Chinese herbal formula shen-ling-bai-zhu-san to treat chronic gastritis: Clinical evidence and potential mechanisms

Table 1 Search strategy

Number	Search terms
1	Mesh descriptor (Medicine, Traditional) explode all trees
2	(Medicine, Chinese Traditional*): ti,ab,kw
3	Mesh descriptor(Drugs, Chinese Herbal) explode all trees,
4	((Chinese Drugs, Plant*) or (Chinese Herbal Drugs*) or (Herbal Drugs, Chinese*) or (Plant Extracts, Chinese*) or (Chinese Plant Extracts*) or(Extracts, Chinese Plant*)): ti,ab,kw
5	Mesh descriptor (shen-ling-bai-zhu) explode all trees
6	((shen-ling-bai-zhu powder*) or (shen-ling-bai-zhu formula*) or (shen-ling-bai-zhu decoction*) or (shen-ling-bai-zhu decoction*) or (Shen-ling-bai-zhu powder*) or (Shen-ling-bai-zhu formula*) or (Shen-ling-bai-zhu formula*)): ti,ab,kw
7	Or 1-6
8	Mesh descriptor: (Chronic gastritis) explode all trees
9	((Chronic gastritis*) or (Digestive System Diseases*) or (Gastrointestinal Diseases*) or (Gastroenteritis*) or (Gastritis*) or (Chronic, gastritis*)): ti, ab, kw
10	Or 8-9
11	Mesh descriptor: (randomized controlled trials) explode all trees
12	(random*) or (randomly*) or (allocation*) or (random allocation*) or (placebo*) or (double blind*) or (clinical trials*) or (randomized control trial*) or (RCT*) or (controlled clinical trials*): ti, ab, kw
13	Or: 11-12
14	7 and 10 and 13

Table 2 Excluded 11 studies after reading the full text

Reason	Ref. (n = 11)
Intervention combined with other decoction (n = 3)	Li GS. Observation on the curative effect of Shenling Baizhu Powder and Taohong Siwu Decoction in treating chronic gastritis. Zhongyi Linchuang Zazhi 2007; 19 (10): 260-261
	Yang Y. Shenlingbaizhu san and zhaqupingwei powder combined with western medicine in the treatment of chronic gastritis randomized paraller controlled study. Shiyong Zhongyi Neike Zazhi 2013; 27 (10): 40-41
	Yang SX. Clinical study on the treatment of Chronic functional diarrhea with Shenling Baizhu Powder and Lizhong Decoction. Yatai Chuantong Yixue 2017; 30 (13): 145-146
Intervention combined with other decoction, no diagnostic criteria (n = 2)	Jin JZ. Shenling Baizhu Powder and Zuojin pill to treat chronic gastritis. Shiyong Zhongyi Neike Zazhi 2011; 27 (11): 752
	Gao CZ, Yang SM. Observation on curative effect of cefaclor combined with Shenlingbaizhu granule and Muxiang Shunqi pill in treating chronic gastritis. Zhonghua Yixue Chuangxin Zazhi 2012; 9 (22): 127-128
No diagnostic criteria (n = 1)	Shi ZR. Clinical observation on 8 cases of chronic gastritis treated by Shenling Baizhu Powder. Neimenggu Zhongyi Zazhi 2014 [DOI: 10.16040/j.cnki.cn15-1101.2014.07.024]
Not CG(n = 1)	Zhang WW. Clinical observation on 96 cases of spleen deficiency and stomachache treated with Shenling Baizhu Powder. Zhongguo Minzuyixue Yu Minzuyaoxue 2013; 9 (12): 80
Intervention combined with acupuncture (n = 3)	Yang FX. Acupuncture combined with Shenling Baizhu Powder to treat chronic gastritis with spleen deficiency and dampness. Kouqiang Yixue Dianzi Zazhi 2015; 6 (13): 140-143
	Wu XR. 30 cases of chronic gastritis with spleen deficiency and dampness treated by acupuncture combined with Shenling Baizhu Powder. Guangming Zhongyi 2015; 30 (5): 1018-1020
	Wu CY. Analysis of curative effect of acupuncture combined with Shenling Baizhu Powder on chronic gastritis with spleen deficiency and dampness. Jixu Yixue Jiaoyu Zazhi 2019; 33 (10): 161-162
Intervention combined with other decoction, WM are inconsistent in two groups (n = 1)	Yan Z. Clinical study of cefaclor combined with Shenling Baizhu granule and Muxiang Shunqi pill in treating chronic gastritis. Yatai Chuantong Yixue 2015; 11 (18): 106-107

Table 3 Characteristics of included studies

Ref.	Study design	Sample size (E/C)	Gender (E/C) and age (yr)	Duration	Interventions		Period	Outcome measure	Balance report of baseline
					Control group	Experimental group
Yun[27], 2014	RCT	48 (24/24)	(13/11) (10/14); (34.96 ± 11. 39)/(34.08 ± 12.82)	Not mentioned	Rabeprazole enteric-coated capsule	Rabeprazole enteric-coated capsule + SLBZD	4 wk	Effective rate	P > 0.05
Chen et al[28], 2014	RCT	79 (40/39)	(24/16) (23/16); (42.6 ± 13.1)/43.5 ± 13.4	6-17 mo/6-19 mo	Triple therapy (clarithromycin sustained-release tablets + rabeprazole sodium capsule + metronidazole tablets)	Triple therapy + SLBZD	4 wk	Effective rate	P > 0.05
Chen et al[29], 2018	RCT	60 (30/30)	(14/16) (15/15); (55.45 ± 6.55)/(55.46 ± 6.44)	3-12 mo	Quadruple therapy (rabeprazole sodium capsule + amoxicillin + clarithromycin sustained-release tablets + biskalcitrate)	Quadruple therapy + SLBZD	8 wk	Effective rate; H. Pylori eradication; adverse event	P > 0.05
Du[30], 2017	RCT	48 (26/22)	(14/12) (12/10); (40.7 ± 6.1)/(41.2 ± 6.6)	7 mo-9 years/6 mo-8 years	Quadruple therapy (amoxicillin clavulanic potassium chewable tablets + metronidazole + omeprazole + compound bismuth aluminate capsule)	SLBZD	5 wk	Effective rate	P > 0.05
Gu[31], 2017	RCT	98 (49/49)	Not mentioned; 19-58	Not mentioned	Triple therapy (omeprazole + clarithromycin + amoxicillin)	Triple therapy + SLBZD	4 wk	Effective rate; H. Pylori eradication rate; adverse event	P > 0.05
Li et al[32], 2020	RCT	66 (33/33)	(19/14) (18/15); (58.54 ± 4.65)/(58.62 ± 4.57)	4-17 years/4-18 years	Triple therapy (mosapride tablet + polyzyme tablets + lansoprazole tablets)	Triple therapy + SLBZD	12 wk	Effective rate	P > 0.05
Tang[33], 2014	RCT	60 (30/30)	(16/14) (17/13); (22-46)/(23-52)	Not mentioned	Omeprazole enteric-coated capsules	Omeprazole Enteric-coated Capsules + SLBZD	8 wk	Effective rate	P > 0.05
Xia[34], 2015	RCT	300 (150/150)	Not mentioned; 18-85	Not mentioned	Omeprazole enteric-coated capsules	SLBZD	8 wk	Effective rate; recurrence rate; adverse event	P > 0.05
Xu et al[35], 2018	RCT	60 (30/30)	(17/13) (16/14); (55.6 ± 16.4)/(56.8 ± 14.9)	4-20 years/4-19 years	Triple therapy (mosapride tablet + polyzyme tablets + lansoprazole tablets)	Triple therapy+SLBZD	12 wk	Effective rate	P > 0.05
Zhang et al[36], 2020	RCT	68 (34/34)	(15/19) (17/17); (44.8 ± 5.0)/(45.2 ± 5.4)	1-12 years/2-14 years	Combination therapy (omeprazole + compound bismuth aluminate granules)	Combination therapy + SLBZD	8 wk	Effective rate; adverse events	P > 0.05
Zhao and Lin[37], 2010	RCT	80 (40/40)	(37/3) (38/2); (46.2 ± 6.7)/(44.2 ± 5.7)	2-7 years/2-8 years	No alcohol, famotidine	No alcohol, famotidine + SLBZD	4 wk	Effective rate;	P > 0.05
Zheng[38], 2014	RCT	92 (46/46)	(28/18) (30/16); ( 34 ± 5.34)/( 33 ± 5.76)	5 mo-6 years/7 mo-6 years	Triple therapy (amoxicillin dispersion tablet + omeprazole enteric-coated capsules + clarithromycin tablet)	SLBZD	4 wk	Effective rate; adverse events; recurrence rate	P > 0.05
Zhuang et al[39], 2019	RCT	106 (53/53)	(65/41); (46.20 ± 8.75)	1-11 years	Triple therapy (omeprazole enteric-coated tablets + clarithromycin dispersible tablets+amoxil capsule)	Triple therapy + SLBZD	4 wk	Effective rate; H. Pylori’s negative conversion rate	P > 0.05
Zou[40], 2015	RCT	170 (85/85)	(86/84); (40.9 ± 11.1)	Not mentioned	Triple therapy (amoxicillin + clarithromycin + omeprazole)	Triple therapy + SLBZD	8 wk	Effective rate; H. Pylori’s negative conversion rate; recurrence rate	P > 0.05

RCT: Randomized controlled trial; H. Pylori: Helicobacter pylori; SLBZS: Shen-ling-bai-zhu san.

Table 4 Methodological quality details of all included studies

Ref.	Baseline	Randomization	Allocation concealment	Blind method	Withdrawal or dropped-out	Follow up	Protocol and registration	Ethics committee approved
Yun[27], 2014	Comparability	Random	NR	NR	NR	NR	NR	NR
Chen et al[28], 2014	Comparability	Random number table	NR	NR	NR	NR	NR	NR
Chen et al[29], 2018	Comparability	Random	NR	NR	NR	NR	NR	NR
Du[30], 2017	Comparability	Random	NR	NR	NR	NR	NR	NR
Gu[31], 2017	Comparability	Random	NR	NR	No cases withdrawal and dropped-out	NR	NR	Approved
Li et al[32], 2020	Comparability	Random	NR	NR	NR	NR	NR	Approved
Tang[33], 2014	Comparability	Random	NR	NR	NR	NR	NR	NR
Xia[34], 2015	Comparability	Random	NR	NR	No cases withdrawal and dropped-out	Recurrence rate	NR	Approved
Xu et al[35], 2018	Comparability	Random	NR	NR	NR	NR	NR	NR
Zhang et al[36], 2020	Comparability	Random	NR	NR	NR	NR	NR	NR
Zhao and Lin[37], 2010	Comparability	Random	NR	NR	NR	NR	NR	NR
Zheng[38], 2014	Comparability	Random	NR	NR	NR	Recurrence rate	NR	NR
Zhuang et al[39], 2019	Comparability	Random number table	NR	NR	NR	NR	NR	NR
Zou[40], 2015	Comparability	Random number table	NR	NR	NR	Recurrence rate	NR	NR

NR: Not Reported.

Table 5 Subgroup analysis of total effectiveness

Subgroup method (total effective rate)	Items	Number of comparisons	Results (risk ratio, 95%CI)	P value for overall effect	I2	P value for subgroup difference
Course of treatment	All comparisons	14	1.29 (1.22,1.37)	< 0.00001	0%
Supplementary Table 1	4 wk	5	1.27 (1.17,1.37)	< 0.00001	0%
	5 wk	1	1.45 (1.04, 2.03)	0.03	NA	0.58
	8 wk	5	1.28 (1.16, 1.40)	0.02	0%
	12 wk	2	1.44 (1.19, 1.74)	0.0002	0%
Comparison type	All comparisons	14	1.23 (1.14, 1.32)	< 0.00001	47%
Supplementary Table 2	SLBZS vs CM	3	1.23 (1.10, 1.38)	0.0003	0%	0.93
	SLBZS + CM vs CM	11	1.23 (1.11, 1.35)	< 0.0001	57%
Intervention method	All comparisons	14	1.29 (1.22, 1.37)	< 0.0001	0%
Supplementary Table 3	Monotherapy	4	1.25 (1.12, 1.40)	< 0.0001	5%
	Combined therapy	1	1.41 (1.08, 1.84)	0.01	NA	0.82
	Triple therapy	7	1.30 (1.21,1.40)	< 0.0001	0%
	Quadruple therapy	2	1.35 (1.11, 1.64)	0.003	0%

NA: Not available; CM: Conventional medicine; SLBZS: Shen-ling-bai-zhu san.

Table 6 Adverse events

Study	Experiment group	Control group
Zhang, 2020	Diarrhea (2/34)	Dizziness (2/34) and dry mouth (1/34)
Chen, 2018	Headache (1/30), diarrhea (1/30), nausea (1/30)	Headache (2/30), diarrhea (1/30), nausea (2/30), constipation (1/30), rash (1/30)
Zheng, 2014	None	Headache and rash (17.39%)

Table 7 GRADE evidence for the effect of Shen-ling-bai-zhu san

Quality assessment							Summary of findings					Importance
							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	RQLQ	Control	Relative (95%CI)	Absolute
Effective rate
14	Randomized trials	Serious1	Serious2	Serious3	No serious imprecision4	None	595/670 (88.8%)	459/665 (69%)	RR 1.45 (1.22 to 1.37)	200 more per 1000 (from 152 more to 255 fewer)	Very low	Critical
								0.676		196 more per 1000 (from 149 fewer to 250 more)
Recurrence rate
3	Randomized trials	Serious1	Serious2	Serious3	No serious imprecision4	None	7/281 (2.5%)	31/281 (11%)	RR 0.24 (0.11 to 0.55)	84 fewer per 1000 (from 50 fewer to 98 fewer)	Very low	Important
								0.177		135 fewer per 1000 (from 58 fewer to 158 fewer)
HP negative conversion rate
4	Randomized trials	No serious limitations1	Very serious2	No serious indirections3	No serious imprecision4	None	207/217 (95.4%)	170/270 (78.3%)	RR 1.2 (1.11 to 1.3)	157 more per 1000 (from 86 more to 135 more)	Moderate	Important
								0.815		163 more per 1000 (from 90 more to 244 more)

¹Randomized controlled trial design method is not reported.

²The risk of bias assessment is mostly “unclear risk” because there are not enough details in articles.

³Studies come from China.

⁴There is significant heterogeneity between studies.