schistosome, the result is BTW3has difference with the others. The effecitve and characteristic have been identified through the extrace against imago, schistosomula and the schistosomes of decreased parziquantel sensitivity in virto and in vivo.
The results are the drug have concentration dependent against schistosome in virto and in vivo. The criticality anthelminthic concentration is male schistosome24μg/mL, femal schistosome32μg/mL, schistosomula32μg/mL, and the schistosomes of decreased parziquantel sensitivity48μg/mL。 Criticality is shrinking, retortion, and epidermis is swelling on the40times mirror. On the100times mirror, epidermis is swelling, Tissue is porosity, intestinal tract is swelling, bending and distribution is confusion. Under the ultrastructural organization, the pleat of tegument is disappeared, becoming the trabs or lump, and mastoid is intumescing and transfiguring. The intine spine and hollow of gynecophoral canal is disappeared.
The effective dosage is400mg/kg in vivo. And the ratio is above65%to1、3、7、14、21、28、35day-old schistosomes, but they are not significant difference. Under the ultrastructural organization, the pleat of tegument is disappeared, becoming the trabs or lump, and mastoid is intumescing and transfiguring. The intine spine and hollow of gynecophoral canal is disappeared. But the change of tegument and gynecophoral canal are not obvious.
3. The study on the absorption characteristic of pulchinenoside
Establishing the absorption model of pulchinenoside based on the active constitutent of pulchinenoside against the schistosome. Through comparing the study on the absorption characteristic of the2pulchinenoside, they have differences in absorption. They could have other sorbefacient constitutent.The absorption of constitutents is moderately, and they are not significant difference. The absorption of pulchinenoside B3、B10, B11are saturated, but the pulchinenoside BD、 B7are passive diffusion. The absorption rate is increasing after adding P-glucoprotein inhibitor. So pulchinenoside could be P-glucoprotein inhibitor.
4. The screening on the preparation of pulchinenoside
The physico-chemical property of the extract determine the dosage form design. Pulchinenoside is subacidity, and the dissolution ability is the best in subalkaline environment. The ability is B7(?)B3(?)B10(?)B11(?)BD in all solvent. They are all stabilization in gastric enzyme and trypsogen in12h. And they are all stabilization in high temperature and glare, but the hygroscopicity is powerful. According to the absorption characteristic and physico-chemical property, we design three different type preparation. Gum Acacia design is low toxicity, and the ratio is above70%after Oral Drug Administration.
5. the pharmacodynamics study on the Gum Acacia design of pulchinenoside
Studying the potency on the Gum Acacia design of pulchinenoside, the result is the ratio of decreasing worms is above65%to different stages after300mg/kg Oral Drug Administration. But they are not significant difference. The usage of different designs is still increasing the ratio of decreasing worms.
引文
[1]Fenwick A. New initiatives against Africa's worms. Trans Soc Trap Med Hyg,2006,100 (3): 200-207.
[2]Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development:systematic review meta-analysis and estimates of people at risk. Lancet Infect Dis,2006,6 (7):411-425.
[3]Chitsulo L, Engels D, Montresor A. The global status of schistosomiasis and its control. Acta Trop,2000,77(1):41-51.
[4]Xiao SH, Yuc WJ, Yang YQ. Susceptibility of schistosoma japonicum of different developmental stages to praziquantel. Chin Mcd J,1987,100 (9):759-768.
[5]Wu Z, Bu K, Yuan L. Factors contributing to reinfection with schistosomiasis japonica after treatment in the lake region of China. Acta Trop,1993,54 (2):83-88.
[6]Doenhoff MJ, Pica-Mattoccia L. Praziquantel for the treatment of schistosomiasis:its use for control in areas with endemic disease and prospects for drug resistance. Expert Rev Anti Infect Ther,2006,4 (2):199-210.
[7]Xiao SH. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop,2005,96 (2-3):153-167.
[8]Utzinger J, Xiao SH, Tanner M. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs,2007,8 (2):105-116.
[9]柳建发,蒋雯雯,周飞,胡奇丰.环孢素A及其衍生物FK506体内抗长爪沙鼠日本血吸虫病的研究.中国人兽共患病学报,2010,26(6)：572-574.
[10]肖培根主编.新编中药志(一).北京,化学工业出版社,2001,328-328.
[11]江苏新医学院.中药大词典(上册).上海, 上海科技出版社,1977,704-704.
[12]国家中医药管理局《中华本草》编委会.中华本草(上册).上海,上海科技出版社,1998,538-538.
[13]闫艳,高兴政.白头翁体外抗阴道毛滴虫的效果及扫描电镜观察.中国寄生虫病防治杂志,2003,16(6)：353-355.
[14]中华人民共和国药典委员会,中华人民共和国药典.一部.北京,化学工业出版社,2005版：68-68.
[15]张旭,乔继英,张荣,魏志超, 蔡娟.鸦胆子、黄连、白头翁和槟榔对人芽囊原虫体外杀虫作用的比较.热带医学杂志,2007,17(11)：1044-1047.
[16]王秋梅,薄涛.白头翁可防治兔球虫.养殖技术顾问,2003,(11)：41-41.
[17]闫艳,高兴政.白头翁体外抗阴道毛滴虫的效果及扫描电镜观察.中国寄生虫病防治杂志,2003,16(6)：353-355.
[18]陈文侃,王碧瑜,卢德育,林强,林丽英.中药白头翁的皂素(Ⅲ)配基结构的研究.化学学报,1983,41(8)：739-745.
[19]贾晓斌,陈彦,李霞,等.中药复方物质基础研究新思路和方法[J].中华中医药杂志2008,23(5)：420.
[20]刘丹,贾晓斌,郁丹红.基于“组分构成”理论的中药质量控制新思路[J].中国中药杂志,2012,37(6)：865-870.
[21]张伯礼,王永炎.方剂关键科学问题的基础研究——以组分配伍研制现代中药[J].中国天然药物,2005,3(5)：258-261.
[22]王睿.实现复方剂量配比优化的ED-NM-MO三联法[M].北京北京中医药大学博士论文,2004
[23]Pica-Mattoccia L, Ruppel A, Xia CM, etal. Praziquantel and the benzodiazepine Ro11-3128 do not compete for the same bindingsites in sehistosomes [J]. Paras itoloty, 2008,135 (Pt 1):47-54.
[24]李欣,蔡茹,张惠琴,等.5种地西泮类衍生物抗血吸虫的初步评价.中国人兽共患病学报,2009,105(4)：899-906.
[25]Xiao SH, Keiser J, Chollet J, etal. In vitro and in vitro activities of synthetic trioxolanes against major human schistosome species [J]. Antimicrob Agents Chemother, 2007,51(4):1440-1445.
[26]郝阳,王立英,周晓农,等.江西省鄱阳湖区血吸虫病传播风险及其原因分析[J].中国血吸虫病防治杂志,2009,21(5)：345-349.
[27]郑浩,孙乐平,朱蓉,等.2010年全国重点水域血吸虫感染哨鼠监测预警情况分析[J].中国血吸虫病防治杂志,2012,24(1)：5-9.]
[28]郑浩,张利娟,朱蓉,等.2011年全国血吸虫病疫情通报[J].中国血吸虫病防治杂志,2012,24 (6)：621-626.]
[1]胡祁生,杨孟祥,王勇,等.吡喹酮对日本血吸虫病兔血清离子浓度的影响.武汉大学学报(医学版),200I,22(4)：344-345
[2]肖树华.吡喹酮的药理、毒性及应用中的一些问题.中国血吸虫病防治杂志,1995,7(3)：189-192.
[3]杭盘宇,梁幼生,戴建荣,等.不同阶段日本血吸虫对吡喹酮敏感性的研究.中国血吸虫病防治杂志,2001,13(6)：343-346.
[4]Xiao SH, Shen BG. Scanning electron microscope observation on tegumental damage of 21-d-old Schi s tosoma japonicum induced by praziquantel. Acta Pharmacologica Sinica,1995,16 (3):273-275.
[5]杨晓明,余炳桢.吡喹酮对日本轿吸虫成虫皮层作用的透射电镜观察.新乡医学院学报,1990,7(1)：89-92.
[6]翟自立,王振果.自由基调节青蒿素类药物的抗血吸虫作用.中国热带医学,2003,3(3)：391-394
[1]AMIDON GL, LENNERNAS H, SHAH VP, etal. A theoretical basis for a biopharmaceutic drug classification the correlation of in vi tro drug product dissolution and in vivo bioavailability[J].Pharm Res,1995,12 (3):413-420.
[2]FAGERHOLM U, JOHANSSON M, LENNERNAS H. Comparison between permeability coefficients in rat and human jejunum[J]. Pharm Res,1996,13(9):1336-1342.
[3]Fagerholm U, Johansson M, Lennernas H. Comparison between permeability coefficients in art and human jejunum[J]. Pharm Res,1996,13(9):1336-1342.]
[4]程晓华,熊玉卿。五环三萜皂苷的药代动力学研究进展[J].中国临床药理学杂志,2008,24(5)：443-446]
[5]Thiebut F, Tsuruo T, Hamada H,etal. Proc Natl Acad Sci USA 1987; 84:7735-8】
[6]S Hoffmeyer,O Burk,O von Richter, etal. Proc Natl Acad Sci USA,2000; 97:3473-3478.
[1]Gryseels B, Polman K, Clerinx J, et al. Human schistosomiasis[J]. The Lancet,2006,368 (9541):1106-1118.
[2]Steinmann P, Keiser J, Bos R, et al. Schistosomiasis and water resources development: systematic review, meta-analysis and estimates of people at risk [J]. Lancet Infect Dis,2006, 6 (7):411-425.
[3]Ribeiro-dos-Santos G, Verjovski-Almeida S, Leite LC. Schistosomiasis:a century searching for chemotherapeutic drugs[J]. Parasitol Res,2006,99 (5):505-521.
[4]Cioli D, Pica-Mattocia L. Praziquantel[J]. Parasitol Res,2003
[5]黄一心.吡喹酮抗血吸虫作用机理的奥秘[J].中国血吸虫病防治杂志,2010,22(2)：101-103.
[6]黄一心,肖树华.抗蠕虫药吡喹酮的研究与应用[M].1版.北京：人民出版社,2008：173.
[7]Dayan AD. Albendazole, mebendazolc and praziquantel. Review of non-clinical toxicity and pharmacokinetics [J]. Acta Tropica,2003,86 (2-3):141-159.
[8]Gonzalez-Esquivel D, Rivera J, Castro N, et al. In vitro characterization of some biopharmaceutical properties of praziquantel [J]. Int J Pharm,2005,295 (1-2),93-99.
[9]Rinaki E,Valsami G, Macheras P. Quantitative biopharmaccutics classification system:the central role of dose/solubility ratio [J]. Pharm Res,2003,20 (12):1917-1924.
[10]Yazdanian M., Glynn SL, Wright JL, et al. Correlating partitioning and Caco-2 cell permeability of structurally diverse small molecular weight compounds [J]. Pharm Res,1998 15(9):1490-1494.
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[29]贺宏斌,石孟芝,彭喜松,等.吡喹酮缓释包埋剂预防小鼠血吸虫病的初步研究[J].热带病与寄生虫学,2003,1(4)：220-221.
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[2]Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development:systematic review meta-analysis and estimates of people at risk. Lancet Infect Dis,2006,6 (7):411-425.
[3]Chitsulo L, Engels D, Montresor A. The global status of schistosomiasis and its control. Acta Trop,2000,77(1):41-51.
[4]Xiao SH, Yuc WJ, Yang YQ. Susceptibility of schistosoma japonicum of different developmental stages to praziquantel. Chin Mcd J,1987,100 (9):759-768.
[5]Wu Z, Bu K, Yuan L. Factors contributing to reinfection with schistosomiasis japonica after treatment in the lake region of China. Acta Trop,1993,54 (2):83-88.
[6]Doenhoff MJ, Pica-Mattoccia L. Praziquantel for the treatment of schistosomiasis:its use for control in areas with endemic disease and prospects for drug resistance. Expert Rev Anti Infect Ther,2006,4 (2):199-210.
[7]Xiao SH. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop,2005,96 (2-3):153-167.
[8]Utzinger J, Xiao SH, Tanner M. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs,2007,8 (2):105-116.
[9]柳建发,蒋雯雯,周飞,胡奇丰.环孢素A及其衍生物FK506体内抗长爪沙鼠日本血吸虫病的研究.中国人兽共患病学报,2010,26(6)：572-574.
[10]肖培根主编.新编中药志(一).北京,化学工业出版社,2001,328-328.
[11]江苏新医学院.中药大词典(上册).上海, 上海科技出版社,1977,704-704.
[12]国家中医药管理局《中华本草》编委会.中华本草(上册).上海,上海科技出版社,1998,538-538.
[13]闫艳,高兴政.白头翁体外抗阴道毛滴虫的效果及扫描电镜观察.中国寄生虫病防治杂志,2003,16(6)：353-355.
[14]中华人民共和国药典委员会,中华人民共和国药典.一部.北京,化学工业出版社,2005版：68-68.
[15]张旭,乔继英,张荣,魏志超, 蔡娟.鸦胆子、黄连、白头翁和槟榔对人芽囊原虫体外杀虫作用的比较.热带医学杂志,2007,17(11)：1044-1047.
[16]王秋梅,薄涛.白头翁可防治兔球虫.养殖技术顾问,2003,(11)：41-41.
[17]闫艳,高兴政.白头翁体外抗阴道毛滴虫的效果及扫描电镜观察.中国寄生虫病防治杂志,2003,16(6)：353-355.
[18]陈文侃,王碧瑜,卢德育,林强,林丽英.中药白头翁的皂素(Ⅲ)配基结构的研究.化学学报,1983,41(8)：739-745.
[19]贾晓斌,陈彦,李霞,等.中药复方物质基础研究新思路和方法[J].中华中医药杂志2008,23(5)：420.
[20]刘丹,贾晓斌,郁丹红.基于“组分构成”理论的中药质量控制新思路[J].中国中药杂志,2012,37(6)：865-870.
[21]张伯礼,王永炎.方剂关键科学问题的基础研究——以组分配伍研制现代中药[J].中国天然药物,2005,3(5)：258-261.
[22]王睿.实现复方剂量配比优化的ED-NM-MO三联法[M].北京北京中医药大学博士论文,2004
[23]Pica-Mattoccia L, Ruppel A, Xia CM, etal. Praziquantel and the benzodiazepine Ro11-3128 do not compete for the same bindingsites in sehistosomes [J]. Paras itoloty, 2008,135 (Pt 1):47-54.
[24]李欣,蔡茹,张惠琴,等.5种地西泮类衍生物抗血吸虫的初步评价.中国人兽共患病学报,2009,105(4)：899-906.
[25]Xiao SH, Keiser J, Chollet J, etal. In vitro and in vitro activities of synthetic trioxolanes against major human schistosome species [J]. Antimicrob Agents Chemother, 2007,51(4):1440-1445.
[26]郝阳,王立英,周晓农,等.江西省鄱阳湖区血吸虫病传播风险及其原因分析[J].中国血吸虫病防治杂志,2009,21(5)：345-349.
[27]郑浩,孙乐平,朱蓉,等.2010年全国重点水域血吸虫感染哨鼠监测预警情况分析[J].中国血吸虫病防治杂志,2012,24(1)：5-9.]
[28]郑浩,张利娟,朱蓉,等.2011年全国血吸虫病疫情通报[J].中国血吸虫病防治杂志,2012,24 (6)：621-626.]
[1]胡祁生,杨孟祥,王勇,等.吡喹酮对日本血吸虫病兔血清离子浓度的影响.武汉大学学报(医学版),200I,22(4)：344-345
[2]肖树华.吡喹酮的药理、毒性及应用中的一些问题.中国血吸虫病防治杂志,1995,7(3)：189-192.
[3]杭盘宇,梁幼生,戴建荣,等.不同阶段日本血吸虫对吡喹酮敏感性的研究.中国血吸虫病防治杂志,2001,13(6)：343-346.
[4]Xiao SH, Shen BG. Scanning electron microscope observation on tegumental damage of 21-d-old Schi s tosoma japonicum induced by praziquantel. Acta Pharmacologica Sinica,1995,16 (3):273-275.
[5]杨晓明,余炳桢.吡喹酮对日本轿吸虫成虫皮层作用的透射电镜观察.新乡医学院学报,1990,7(1)：89-92.
[6]翟自立,王振果.自由基调节青蒿素类药物的抗血吸虫作用.中国热带医学,2003,3(3)：391-394
[1]AMIDON GL, LENNERNAS H, SHAH VP, etal. A theoretical basis for a biopharmaceutic drug classification the correlation of in vi tro drug product dissolution and in vivo bioavailability[J].Pharm Res,1995,12 (3):413-420.
[2]FAGERHOLM U, JOHANSSON M, LENNERNAS H. Comparison between permeability coefficients in rat and human jejunum[J]. Pharm Res,1996,13(9):1336-1342.
[3]Fagerholm U, Johansson M, Lennernas H. Comparison between permeability coefficients in art and human jejunum[J]. Pharm Res,1996,13(9):1336-1342.]
[4]程晓华,熊玉卿。五环三萜皂苷的药代动力学研究进展[J].中国临床药理学杂志,2008,24(5)：443-446]
[5]Thiebut F, Tsuruo T, Hamada H,etal. Proc Natl Acad Sci USA 1987; 84:7735-8】
[6]S Hoffmeyer,O Burk,O von Richter, etal. Proc Natl Acad Sci USA,2000; 97:3473-3478.
[1]Gryseels B, Polman K, Clerinx J, et al. Human schistosomiasis[J]. The Lancet,2006,368 (9541):1106-1118.
[2]Steinmann P, Keiser J, Bos R, et al. Schistosomiasis and water resources development: systematic review, meta-analysis and estimates of people at risk [J]. Lancet Infect Dis,2006, 6 (7):411-425.
[3]Ribeiro-dos-Santos G, Verjovski-Almeida S, Leite LC. Schistosomiasis:a century searching for chemotherapeutic drugs[J]. Parasitol Res,2006,99 (5):505-521.
[4]Cioli D, Pica-Mattocia L. Praziquantel[J]. Parasitol Res,2003
[5]黄一心.吡喹酮抗血吸虫作用机理的奥秘[J].中国血吸虫病防治杂志,2010,22(2)：101-103.
[6]黄一心,肖树华.抗蠕虫药吡喹酮的研究与应用[M].1版.北京：人民出版社,2008：173.
[7]Dayan AD. Albendazole, mebendazolc and praziquantel. Review of non-clinical toxicity and pharmacokinetics [J]. Acta Tropica,2003,86 (2-3):141-159.
[8]Gonzalez-Esquivel D, Rivera J, Castro N, et al. In vitro characterization of some biopharmaceutical properties of praziquantel [J]. Int J Pharm,2005,295 (1-2),93-99.
[9]Rinaki E,Valsami G, Macheras P. Quantitative biopharmaccutics classification system:the central role of dose/solubility ratio [J]. Pharm Res,2003,20 (12):1917-1924.
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