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胆舒胶囊治疗慢性胆囊炎和胆结石的临床效果及安全性
DOI: 10.3969/j.issn.1001-5256.2022.09.025
伦理学声明：本研究于2016年12月15日经由上海市普陀区中心医院伦理委员会审批，批号：20170011，所纳入患者均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：彭雪莲负责撰写论文；彭雪莲、徐小青、曹勤负责收集、处理数据；曹勤负责拟定写作思路并指导完成。
Clinical efficacy and safety of Danshu Capsule in treatment of chronic cholecystitis and gallstones
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摘要:
目的 通过一项大样本、多中心、开放性真实世界研究, 全面评价胆舒胶囊治疗慢性胆囊炎、胆囊结石的疗效和安全性。 方法 选取2017年1月-2019年12月全国329家医院的慢性胆囊炎、胆结石患者9579例, 分为胆结石组(n=1148)、慢性胆囊炎组(n=5360)和慢性胆囊炎伴胆结石组(n=3071)。所有患者均服用胆舒胶囊, 3次/d, 1~2粒/次, 饭后口服, 持续治疗4周。记录服药前及治疗结束时的腹痛特征、胆源性消化不良症状、中医证候以及胆囊影像学指标, 以评价治疗前后用药效果; 观察并记录药物不良反应以评价药物安全性。非正态分布的计量资料治疗前后指标变化比较采用Wilcoxon符号秩和检验, 组间比较采用Wilcoxon秩和检验方法。计数资料治疗前后指标变化比较采用配对χ2检验, 多组间比较采用Kruskal-Wallis H法, 进一步两两比较采用Logistic回归分析和Nemenyi检验。 结果 经胆舒胶囊干预后, 所有患者脂餐诱发疼痛总发生率较治疗前明显下降(χ2=32.422, P < 0.001);疼痛发作频率、疼痛持续时间、疼痛程度评分均明显低于治疗前(Z值分别为-1.985、-2.887、-3.178, P值均 < 0.05);腹胀、饱胀、嗳气、恶心症状评分较治疗前均明显下降(P值均 < 0.001), 胆源性消化不良症状总分明显下降(Z=-4.128, P < 0.001);右上腹痛、口苦、泛酸、胸闷不舒、脘腹胀闷、食少纳呆、肢体困重等中医证候评分均较治疗前明显下降(P值均 < 0.05), 中医证候评分总分明显下降(Z=3.860, P < 0.001)。亚组分析结果显示, 胆结石组、慢性胆囊炎组、慢性胆囊炎伴胆结石组疼痛程度、频率、持续时间, 以及胆源性消化不良和中医证候评分较治疗前均明显下降(P值均 < 0.05), 治疗后脂餐诱发疼痛的患者占比均明显减少(P值均 < 0.001)。慢性胆囊炎组的疼痛发作频率评分、疼痛持续时间评分、疼痛程度评分下降幅度高于其他两组, 差异均有统计学意义(P值均 < 0.05)。超声检查结果显示, 经治后所有患者胆囊透声不佳、胆囊壁厚度及胆囊壁增厚或毛糙的发生率均明显降低, 胆囊结石数目和直径均明显减小(P值均 < 0.05);胆舒胶囊改善胆囊壁病变的总有效率为74.75%, 改善胆囊结石的总有效率为67.40%。84例患者报告了不良事件, 主要为消化系统症状, 不良事件的总发生率为0.87%。 结论 胆舒胶囊可以显著缓解慢性胆囊炎、胆结石患者的疼痛症状, 改善胆源性消化不良症状、中医证候及胆囊影像学指标, 且不良反应发生率低, 是治疗慢性胆囊炎和胆结石安全有效的药物。 Abstract:Objective To investigate the clinical efficacy and safety of Danshu Capsule in the treatment of chronic cholecystitis and gallstones through a large-sample, multicenter, open-label real-world research. Methods A total of 9579 patients with chronic cholecystitis and/or gallstones who were treated in 329 hospitals of China from January 2017 to December 2019 were enrolled and divided into gallstones group with 1148 patients, chronic cholecystitis group with 5360 patients, and chronic cholecystitis+gallstones group with 3071 patients.All patients were treated with oral administration of Danshu Capsule at a frequency of 1-2 capsules/time, three times a day after meals, for 4 consecutive weeks.Abdominal pain, biliary dyspepsia, traditional Chinese medicine (TCM) syndromes, and imaging findings of the biliary system were recorded before and after treatment to evaluate the efficacy of medication, and adverse drug reactions were monitored to evaluate the safety of Danshu Capsule.The Wilcoxon signed-rank test was used for comparison of non-normally distributed continuous data before and after treatment, and the Wilcoxon rank-sum test was used for comparison between any two groups.The paired chi-square test was used for comparison of categorical data before and after treatment; the Kruskal-Wallis H method was used for comparison between multiple groups, and the Logistic regression analysis and the Nemenyi test was used for further comparison between two groups. Results After treatment with Danshu Capsule, all patients had significant reductions in the overall incidence rate of pain induced by lipid meal (χ2=32.422, P < 0.001), the frequency, duration, and degree of pain (Z=-1.985, -2.887, and-3.178, all P < 0.05), the symptom scores of abdominal distension, abdominal fullness, belching, and nausea (all P < 0.001), and the total symptom score of biliary dyspepsia (Z=-4.128, P < 0.001);there were also significant reductions in the TCM syndrome scores of right upper quadrant pain, bitter taste, acid regurgitation, chest distress, abdominal distension, poor appetite, and heaviness of limbs (all P < 0.05) and a significant reduction in total TCM syndrome score (Z=3.860, P < 0.001).Subgroup analysis showed that after treatment, the gallstones group, the chronic cholecystitis group, and the chronic cholecystitis+gallstones group had significant reductions in the degree, frequency, and duration of pain, the symptom score of biliary dyspepsia, and TCM syndrome score (all P < 0.05), as well as a significant reduction in the number of patients with pain induced by lipid meal (P < 0.001).The chronic cholecystitis group had significantly greater reductions in the score of pain frequency, the score of pain duration, the score of pain degree compared with the other two groups (all P < 0.05).Ultrasound examination showed that after treatment, all patients had significant reductions in poor sound transmission of gallbladder, gallbladder wall thickness, incidence rate of gallbladder wall thickening or roughness, and the number and size of gallstones (all P < 0.05).Danshu Capsule showed an overall response rate of 74.75% in the treatment of gallbladder wall lesion and an overall response rate of 67.40% in the treatment of gallstones.A total of 84 patients reported adverse events, mainly gastrointestinal symptoms, and the overall incidence rate of adverse reactions was 0.87%. Conclusion Danshu Capsule can significantly alleviate the symptom of pain and improve the symptoms of biliary dyspepsia, TCM syndrome, and gallbladder imaging findings in patients with chronic cholecystitis and/or gallstones, with a low incidence rate of adverse reactions, and therefore, it is a safe and effective drug for the treatment of chronic cholecystitis and gallstones. -
Key words:
- Cholecystitis /
- Choledocholithiasis /
- Drug Therapy
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表 1 治疗前后疼痛症状情况比较
Table 1. Comparison of pain symptoms before and after treatment
项目 治疗前 治疗后 统计值 P值 脂餐诱发疼痛[例(%)] 6593(68.83) 2019(21.08) χ2=32.422 ＜0.001 疼痛发作频率评分(分) 3(1~6) 1(2~4) Z=-1.985 0.047 疼痛持续时间评分(分) 4(2~8) 0(0~2) Z=-2.887 0.003 疼痛程度评分(分) 4(3~7) 1(0~3) Z=-3.178 0.001 
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表 2 治疗后疼痛缓解起效时间
Table 2. The onset time of pain relief after treatment
用药后疼痛缓解起效时间 例(%) 疼痛无明显缓解 177(1.85) ＞1 h 2421(25.27) ＞30 min 3627(37.86) ＞20 min 2979(31.10) ＞10 min 212(2.21) 未评价 163(1.70)
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表 3 治疗前后胆源性消化不良症状评分比较
Table 3. Comparison of the symptom score of biliary dyspepsia before and after treatment
评价指标 治疗前 治疗后 Z值 P值 总分(分) 6(4~6) 2(0~4) -4.128 ＜0.001 腹胀(分) 2(2~6) 0(2~4) -5.254 ＜0.001 饱胀(分) 2(2~4) 0(0~2) -3.768 ＜0.001 嗳气(分) 2(2~4) 0(0~2) -4.499 ＜0.001 恶心(分) 2(0~4) 0(0~2) -4.526 ＜0.001
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表 4 治疗前后中医证候评分比较
Table 4. Comparison of TCM syndrome score before and after treatment
评价指标 治疗前 治疗后 Z值 P值 右上腹痛(分) 2(1~4) 0(0~2) -2.154 0.031 口苦(分) 2(1~3) 0(0~2) 1.903 0.044 恶心(分) 2(0~3) 1(0~2) 2.870 0.037 嗳气(分) 1(1~3) 1(0~2) 3.005 0.003 泛酸(分) 1(0~3) 0(0~2) 2.162 0.031 胸闷不舒(分) 1(0~3) 0(0~1) 2.921 0.003 脘腹胀闷(分) 2(1~3) 0(0~1) 2.021 0.043 食少纳呆(分) 1(1~3) 0(0~1) 2.043 0.041 肢体困重(分) 1(0~2) 0(0~1) 2.351 0.019 总分(分) 6(3~8) 1(1~3) 3.860 ＜0.001
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表 5 基于影像学结果的总体疗效评价
Table 5. Evaluation of overall therapeutic efficacy based on radiological results
项目 例数 痊愈 显效 有效 无效 总有效 胆囊壁病变[例(%)] 8177 4875(59.61) 934(11.42) 303(3.71) 2065(25.30) 6112(74.75) 胆囊结石[例(%)] 2721 1470(54.02) 225(8.27) 139(5.11) 887(32.60) 1834(67.40)
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表 6 胆囊壁病变、胆囊结石数目及直径比较
Table 6. Comparison of gallbladder wall lesion and the number and diameter of gallstones
项目 治疗前 治疗后 统计值 P值 胆囊透声不佳[例(%)] 3361(35.09) 1536(16.04) χ2=20.797 ＜0.001 胆囊壁 增厚[例(%)] 4916(51.32) 1648(17.20) χ2=23.278 ＜0.001 毛糙[例(%)] 6700(69.94) 2370(24.74) χ2=32.116 ＜0.001 厚度(mm) 4.2(1.3~5.4) 2.5(0.5~3.2) Z=2.070 0.038 胆囊结石 数目(个) 4(2~8) 3(2~5) Z=3.005 0.003 直径(cm) 0.7(0.3~1.2) 0.5(0.3~0.8) Z=2.162 0.031
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表 7 不同亚组临床获益分析与比较
Table 7. Comparison of clinical benefits between different subgroups
组别 疼痛程度评分(分) 疼痛发作频率评分(分) 疼痛持续时间评分(分) 胆源性消化不良评分(分) 中医证候总分(分) 胆结石组(n=1148) 治疗前 3.1(1.5~4.4)1)2) 2.9(0.9~4.4)1)2) 2.0(1.0~3.5)1)2) 6.2(4.8~8.3)2) 7.4(5.6~10.3)2) 治疗后 0.7(0.3~1.9)3) 0.7(0.1~1.9)3) 0.5(0.2~1.7)3) 1.5(0.5~2.6)3) 1.4(0.3~2.7)3) 较治疗前变化 -2.2(-3.4~-0.9)1)2) -1.9(-3.7~-0.7)1)2) -1.6(-2.8~-0.7)1)2) -5.6(-6.8~-4.2)1) -6.6(-8.4~-5.3)1) 慢性胆囊炎组(n=5360) 治疗前 2.8(1.7~4.0)2) 2.4(1.2~3.7)2) 2.2(1.1~4.4)2) 6.4(4.5~8.3)2) 7.9(5.8~9.3)2) 治疗后 0.3(0.1~1.5)3) 0.3(0.1~1.6)3) 0.2(0.1~1.5)3) 0.7(0.4~1.8)3) 0.6(0.3~2.0)3) 较治疗前变化 -2.8(-4.0~-0.7)2) -2.3(-3.9~-1.0)2) -2.0(-3.3~-0.8)2) -4.7(-6.5~-2.3)2) -5.8(-7.7~-3.5)2) 慢性胆囊炎伴胆结石组(n=3071) 治疗前 3.8(1.8~6.5)1) 3.9(1.5~5.5)1) 3.6(1.9~5.5)1) 7.1(5.2~9.2)1) 9.4(6.7~-12.3)1) 治疗后 0.5(0.3~1.7)3) 0.5(0.2~1.8)3) 0.6(0.4~1.5)3) 0.9(0.7~2.2)3) 1.3(1.0~2.5)3) 较治疗前变化 -2.3(-3.5~-1.3)1) -2.0(-3.3~-1.1)1) -1.9(-3.0~-0.8)1) -4.8(-6.9~-3.1)1) -6.4(-8.3~-4.5)1) 注：与慢性胆囊炎组比较，1)P＜0.05；与慢性胆囊炎伴胆结石组比较，2)P＜0.05；与治疗前比较，3)P＜0.05。
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表 8 不同亚组脂餐诱发疼痛及疼痛缓解起效情况比较
Table 8. Comparison of pain induced by high-fat diet and the onset time of pain relief between different subgroups
项目 胆结石组(n=1148) 慢性胆囊炎组(n=5360) 慢性胆囊炎伴胆结石组(n=3071) 脂餐是否诱发疼痛[例(%)] 治疗前选“是” 730(63.59) 3474(64.81) 2389(77.79)2) 治疗后选“是” 273(23.78)1)2) 933(17.41)1) 813(26.47)1)2) 用药后疼痛缓解起效时间[例(%)] ＞30 min 424(36.93) 2061(38.45) 1142(37.19) ＞20 min 367(31.97) 1657(30.91) 955(31.10) ＞1 h 292(25.44) 1328(24.78) 801(26.08) ＞10 min 22(1.92) 122(2.28) 68(2.21) 无明显缓解 16(1.39) 110(2.05) 51(1.66) 未评价 27(2.35) 82(1.53) 54(1.76) 注：与治疗前比较，1)P＜0.001；与慢性胆囊炎组比较，2)P＜0.05。
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表 9 不良事件发生情况
Table 9. Incidence of adverse events
部位 事件 例数 发生率(%) 消化系统 胃部寒凉不适 25 0.26 腹泻/排便次数增加 13 0.14 腹胀 12 0.13 口干口苦 11 0.11 嗳气 8 0.08 恶心呕吐 4 0.04 口腔或咽喉不适 3 0.03 腹痛 1 0.01 便秘 1 0.01 反酸 2 0.02 其他 头晕头疼 2 0.02 小便黄 1 0.01 皮疹 1 0.01 总计 84 0.87
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