大黄蟅虫丸治疗下肢深静脉血栓形成后遗症的实验和临床研究
摘要
目的：通过对大黄蟅虫丸对大鼠静脉血栓模型和静脉内皮损伤模型的相关指标和超微结构影响的观察，并通过其对下肢深静脉血栓形成后遗症(Deep venous postthrombotic syndrome DVTS)病人的临床观察，探讨大黄蟅虫丸治疗下肢深静脉血栓形成后遗症的机理。
方法：①实验研究：建立深静脉血栓形成模型大鼠(结扎下腔静脉法，简称模型一组)和静脉内皮损伤模型大鼠(导丝破坏法，简称模型二组)。模型一组和模型二组各随机分为大黄蟅虫丸高中低剂量组、阳性药物(通塞脉片)对照组、模型组、空白组，并观察大黄蟅虫丸对两类大鼠模型各组的组织型纤溶酶原激活物(t-PA)、组织型纤溶酶原活化剂抑制物1(PAI-1)、D-二聚体活性测定(D-Dimer)、内皮素(ET)、一氧化氮合酶(NOS)、血栓素B_2(TXB_2)、6-酮-前列腺素F_(1α)(6-K-PGF_(1α))、内皮细胞P-选择素、静脉标本光、电镜下超微结构等指标的影响。②临床研究：观察大黄蟅虫丸对下肢深静脉血栓形成后遗症(DVTS)病人肢体静脉光电容积描记血流图(photoplethysmography PPG)、凝血系列指标、P-选择素、组织型纤溶酶原激活物(t-PA)、血栓素B_2(TXB_2)、Ⅷ因子抗原(VWF-Ag)、6-酮-前列腺素F_(1α)(6-K-PGF_(1α))等相关指标的影响。
结果：①实验研究表明大黄蟅虫丸对两组给药大鼠模型的各项指标及超微结构均有不同程度的影响；a大黄蟅虫丸可升高模型一组、模型二组给药大鼠的t-PA含量，可降低模型一组、模型二组给药大鼠的PAI-1和D-Dimer含量，以上指标与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组各项指标相比较无显著性差异(P＞0.05)。b大黄蟅虫丸可升高模型一组、模型二组给药大鼠的TNOS含量，能降低模型一组、模型二组给药大鼠的iNOS含量，与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组之间相比较无显著性差异(P＞0.05)。c大黄蟅虫丸可升高模型一组和模型二组给药大鼠的6-K-PGF_(1α)含量、降低TXB_2及ET含量，数据与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组之间相比较无显著性差异(P＞0.05)。d大黄蟅虫丸可降低内皮细胞表达P-选择素的数量，低于造模后的各对照组，有显著性差异(P＜0.05)。e光、电镜下超微结构观察表明：大黄蟅虫丸有抑制血栓形成、保护内皮的作用。②临床研究表明各项指标得到改善；观察32例病例，结果治疗后症状和体征及肢体静脉光电容积描记血流图(photoplethysmography PPG)明显好转、治疗后PT、APTT、FIB、血清P-选择素、t-PA、TXB_2、6-K-PGF_(1α)、VWF-Ag等指标明显改善、经统计学处理有显著意义。
结论：①实验研究表明大黄蟅虫丸对大鼠静脉血栓模型和静脉内皮损伤模型的各项指标有明显改善，具有抑制血栓、保护内皮细胞、促进血管修复的作用。②临床研究表明大黄蟅虫丸是治疗下肢深静脉血栓形成后遗症的一种有效、作用机制可靠的药物。古方新用、为大黄蟅虫丸在血管病领域的临床应用提供了依据。
Objective:To observe the effect of Dahuang Zhechong Pill onthe related indexes and ultrastructure in the venous thrombosis modeland the damaged venous model in ratsand to observe, the thetherapeutic efficacy of Dahuang Zhechong Pill in sequela of the deepvenous thrombosis. Study the therapeutic mechanism of DahuangZhechong Pill on the patients with sequela of the deep venousthrombosis though the indexes.
Research technique:①Experimental Research:building thevenous thrombosis model though inferior vena cava ligation (the firstmodel group for short), simultaneously building the damaged venousmodel by the guidewires (the second model group for short). Twomodle groups divide randomly into six groups, including the lowdosage group of Dahuang Zhechong Pill, the medium dosage group ofDahuang Zhechong Pill, the high dosage group of Dahuang ZhechongPill, the control group, the model group and the blank group. Studythe effects of Dahuang Zhechong Pill on Indexes in two model groups,including the tissue plasminogen activator (t-PA), plasminogenactivator inhibitor-1(PAI-1), D-Dimer, endothelin(ET), nitric oxidesynthase (NOS), thromboxane B_2 (TXB_2,), 6-keto-prostaglandin F_1α(6-K-PGF_1α), P-selectin and intrastruction of venous specimen forlight microscope and electron microscopic examination,ect.②Clinical Research:to study the effects of Dahuang Zhechong Pill onrelated Indexes on the patients with the deep venous postthromboticsyndrome, for example: photoplethysmography , hemagglutination test,P-selectin, tissue plasminogen activator (t-PA), thromboxane B_2(TXB_2),Ⅷfactor antigen (VWF-Ag), 6-keto-prostaglandin F_1α(6-K-PGF_1α),ect.
Findings:
1、Experimental Study
With respects to related indexes and ultrastructure ,the studyshows that there was significant difference between the venousthrombosis model group and the damaged venous model group.
①Dahuang Zhechong Pill has regulatory effect in the content oft-PA of the first model group and the second model group. It also candecrease the contents of PAI-1 and D-Dimer of the first model groupand the second model group. There was significant differencebetween the first model groups and the model group(p＜0.05). Therewas significant difference between the second model group and themodel group(p＜0.05).There was no difference between the firstmodel group and the blank group (p＞0.05). There was no differencebetween the second model group and the blank group (p＞0.05).Therewas no difference between the first model group and the secondmodel group(p＞0.05).
②Dahuang Zhechong Pill can increase the content of TNOS of thefirst model group and the second model group, but it can decrease thecontent of iNOS in both the first model group and the second modelgroup. There was significant difference between the first modelgroup and the model group(p＜0.05). There was significant differencebetween the second model group and the model group(p＜0.05). Therewas no difference between the blank group and the first group(p＞0.05). There was no difference between the blank group and thesecond group (p＞0.05). There was no difference between the firstmodel group and the second venous model group(p＜0.05).
③Dahuang Zhechong Pill can increase the content of 6-K-PGF1_aof the first model group and the second group, but it can decrease thecontents of TXB_2, and ET in the first model group and the secondmodel group. There was significant difference between the firstmodel group and the model group(p＜0.05). There was significantdifference between the second model group and the model group(p＜0.05). There was no difference between the blank group andthe first group (p＞0.05). There was no difference between the blankgroup and the second group (p＞0.05). There was no differencebetween the first model group and the second venous modelgroup(p＜0.05).
④Dahuang Zhechong Pill has negative effect in the quantity ofP-selectin of the first model group and the second model group. Therewas significant difference between the first model groups and thecontrol group(p＜0.05). There was significant difference between thesecond model group and the control group(p＜0.05). There wassignificant difference between the first model groups and the modelgroup(p＜0.05). There was significant difference between the secondmodel group and the model group(p＜0.05).There was significantdifference between the first model groups and the blankgroup(p＜0.05). There was significant difference between the secondmodel group and the blank group(p＜0.05).
⑤To study the intrastructions for light microscope examinationand electron microscopic examination,the study shows that DahuangZhechong Pill has an obvious inhibiting effect on thrombosis,and hasprotective effects on endothelial cells.
2、Clinical Study
Dahuang Zhechong Pill has positive remarkedly effects onrelated indexes. Though observing 32 example cases,the study showsthat symptoms and physical signs obvious change for the better afterthe treatment. The related indexes, such as PT, APTT, FIB, P-selectin,t-PA, TXB_2, 6-K-PGF_1α, VWF-Ag,ete,had improved. The results havethe significance after statistics processing.
Conclusions:
1.Experimental study shows that Dahuang Zhechong Pill canimproved the related indexes on the venous thrombosis model group and the damaged venous model group. Dahuang Zhechong Pill has anobvious inhibiting effect on thrombosis,and has protective effects onendothelial cells and vascular repair.
2. Clinical study show that Dahuang Zhechong Pill is a kind ofeffective and reliable medicine for treating patients with DVTS. Thestudy is a new application of old herb prescription, and has providedthe science objective basis for Dahuang Zhechong Pill of clinicalapplication in angiopathy field.
方法：①实验研究：建立深静脉血栓形成模型大鼠(结扎下腔静脉法，简称模型一组)和静脉内皮损伤模型大鼠(导丝破坏法，简称模型二组)。模型一组和模型二组各随机分为大黄蟅虫丸高中低剂量组、阳性药物(通塞脉片)对照组、模型组、空白组，并观察大黄蟅虫丸对两类大鼠模型各组的组织型纤溶酶原激活物(t-PA)、组织型纤溶酶原活化剂抑制物1(PAI-1)、D-二聚体活性测定(D-Dimer)、内皮素(ET)、一氧化氮合酶(NOS)、血栓素B_2(TXB_2)、6-酮-前列腺素F_(1α)(6-K-PGF_(1α))、内皮细胞P-选择素、静脉标本光、电镜下超微结构等指标的影响。②临床研究：观察大黄蟅虫丸对下肢深静脉血栓形成后遗症(DVTS)病人肢体静脉光电容积描记血流图(photoplethysmography PPG)、凝血系列指标、P-选择素、组织型纤溶酶原激活物(t-PA)、血栓素B_2(TXB_2)、Ⅷ因子抗原(VWF-Ag)、6-酮-前列腺素F_(1α)(6-K-PGF_(1α))等相关指标的影响。
结果：①实验研究表明大黄蟅虫丸对两组给药大鼠模型的各项指标及超微结构均有不同程度的影响；a大黄蟅虫丸可升高模型一组、模型二组给药大鼠的t-PA含量，可降低模型一组、模型二组给药大鼠的PAI-1和D-Dimer含量，以上指标与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组各项指标相比较无显著性差异(P＞0.05)。b大黄蟅虫丸可升高模型一组、模型二组给药大鼠的TNOS含量，能降低模型一组、模型二组给药大鼠的iNOS含量，与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组之间相比较无显著性差异(P＞0.05)。c大黄蟅虫丸可升高模型一组和模型二组给药大鼠的6-K-PGF_(1α)含量、降低TXB_2及ET含量，数据与模型组比较均有显著性差异，(P＜0.05)，与空白组相比无显著性差异(P＞0.05)。模型一组和模型二组之间相比较无显著性差异(P＞0.05)。d大黄蟅虫丸可降低内皮细胞表达P-选择素的数量，低于造模后的各对照组，有显著性差异(P＜0.05)。e光、电镜下超微结构观察表明：大黄蟅虫丸有抑制血栓形成、保护内皮的作用。②临床研究表明各项指标得到改善；观察32例病例，结果治疗后症状和体征及肢体静脉光电容积描记血流图(photoplethysmography PPG)明显好转、治疗后PT、APTT、FIB、血清P-选择素、t-PA、TXB_2、6-K-PGF_(1α)、VWF-Ag等指标明显改善、经统计学处理有显著意义。
结论：①实验研究表明大黄蟅虫丸对大鼠静脉血栓模型和静脉内皮损伤模型的各项指标有明显改善，具有抑制血栓、保护内皮细胞、促进血管修复的作用。②临床研究表明大黄蟅虫丸是治疗下肢深静脉血栓形成后遗症的一种有效、作用机制可靠的药物。古方新用、为大黄蟅虫丸在血管病领域的临床应用提供了依据。
Objective:To observe the effect of Dahuang Zhechong Pill onthe related indexes and ultrastructure in the venous thrombosis modeland the damaged venous model in ratsand to observe, the thetherapeutic efficacy of Dahuang Zhechong Pill in sequela of the deepvenous thrombosis. Study the therapeutic mechanism of DahuangZhechong Pill on the patients with sequela of the deep venousthrombosis though the indexes.
Research technique:①Experimental Research:building thevenous thrombosis model though inferior vena cava ligation (the firstmodel group for short), simultaneously building the damaged venousmodel by the guidewires (the second model group for short). Twomodle groups divide randomly into six groups, including the lowdosage group of Dahuang Zhechong Pill, the medium dosage group ofDahuang Zhechong Pill, the high dosage group of Dahuang ZhechongPill, the control group, the model group and the blank group. Studythe effects of Dahuang Zhechong Pill on Indexes in two model groups,including the tissue plasminogen activator (t-PA), plasminogenactivator inhibitor-1(PAI-1), D-Dimer, endothelin(ET), nitric oxidesynthase (NOS), thromboxane B_2 (TXB_2,), 6-keto-prostaglandin F_1α(6-K-PGF_1α), P-selectin and intrastruction of venous specimen forlight microscope and electron microscopic examination,ect.②Clinical Research:to study the effects of Dahuang Zhechong Pill onrelated Indexes on the patients with the deep venous postthromboticsyndrome, for example: photoplethysmography , hemagglutination test,P-selectin, tissue plasminogen activator (t-PA), thromboxane B_2(TXB_2),Ⅷfactor antigen (VWF-Ag), 6-keto-prostaglandin F_1α(6-K-PGF_1α),ect.
Findings:
1、Experimental Study
With respects to related indexes and ultrastructure ,the studyshows that there was significant difference between the venousthrombosis model group and the damaged venous model group.
①Dahuang Zhechong Pill has regulatory effect in the content oft-PA of the first model group and the second model group. It also candecrease the contents of PAI-1 and D-Dimer of the first model groupand the second model group. There was significant differencebetween the first model groups and the model group(p＜0.05). Therewas significant difference between the second model group and themodel group(p＜0.05).There was no difference between the firstmodel group and the blank group (p＞0.05). There was no differencebetween the second model group and the blank group (p＞0.05).Therewas no difference between the first model group and the secondmodel group(p＞0.05).
②Dahuang Zhechong Pill can increase the content of TNOS of thefirst model group and the second model group, but it can decrease thecontent of iNOS in both the first model group and the second modelgroup. There was significant difference between the first modelgroup and the model group(p＜0.05). There was significant differencebetween the second model group and the model group(p＜0.05). Therewas no difference between the blank group and the first group(p＞0.05). There was no difference between the blank group and thesecond group (p＞0.05). There was no difference between the firstmodel group and the second venous model group(p＜0.05).
③Dahuang Zhechong Pill can increase the content of 6-K-PGF1_aof the first model group and the second group, but it can decrease thecontents of TXB_2, and ET in the first model group and the secondmodel group. There was significant difference between the firstmodel group and the model group(p＜0.05). There was significantdifference between the second model group and the model group(p＜0.05). There was no difference between the blank group andthe first group (p＞0.05). There was no difference between the blankgroup and the second group (p＞0.05). There was no differencebetween the first model group and the second venous modelgroup(p＜0.05).
④Dahuang Zhechong Pill has negative effect in the quantity ofP-selectin of the first model group and the second model group. Therewas significant difference between the first model groups and thecontrol group(p＜0.05). There was significant difference between thesecond model group and the control group(p＜0.05). There wassignificant difference between the first model groups and the modelgroup(p＜0.05). There was significant difference between the secondmodel group and the model group(p＜0.05).There was significantdifference between the first model groups and the blankgroup(p＜0.05). There was significant difference between the secondmodel group and the blank group(p＜0.05).
⑤To study the intrastructions for light microscope examinationand electron microscopic examination,the study shows that DahuangZhechong Pill has an obvious inhibiting effect on thrombosis,and hasprotective effects on endothelial cells.
2、Clinical Study
Dahuang Zhechong Pill has positive remarkedly effects onrelated indexes. Though observing 32 example cases,the study showsthat symptoms and physical signs obvious change for the better afterthe treatment. The related indexes, such as PT, APTT, FIB, P-selectin,t-PA, TXB_2, 6-K-PGF_1α, VWF-Ag,ete,had improved. The results havethe significance after statistics processing.
Conclusions:
1.Experimental study shows that Dahuang Zhechong Pill canimproved the related indexes on the venous thrombosis model group and the damaged venous model group. Dahuang Zhechong Pill has anobvious inhibiting effect on thrombosis,and has protective effects onendothelial cells and vascular repair.
2. Clinical study show that Dahuang Zhechong Pill is a kind ofeffective and reliable medicine for treating patients with DVTS. Thestudy is a new application of old herb prescription, and has providedthe science objective basis for Dahuang Zhechong Pill of clinicalapplication in angiopathy field.
引文
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