전체메뉴

Journal of Pharmacopuncture

Article Search

JoP

Review Article

Split Viewer

Article

Review Article

J Pharmacopuncture 2023; 26(2): 124-138

Published online June 30, 2023 https://doi.org/10.3831/KPI.2023.26.2.124

Copyright © The Korean Pharmacopuncture Institute.

Efficacy of Herbal Medicines on Lung Function in Asthma: a systematic review and meta-analysis of randomized controlled trials

Alireza Derakhshan1† , Masoumeh Sadeghi2† , Amir-Mohammad-Hashem Asnaashari3* , Mohsen Dehghani4 , Roshanak Salari1 , Majid Khadem-Rezaiyan5 , Majid Mirsadraee6 , Shahin Saeidinejat1* , Shima Jalali7 , Shabnam Jalali7

1Faculty of Traditional Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2Department of Epidemiology, Faculty of Health, Mashhad University of Medical Sciences, Mashhad, Iran
3Lung Disease Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
5Department of Community Medicine and Public Health, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
6Department of Internal Medicine, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran
7Department of Internal, Mashhad University of Medical Sciences, Mashhad, Iran

Correspondence to:Shahin Saeidinejat
Social Determinants of Health Research Center, Health School, Mashhad University of Medical Sciences, Shahid Fakoury Blvd, Mashhad 97165-91778, Iran
Tel: +98-915-5154-2384
E-mail: saeedish1@mums.ac.ir

Amir-Mohammad-Hashem Asnaashari
Lung Disease Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Shahid Fakoury Blvd, Mashhad 97165-91778, Iran
Tel: +98-915-110-5773
E-mail: AsnaashariAH@mums.ac.ir

These authors contributed equally to this work.

Received: September 14, 2022; Revised: September 20, 2022; Accepted: February 17, 2023

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives: The present study was designed to conduct a comprehensive systematic review and meta-analysis to assess the efficacy of herbal medicines as add-on therapy on lung function in asthmatic patients.
Methods: A comprehensive search of online databases was performed up to December 2021 to identify randomized controlled trials that used orally herbal preparations for asthma as add-on therapy. Studies were assessed for methodological quality using the Cochrane Collaboration’s Risk of Bias tool. The main outcome was percent predicted value of forced expiratory volume (% predicted FEV1). Pooled weighted mean difference (WMD) estimate with corresponding 95% confidence interval (CI) was calculated using inversevariance weights method while random effects meta-analysis was used, taking into account clinical and conceptual heterogeneity.
Results: As a result, 1,525 studies were identified. 169 studies were reviewed in-depth and 23 studies met our systematic review inclusion criteria. Finally, nine randomized controlled trials were included in the meta-analysis. Findings indicated that use of herbal medicines in patients with asthma significantly improved % predicted FEV1 (WMD: 3.73, 95% CI: 1.76-5.70), with no evidence for significant heterogeneity (p = 0.56 [Q statistic], I2 = 0.0%). In subgroup analysis by age, improvement in % predicted FEV1 was higher and significant in adults (WMD: 5.16; 95% CI: 2.68-7.63) compared to children (WMD = 1.27; 95% CI: −1.98-4.51). Sensitivity analysis showed the significant effect of herbal medicine consumption on improving FEV1 was consistently (range of summary WMDs: 3.27-4.59), indicating that the meta-analysis model was robust. There was no evidence of publication bias both visually and statistically.
Conclusion: Findings support, the complementary use of herbal medicines resulted in significant improvement in the lung function compared to standard treatment in asthmatic patients with no considerable adverse events. This improvement is more likely to be observed amongst adults.

Keywords: persian medicine, asthma, herbal drug, forced expiratory volume, meta-analysis

INTRODUCTION

Asthma is a chronic disease that can be controlled by a variety of medications, which can reduce airway inflammation and smooth muscle spasm, in the absence of a definitive cure [1]. There is a long history of using herbal remedies for asthma, with some common asthma medications, such as anticholinergics, β2 agonists, and methylxanthines, having natural sources [2, 3]. In recent decades, the use of herbal medicines in asthma management has increased, particularly for traditional medicine such as Chinese, Korean, and Iranian medicine, where many different formulations have been used to treat asthma [4-6]. However, despite the multiplicity of drug formulations in traditional medical texts, few studies have analyzed their effectiveness and possible side effects [7-10]. Given the popularity of herbal medicines in recent years, it seems necessary, therefore, to evaluate the performance of these traditional remedies as well as their side effects [10-14]. The physiologic effects of medicinal plants vary depending on the plant or the various compounds within each formulation. The mechanisms of their effectiveness are complex, but experimental evidence does suggest that traditional formulations can reduce bronchospasm, airway inflammation, mucus buildup, and hyperresponsiveness in asthma patients [15-17].

There are several studies regarding the effects of herbal medicines on asthma. Most studies have examined the effect of one type of botanical plant in the treatment of asthma [2, 3, 6, 8-11, 15-26]. Few studies have investigated the effect of herbal remedies on asthma in general [27-32], although several studies have confirmed the effectiveness of herbal drugs in the treatment of asthma [33-37]. However, conflicting findings have also been observed from studies countries such as the USA, Brazil, the UK, New Zealand, and many Asian countries, although the variations in patient age, sample size, type of treatment, and other factors, could account for the inconsistencies in the findings.

Considering the conflicting results on the effect of herbal medicine on the predicted value of forced expiratory volume in asthmatic patients, there is value in conducting a comprehensive systematic review since it is vital to determine whether oral herbal preparations as add-on therapies for asthma can be effective in respiratory function tests. In addition, increasing the percent-predicted forced expiratory volume in one second (FEV1) output is vitally important. Therefore, we aimed to quantify the efficacy of herbal medicines on the predicted value of FEV by conducting a meta-analysis of relevant randomized controlled trials (RCTs). We conducted subgroup analyses based on patients’ ages and considered the methodological limitations of the included studies and determined the potential sources of heterogeneity across the studies both statistically and clinically.

MATERIALS AND METHODS

This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021268901, https://www.crd.york.ac.uk/PROSPERO/). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to review trials and to conduct and report the current systematic review and meta-analysis [38].

1. Search strategy

A comprehensive search of online electronic databases (Medline, Cochrane Library, EMBASE, Web of Science, and Scopus) was performed up until December 2021. The search was limited to blinded RCTs published in English. MeSH keywords were as follows: “herb” OR “herbal” OR “botanical” OR “medicinal plants” OR “Phototherapy” OR “Phytomedicine” OR “traditional medicine” AND “asthma” OR “dyspnea.” Reference lists of retrieved studies and previously published reviews as well as gray literature were also reviewed in order to identify other relevant RCTs. Duplicate studies and publications were removed. The numbers and names of the authors (reviewers) who conducted the search, extracted the data, and assessed study quality were mentioned in the “search strategy,” “data extraction,” and “risk of bias assessment” sections, respectively. In order to resolve any disagreements, the authors first discussed among themselves, and any unresolved issues were arbitrated by a methodologist (third person). A comprehensive search of electronic databases as well as a reference list of retrieved studies was checked for additional pertinent studies.

2. Selection criteria

The RCTs included in this systematic review had to use orally administered herbal preparations for asthma. Patients of any sex or age, which were randomly assigned to either an intervention group (herbal medicines as add-on therapy to standard treatments) or a control group (standard treatment only or placebo with standard treatment) were considered in the review. Original, peer-reviewed RCTs, were included while single-arm before-after clinical trials were excluded. Interventions included oral herbal therapy plus standard treatment for at least one week. Herbs are defined as either the entire plant or roots, bark, stems, flowers, or fruits, which have been used as crude plants or extracts. The main outcomes of the present systematic review were respiratory function test parameters including FEV1 or peak expiratory flow rate (PEFR).

The reporting of PEFR data in some studies was neither accurate nor sufficient. Most studies reported either absolute or percent-predicted values of FEV1 or both. However, our meta-analysis only included studies that reported percent-predicted values of FEV1. Studies that did not provide data on the mean and standard deviation of predicted FEV1 in each intervention and control group were excluded. The diagnosis of asthma in the included studies was based on the Global Asthma Initiative (GINA) or equivalent criteria, such as an expert consensus-based assessment of symptoms and a respiratory function test, as determined by the results of the included studies [39, 40]. Cough-variant asthma, drug-induced asthma, and acute exacerbations of asthma were excluded. Persistent and moderate-to-severe asthma were also excluded from the meta-analysis in order to homogenize the study population in included studies. All designs and study types that were not RCTs were excluded from this review. Fig. 1 displays a flow diagram showing how the studies were selected.

Figure 1. PRISMA flow diagram for selection of studies.

3. Data extraction and risk of bias assessment

The main characteristics of the included studies in this systematic review were author’s name, year, country, gender, age, study population, duration of follow-up, herbal name and form, respiratory function tests, mean and standard deviations, sample size for intervention and control groups, and study quality. Two reviewers (SS, MM) independently extracted data from all studies, and any discrepancies between investigators were resolved by discussion or after arbitration by a third reviewer (MS). The methodological quality (risk of bias) of the included RCTs was assessed using the Cochrane Collaboration’s Risk of Bias tool [41]. The seven risk areas that were rigorously assessed were sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases. Studies included in the systematic review were considered for “low risk,” “unclear risk,” or “high risk” of bias by two methodologist reviewers (MS, MD), with any discrepancies resolved by consensus.

4. Statistical analysis

Most RCTs report FEV1 (absolute volume or percent-predicted value) as the primary clinical outcome and consider it as a continuous variable. Studies that provided sufficient data on sample size, mean, and standard deviation/error of percent-predicted values for FEV1 in each intervention group and control group were included in the meta-analysis. Mean differences and 95% confidence intervals (CIs) were calculated using data from each study. Pooled weighted mean difference (WMD) was estimated, with the corresponding 95% CIs calculated using inverse variance weighting [42]. A random-effects meta-analysis was used to account for conceptual and clinical heterogeneity between studies, with a Forest plot displaying the WMD and corresponding 95% CIs for visual inspection across studies. Heterogeneity between studies was assessed using the I2 statistic [43] (I2 = 0% means no observed heterogeneity and I2 ≥ 50% indicates substantial heterogeneity), while Cochran’s Q statistic was used to analyze the statistical significance of the heterogeneity [44]. Sensitivity analysis was performed by successively removing a specific study or group of studies to find which study (if any) had the greatest impact on the pooled estimates and to assess the robustness of the pooled results.

A subgroup meta-analysis on the effect of herbal remedies on the percent-predicted FEV1 by age group in asthmatic patients (adults and children) was also performed. Visual inspection of funnel plots was performed to assess publication bias [45], i.e. WMD was plotted against the inverse of the square of the standard error (a measure of study precision). The funnel plots were inspected visually to assess publication bias. Egger’s regression asymmetry test and Begg’s adjusted rank correlation test were also performed [46, 47]. All statistical analyses were performed using Stata version 14.0 software (Stata Corp., College Station, TX, USA). Statistical tests were two-tailed, and significance levels were considered as less than 0.10 for analyses.

RESULTS

A comprehensive literature search identified 1,525 relevant studies. After removing duplicates and screening of titles and abstracts, 169 studies were selected for an in-depth full-text review (Fig. 1). Twenty-three RCTs have pre-determined eligibility criteria for inclusion in the systematic review with 2,584 participants. Finally, nine studies [7, 34-37, 48-51] were included in the meta-analysis that reported percent-predicted values of FEV1 as the main outcome with complete statistical data (Fig. 1).

Table 1 presents the main characteristics of the 23 RCTs [7, 34-37, 48-68]. All included studies used botanicals from Persian, Chinese, Ayurveda, European and South American Materia Medica that meet the inclusion criteria; used extracts or compounds derived from herbs, combine herbal medicine with the pharmacotherapy (add-on therapy) and treatment duration was more than one week.

M, male; F, female; NR, not reported; FEV1, forced expiratory volume 1th second; n, number of cases; sd, standard deviation..

&md=tbl&idx=1' data-target="#file-modal"">Table 1

Main characteristics of randomized controlled trials included in the systematic review.

Study, year
(country)
SexAgeStudy populationHerbal medicine nameOutcomeIntervention groupControl group


n1mean1sd1n2mean2sd2
Urata et al. [36], 2002 (Japan)M/F42 ± 7Patients with mild or moderate asthma, 4 weeks follow-upTJ-96 capsule, freeze dried powder of SaibokuFEV-11686.97.11782.15.6
Wen et al. [53], 2005M/F18-65Patients with moderate-severe allergic asthma, 4 weeks follow-upASHMI capsule of Ganoderma lucidum, Sophora flavescens, and Glycyrrhiza uralensisFEV-14684.3612.94688.4612.6
Chang et al. [54], 2006 (China)M/F5-20Patients with mild or moderate asthma, 24 weeks follow-upSTA-1 capsule of decoction of Rehmanniae Preparata, Cortex Moutan Radicis, Fructus Corni, Poria, Rhizoma Alismatis and Dioscoreae, Ophiopogonis, Glycyrrhizae, Panacis Quinquefolii and Tuber PinelliaFEV-14480.70NR1676.5NR
Chang et al. [54], 2006 (China)M/F5-20Patients with mild or moderate asthma, 24 weeks follow-upSTA-2 capsule of boiled of Rehmanniae Preparata, Cortex Moutan Radicis, Fructus Corni, Poria, Rhizoma Alismatis and Dioscoreae, Ophiopogonis, Glycyrrhizae, Panacis Quinquefolii and Tuber PinelliaFEV-14488.9NR1676.5NR
Wong et al. [51], 2009 (China)M/FLow than 18Patients with mild or moderate asthma, 24 weeks follow-upCUF2 capsule of Astragalus mongholius Bunge, Cordyceps sinensis Sacc., stemonae, Bulbus fritillariae cirrhosae, and scutellariaeFEV-1439615429619
Houssen et al. [34], 2010 (Egypt)M/F18-60Patients with mild or moderate asthma, 4 weeks follow-upCapsule of Glyserizia Glabra, Curcumim, Boswelic acidFEV-13972.7510.412468.413.62
Salem et al. [35], 2017(Saudi Arabia)M/F18-65Controlled asthmatic patients, 12 weeks follow-upNS-1 capsule of Black SeedFEV-12687.715.82480.820.6
Salem et al. [35], 2017(Saudi Arabia)M/F18-65Patients with mild or moderate asthma, 12 weeks follow-upNS-2 capsule of Black SeedFEV-12685.522.92480.820.6
Wang et al. [49], 2017(China)M/F18-60Patients with mild or moderate asthma, 12 weeks follow-upPCKLSachet of not reportedFEV-13673.214.33667.714.5
Hosseini et al. [48], 2018 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upCapsule of saffronFEV-14080.1512.594073.2112.15
Nejatbakhsh et al. [37], 2017 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upSyrup of Squill OxymelFEV-13871.4421.863861.6714.2
Nejatbakhsh et al. [37], 2017 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upSyrup of OxymelFEV-13861.1115.73861.6714.2
Chan et al. [7], 2006 (Taiwan)M/F8-15Children with mild or moderate asthma, 12 weeks follow-upDCT capsule of G. biloba, E. sinica,T. farfara, M. alba, P. ternata, P. frutescens, P. armeniaca, S. baricalensis, and G. uralensisFEV-12893.85102.712487.9798.53
Chan et al. [50], 2016(Taiwan)M/F6-18Children with mild or moderate asthma, 24 weeks follow-upYPFS sachet of not reportedFEV-12892.32.62995.32.7
Murali et al. [55], 2006 (India)M/F15-50Patients with moderate stable asthma, 12 weeks follow-upDCBT4567-Astha-15capsule of Woodfordia, Solanum xanthocarpum, Adathoda vasika, Acacia arabica, Ellateria cardamomum, Piper nigrum, Achyranthus aspera, Zingiber officinalis, Hollarhena antidysenterica, Curcuma longa, Syzygium aromaticum, Calotropis procera, Enicostemma littorale, Piper longumFEV-1191.690.52221.50.51
Rouhi et al. [56], 2006 (Pakistan)M/FNRPatients with low to severe asthma, 8 weeks follow-upOral drop of GingerFEV14647.31NR4645.31NR
Boskabady et al. [57], 2007 (Iran)M/F48.2 ± 11.9Patients with persistent mild or moderate asthma, 12 weeks follow-upCapsule of Black SeedFEV11529.4727.141430.324.31
Thomas et al. [59], 2007 (Scotland)M/F18-75Patients with persistent asthma, 12 weeks follow-upAKL1 capsules of not reporterNR16NRNR16NRNR
Watson et al. [60], 2008 (USA)M/F18-60Patients with asthma, 4 weeks follow-upTablet of purple passion fruitNR22NRNR21NRNR
Smith et al. [63], 2015 (USA)M/F> 12Patients with poor control asthma, 24 weeks follow-upTablet of Soy IsoflavoneFEV11932.393.681932.443.19
Kong et al. [64], 2017 (China)M/FNRPatients asthma, 48 weeks follow-upBSYQ capsule of RadixAstragali, HerbaEpimedii, RehmanniaeRadiNR109NRNR107NRNR
Kong et al. [64], 2017 (China)M/FNRPatients asthma, 48 weeks follow-upBSFCcapsule of Herba Epimedii, Rehmanniae Radi, Cuscutaesemen, soraleae, oraleacoryl., ioscorea opposita Citri Reticulatae AconitilateralisNR112NRNR107NRNR
Koshak et al. [65], 2017 (UK)M/F18-65Patients with mild or moderate asthma, 4 weeks follow-upNSO capsules of Black seedNR40NRNR40NRNR
Power et al. [66], 2017 (New Zealand)M/F18-75Patients with mild asthma, 4 weeks follow-upBFPE BerryfruitFEV1143.540.98143.561
Yugandhar et al. [67], 2018 (India)M/F21-60Patients with mild or moderate asthma, 6 weeks follow-upLi131019Fserrata, Marmelos fruitFEV1161.710.32131.540.22
Manarin et al. [68], 2019 (Brazil)M/F7-18Patients with persistent moderate to severe asthma, 8 weeks follow-upCapsule of Curcuma longaFEV140NRNR27NRNR
Hsu et al. [52], 2005(Taiwan)M/F5-18Patients with persistent mild or moderate asthma, 16 weeks follow-upMMDT40 mg/dayTuber Ophiopogonis Japonici, Panacis Quinquefoli. Tuber Pinellia, Rhizoma Pinellia Ternatae, Glycyrrhizae Uralensis, Herba Tridacis procumbentisFEV-14073.812.42070.213.7
Hsu et al. [52], 2005(Taiwan)M/F5-18Patients with persistent mild or moderate asthma, 16 weeks follow-upMMDT80 mg/dayTuber Ophiopogonis Japonici, Panacis Quinquefoli. Tuber Pinellia, Rhizoma Pinellia Ternatae, Glycyrrhizae Uralensis, Herba Tridacis procumbentisFEV-14087.712.62070.213.7

M, male; F, female; NR, not reported; FEV1, forced expiratory volume 1th second; n, number of cases; sd, standard deviation..



Symptom improvement was assessed in all studies. In 15 studies, one specific medicinal plant was used for the intervention. The single plants or their extracts which were used as interventions were Nigella sativa [35, 57, 65], Crocus sativus [48], Zingiber officinalis [56], Berry fruit polyphenolic extract [66], Magnoliae Flos [62], Aegle marmelos [67], Passiflora edulis [60], Saiboku [36], Sophora flavescens [58], Soy Isoflavone [63], Drimia maritima [37], Curcuma longa [68], and Viola odorata [69]. Combinations of several plants (between 3 and 15 components) were used in nine studies [7, 34, 52-55, 61, 62, 64], although the combined formulas were not mentioned in three studies [49, 50, 59]. Interventional medications used specific brands in 15 studies [7, 36, 49-55, 59, 61, 62, 64, 66, 67] with Glycyrrhiza (Licorice root), Rehmannia and Ginco Biloba, Curcuma longa, Zingiber officinale, and ginseng the most repeatedly used ingredients in these formulations. Nineteen studies used capsules, with the remaining studies using tablets [60, 63], powder [58], sachets [49, 50], syrups [37], or drops [56, 69]. All administration types were typical of herbal prescriptions and in appropriate dosages according to recommendations. Details of the type of drugs used as standard treatment, which were beta2 agonists and inhaled corticosteroids [58], theophylline [55, 57], oral corticosteroids [53], inhaled corticosteroids and oral theophylline [57] and Montelukast [50, 67], were only reported in five studies. Finally, the placebos, which were charcoal powder [35], boiled honey [37], lactose [34, 55], maltodextrin [50], virgin olive oil [65], and semi-roasted glucose solution [57], were only mentioned in seven studies.

The results of a random-effects meta-analysis of RCTs using Forest plots showed that herbal prescriptions significantly improved respiratory function test results in asthmatics (Fig. 2). The WMD of the percent-predicted FEV1 in asthma patients taking herbal medicines was 3.73 (95% CI: 1.76-5.70) compared with standard asthma medicines. There was no evidence for significant heterogeneity across studies (p = 0.56 [Q statistic], I2 = 0.0%). Subgroup meta-analysis by age demonstrated that there was substantial variation in the percent-predicted FEV1 levels between patients treated with herbal medicines and the control group in adults (WMD = 5.16, 95% CI: 2.68-7.63) compared with children (WMD = 1.27; 95% CI, –1.98-4.51). In other words, improvement in percent-predicted FEV1 was significantly higher in adult asthmatic patients compared with children. No statistical heterogeneity was found within any of the subgroups (Fig. 3). Sensitivity analysis by successively removing a particular study at a time to assess the influence of every single study on the pooled WMD showed that herbal medicines consistently and significantly improved percent-predicted FEV1 (range of summary WMDs: 3.27-4.59), indicating the robustness of our meta-analysis findings. A visual inspection and assessment of the funnel plot using statistical tests indicated that publication bias was unlikely in studying the effects of herbal medicines on respiratory function tests in asthmatics (Fig. 4). Also, statistical tests showed no evidence of publication bias both visually and statistically (p = 0.53, for Begg’s adjusted rank correlation test: 0.53 and p = 0.58, for Egger’s regression asymmetry test).

Figure 2. Forest plot of the efficacy of herbal medicine as add-on therapy on lung function (percent predicted FEV1) in patients with asthma using random effects meta-analysis. Diamond represents the summary weighted mean difference (pooled WMD) estimate and its width shows corresponding 95% CI with random effects estimate. The size of the square and its central point reflects the study specific statistical weight (inverse of variance) and point estimate of the WMD and horizontal line reflects corresponding 95% CI of the study. I2 test and Cochran’s Q statistic were used to assessing the statistical heterogeneity (p < 0.10) across studies.

Figure 3. Subgroup meta-analysis of the effect of herbal medicine on lung function (percent predicted FEV1) in patients with asthma based on patients’ age (adults vs. children).

Figure 4. Begg’s funnel plot for assessing the presence of publication bias. Weighted mean difference was plotted against the precision of the study (p = 0.53, for Begg’s adjusted rank correlation test and p = 0.58, for Egger’s regression asymmetry test).

Cochrane’s Risk of Bias (ROB) tool for randomized controlled studies was used to assess the risk of bias for all 23 studies included in the systematic review (Table 2). The results showed that 20% and almost half (48%) of the studies were placed at high and low risk of bias respectively. Sequence generation and allocation concealment were major problems in three studies, while only two studies had a bias regarding the selective outcome reporting area. The blinding of participants, personnel, and outcome assessors was accurately conducted in approximately half of the studies. The majority of the studies (about 90%) included in the meta-analysis were either in the unclear or low-risk bias categories.

+Low risk of bias, ?unclear risk of bias, -high risk of bias..

&md=tbl&idx=2' data-target="#file-modal"">Table 2

Risk of bias/methodological quality assessment of randomized controlled trials using Cochran risk of bias tool (ROB).

StudySequence generationAllocation concealmentBlinding of
participants & personnel
Blinding of
outcome assessor
Incomplete
outcome data
Selective outcome reportingOther sources of biasOverall bias
Urata et al. [36], 2002?????+??
Wen et al. [53], 2005????+++?
Chang et al. [54], 2006????+++?
Wong et al. [51], 2009????+++?
Houssen et al. [34], 2010--------
Salem et al. [35], 2017++??+++?
Wang et al. [49], 2017++++++++
Hosseini et al. [48], 2018++++++++
Nejatbakhsh et al. [37], 2017++++++++
Chan et al. [7], 2006++++++++
Chan et al. [50], 2016++++++++
Murali et al. [55], 2006????++++
Rouhi et al. [56], 2006--------
Boskabady et al. [57], 2007?????+--
Thomas et al. [59], 2007?????+??
Watson et al. [60], 2008????+++?
Smith et al. [63], 2015++--++--
Kong et al. [64], 2017++++++++
Koshak et al. [65], 2017----+++-
Power et al. [66], 2017++++++++
Yugandhar et al. [67], 2018++++++++
Manarin et al. [68], 2019++++++++
Hsu et al. [52], 2005++++++++

+Low risk of bias, ?unclear risk of bias, -high risk of bias..


DISCUSSION

Herbal compounds have a long history of treating asthma. The present systematic review and meta-analysis indicated that using herbal medicines as add-on therapy to standard treatment showed improvements in the respiratory function test, particularly the percent-predicted FEV1 in asthma patients. It also shows that the use of botanicals as a complementary treatment is more effective in adults than in children. In most studies, the target group consisted of patients with mild to moderate asthma. However, severe asthma patients were investigated in three studies [53, 58, 63], and patients with stable asthma were included in five studies [52, 57, 59, 62, 68]. Since the current meta-analysis included studies that involved mild to moderate asthmatic patients, differences in the target population did not confound the main findings, and the patients were homogeneous in this respect.

In seven studies, the target group of the intervention was asthma patients under 18 years old [7, 50-52, 54, 63, 69]; three of these studies were ultimately included in the meta-analysis [7, 50, 51]. In the subgroup meta-analysis of children and adults, treatment with herbal medicines did not significantly improve lung capacity in children. This may be because of the limited number of studies related to children. In general, interventional studies in children have more ethical considerations than adults. Traditional medicine textbooks also mention various restrictions on the use of medicinal plants with children. More studies are needed, therefore, to clarify the effect of herbal medicines on pediatric asthma. Certainly, constructive answers can be obtained if the intervention is performed with the same plant in both the children and adult groups.

Asthma can be treated by reducing inflammation of the ducts, enhancing mucus absorption, and improving smooth muscle relaxation. The medicinal plants used in the included clinical trials had similar effects. The mechanisms of action expressed for the effect of herbal interventions included inhibition of airway inflammation [57], inhibition of eosinophilic p38-dependent leukotriene synthesis [63], reducing asthma symptoms through a direct effect on the gastrointestinal tract [56], and reducing advanced pro-inflammatory glycosylation of IgE in the gut [66]. The effects of the plants selected for intervention in the included studies were investigated by dividing them into two categories: single-plant interventions and formula or multidrug interventions. In the single-plant studies, commonalities were observed in the molecular types that make up plants, including polyphenols, despite differences in plant names and classes. Polyphenols are micronutrients found in fruits, vegetables, tea, and spices. There are more than 8,000 polyphenols, including flavonoids such as quercetin, polyphenol amides such as capsaicin, phenolic acids such as gallic acid, and others such as salicylic acid.

Polyphenols are potent antioxidants that can mitigate or reverse cellular damage, thereby reducing the risk of many chronic diseases. They can also help maintain heart health, blood pressure, blood sugar levels, and chronic inflammation. The antioxidant and anti-inflammatory effects of polyphenols can inhibit tumor growth and kill active cancer cells, activate the immune system, and enhance the gut microbiota. Different classes of polyphenols, including anthocyanin, have strong protective effects on pulmonary function parameters. Polyphenols inhibit the induced expression of nitric oxide synthase and prevent oxidative and nitric oxidative damage to the lung [70-72].

From among the polyphenols in the present study, quercetin, terpene, and kaempferol of flavonoids and turmerones, saponin, gallic acid, and frolic acid of phenolic acids, more than their other groups, were observed in the compounds used for drug intervention [70, 72-80]. Although the main isoforms of polyphenolic molecules are different in each plant, all these forms have relatively similar functions in the human body, all causing reduced inflammation and mucus and relaxation of smooth muscle [35, 48, 53, 56, 57, 62, 81]. It also seems the variety in plant selection is caused by availability, cost, or other reasons.

Razi suggests that it is preferable to use one type of herbal drug in therapy [82]. Formulated and multi-herbal therapies are used in cases of advanced disease. In the present study, 15 single herbs and eight formulation studies were reviewed. Most single-plant studies either did not provide complete results, or the results and data were not suitable for meta-analysis; so most of the studies with formulations were included in the meta-analysis. Further meta-analyses comparing single-plant and formulation studies will be useful. Common adverse events reported in the included studies were mild and low-risk and reported in the studies on interventions using formulations that were negligible.

1. Strengths and limitations of the study

All designs were RCTs and the blinding process was conducted as accurately as possible in most included studies. The studies included in the meta-analysis were homogenous in terms of disease severity, with most patients having mild to moderate asthma. Hence, one of the reasons for the lack of heterogeneity between studies in the current meta-analysis was the presence of these two important and influential factors (i.e., homogeneous design and population). Also, despite the variety of herbal drugs that are used as interventions, they all share active molecules of polyphenols with anti-inflammatory and antioxidant effects. Nevertheless, the findings of this meta-analysis should be interpreted with caution in the context of limitations of the available data.

Since FEV1 was the main data for the meta-analysis, the difference in the type of reporting was one of the limitations of the present study. Five studies did not report pulmonary function tests as outcomes [56, 58, 59, 68, 83]. FEV1 has been presented in various methods and formats in other studies. For example, in four studies, respiration volume was recorded without mentioning the percent-predicted, [55, 57, 62, 66], and only changes in respiration volume were reported in some studies [49, 53, 65, 67]. Also, the results in four studies were presented in graphs and could not be extracted for meta-analysis [51, 60, 61, 64].

CONCLUSION

The findings of the present systematic review and meta-analysis indicated that the complementary use of herbal medicines resulted in significant improvements in lung function (percent-predicted FEV1) compared with standard treatment in asthmatic patients with no significant adverse events. Improvements in percent-predicted FEV1 were more likely to be observed among adults, which was significantly higher in adults than in children. Our meta-analysis sought to fill in the research gap and provide new up-to-date evidence. However, further RCTs with larger sample sizes and scales and high validity will be needed to establish and confirm our findings.

ACKNOWLEDGEMENTS

The research was supported by the Vice-Chancellor for Research at the Mashhad University of Medical Sciences (MUMS) as part of a traditional Persian medical doctoral dissertation. Funding sources had no role in study design, data collection, analysis, interpretation, and manuscript preparation.

AUTHORS’ CONTRIBUTIONS

SS and RS conceived the idea. SS and AD designed the study. SS, AA, MM, and FJ collected data, reviewed literature and extracted data. MS and MD rechecked the quality assessment of studies and participated in analysis of data and interpreted the results. SS, RS, and MS conceived the study aims and design, provide the data the analysis. MS, MD, AD and MK performed data re-analysis. They played an important role in interpreting the data, drafting, Manu scripting and revising it. All authors contributed to the discussion and endorsement of the final version. The responsible author had full access to all study data and was ultimately responsible for the decision to submit.

INSTITUTIONAL STATEMENT

This study does not require ethical approval. It is registered on the Prospero (Code: CRD42021268901).

CONFLICTS OF INTEREST

The authors declared there were no conflicts of interest related to the study.

FUNDING

Vice-Chancellor for Research, Mashhad University of Medical Sciences (MUMS).

Fig 1.

Figure 1.PRISMA flow diagram for selection of studies.
Journal of Pharmacopuncture 2023; 26: 124-138https://doi.org/10.3831/KPI.2023.26.2.124

Fig 2.

Figure 2.Forest plot of the efficacy of herbal medicine as add-on therapy on lung function (percent predicted FEV1) in patients with asthma using random effects meta-analysis. Diamond represents the summary weighted mean difference (pooled WMD) estimate and its width shows corresponding 95% CI with random effects estimate. The size of the square and its central point reflects the study specific statistical weight (inverse of variance) and point estimate of the WMD and horizontal line reflects corresponding 95% CI of the study. I2 test and Cochran’s Q statistic were used to assessing the statistical heterogeneity (p < 0.10) across studies.
Journal of Pharmacopuncture 2023; 26: 124-138https://doi.org/10.3831/KPI.2023.26.2.124

Fig 3.

Figure 3.Subgroup meta-analysis of the effect of herbal medicine on lung function (percent predicted FEV1) in patients with asthma based on patients’ age (adults vs. children).
Journal of Pharmacopuncture 2023; 26: 124-138https://doi.org/10.3831/KPI.2023.26.2.124

Fig 4.

Figure 4.Begg’s funnel plot for assessing the presence of publication bias. Weighted mean difference was plotted against the precision of the study (p = 0.53, for Begg’s adjusted rank correlation test and p = 0.58, for Egger’s regression asymmetry test).
Journal of Pharmacopuncture 2023; 26: 124-138https://doi.org/10.3831/KPI.2023.26.2.124

Table 1 . Main characteristics of randomized controlled trials included in the systematic review.

Study, year
(country)
SexAgeStudy populationHerbal medicine nameOutcomeIntervention groupControl group


n1mean1sd1n2mean2sd2
Urata et al. [36], 2002 (Japan)M/F42 ± 7Patients with mild or moderate asthma, 4 weeks follow-upTJ-96 capsule, freeze dried powder of SaibokuFEV-11686.97.11782.15.6
Wen et al. [53], 2005M/F18-65Patients with moderate-severe allergic asthma, 4 weeks follow-upASHMI capsule of Ganoderma lucidum, Sophora flavescens, and Glycyrrhiza uralensisFEV-14684.3612.94688.4612.6
Chang et al. [54], 2006 (China)M/F5-20Patients with mild or moderate asthma, 24 weeks follow-upSTA-1 capsule of decoction of Rehmanniae Preparata, Cortex Moutan Radicis, Fructus Corni, Poria, Rhizoma Alismatis and Dioscoreae, Ophiopogonis, Glycyrrhizae, Panacis Quinquefolii and Tuber PinelliaFEV-14480.70NR1676.5NR
Chang et al. [54], 2006 (China)M/F5-20Patients with mild or moderate asthma, 24 weeks follow-upSTA-2 capsule of boiled of Rehmanniae Preparata, Cortex Moutan Radicis, Fructus Corni, Poria, Rhizoma Alismatis and Dioscoreae, Ophiopogonis, Glycyrrhizae, Panacis Quinquefolii and Tuber PinelliaFEV-14488.9NR1676.5NR
Wong et al. [51], 2009 (China)M/FLow than 18Patients with mild or moderate asthma, 24 weeks follow-upCUF2 capsule of Astragalus mongholius Bunge, Cordyceps sinensis Sacc., stemonae, Bulbus fritillariae cirrhosae, and scutellariaeFEV-1439615429619
Houssen et al. [34], 2010 (Egypt)M/F18-60Patients with mild or moderate asthma, 4 weeks follow-upCapsule of Glyserizia Glabra, Curcumim, Boswelic acidFEV-13972.7510.412468.413.62
Salem et al. [35], 2017(Saudi Arabia)M/F18-65Controlled asthmatic patients, 12 weeks follow-upNS-1 capsule of Black SeedFEV-12687.715.82480.820.6
Salem et al. [35], 2017(Saudi Arabia)M/F18-65Patients with mild or moderate asthma, 12 weeks follow-upNS-2 capsule of Black SeedFEV-12685.522.92480.820.6
Wang et al. [49], 2017(China)M/F18-60Patients with mild or moderate asthma, 12 weeks follow-upPCKLSachet of not reportedFEV-13673.214.33667.714.5
Hosseini et al. [48], 2018 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upCapsule of saffronFEV-14080.1512.594073.2112.15
Nejatbakhsh et al. [37], 2017 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upSyrup of Squill OxymelFEV-13871.4421.863861.6714.2
Nejatbakhsh et al. [37], 2017 (Iran)M/F18-65Patients with mild or moderate asthma, 8 weeks follow-upSyrup of OxymelFEV-13861.1115.73861.6714.2
Chan et al. [7], 2006 (Taiwan)M/F8-15Children with mild or moderate asthma, 12 weeks follow-upDCT capsule of G. biloba, E. sinica,T. farfara, M. alba, P. ternata, P. frutescens, P. armeniaca, S. baricalensis, and G. uralensisFEV-12893.85102.712487.9798.53
Chan et al. [50], 2016(Taiwan)M/F6-18Children with mild or moderate asthma, 24 weeks follow-upYPFS sachet of not reportedFEV-12892.32.62995.32.7
Murali et al. [55], 2006 (India)M/F15-50Patients with moderate stable asthma, 12 weeks follow-upDCBT4567-Astha-15capsule of Woodfordia, Solanum xanthocarpum, Adathoda vasika, Acacia arabica, Ellateria cardamomum, Piper nigrum, Achyranthus aspera, Zingiber officinalis, Hollarhena antidysenterica, Curcuma longa, Syzygium aromaticum, Calotropis procera, Enicostemma littorale, Piper longumFEV-1191.690.52221.50.51
Rouhi et al. [56], 2006 (Pakistan)M/FNRPatients with low to severe asthma, 8 weeks follow-upOral drop of GingerFEV14647.31NR4645.31NR
Boskabady et al. [57], 2007 (Iran)M/F48.2 ± 11.9Patients with persistent mild or moderate asthma, 12 weeks follow-upCapsule of Black SeedFEV11529.4727.141430.324.31
Thomas et al. [59], 2007 (Scotland)M/F18-75Patients with persistent asthma, 12 weeks follow-upAKL1 capsules of not reporterNR16NRNR16NRNR
Watson et al. [60], 2008 (USA)M/F18-60Patients with asthma, 4 weeks follow-upTablet of purple passion fruitNR22NRNR21NRNR
Smith et al. [63], 2015 (USA)M/F> 12Patients with poor control asthma, 24 weeks follow-upTablet of Soy IsoflavoneFEV11932.393.681932.443.19
Kong et al. [64], 2017 (China)M/FNRPatients asthma, 48 weeks follow-upBSYQ capsule of RadixAstragali, HerbaEpimedii, RehmanniaeRadiNR109NRNR107NRNR
Kong et al. [64], 2017 (China)M/FNRPatients asthma, 48 weeks follow-upBSFCcapsule of Herba Epimedii, Rehmanniae Radi, Cuscutaesemen, soraleae, oraleacoryl., ioscorea opposita Citri Reticulatae AconitilateralisNR112NRNR107NRNR
Koshak et al. [65], 2017 (UK)M/F18-65Patients with mild or moderate asthma, 4 weeks follow-upNSO capsules of Black seedNR40NRNR40NRNR
Power et al. [66], 2017 (New Zealand)M/F18-75Patients with mild asthma, 4 weeks follow-upBFPE BerryfruitFEV1143.540.98143.561
Yugandhar et al. [67], 2018 (India)M/F21-60Patients with mild or moderate asthma, 6 weeks follow-upLi131019Fserrata, Marmelos fruitFEV1161.710.32131.540.22
Manarin et al. [68], 2019 (Brazil)M/F7-18Patients with persistent moderate to severe asthma, 8 weeks follow-upCapsule of Curcuma longaFEV140NRNR27NRNR
Hsu et al. [52], 2005(Taiwan)M/F5-18Patients with persistent mild or moderate asthma, 16 weeks follow-upMMDT40 mg/dayTuber Ophiopogonis Japonici, Panacis Quinquefoli. Tuber Pinellia, Rhizoma Pinellia Ternatae, Glycyrrhizae Uralensis, Herba Tridacis procumbentisFEV-14073.812.42070.213.7
Hsu et al. [52], 2005(Taiwan)M/F5-18Patients with persistent mild or moderate asthma, 16 weeks follow-upMMDT80 mg/dayTuber Ophiopogonis Japonici, Panacis Quinquefoli. Tuber Pinellia, Rhizoma Pinellia Ternatae, Glycyrrhizae Uralensis, Herba Tridacis procumbentisFEV-14087.712.62070.213.7

M, male; F, female; NR, not reported; FEV1, forced expiratory volume 1th second; n, number of cases; sd, standard deviation..


Table 2 . Risk of bias/methodological quality assessment of randomized controlled trials using Cochran risk of bias tool (ROB).

StudySequence generationAllocation concealmentBlinding of
participants & personnel
Blinding of
outcome assessor
Incomplete
outcome data
Selective outcome reportingOther sources of biasOverall bias
Urata et al. [36], 2002?????+??
Wen et al. [53], 2005????+++?
Chang et al. [54], 2006????+++?
Wong et al. [51], 2009????+++?
Houssen et al. [34], 2010--------
Salem et al. [35], 2017++??+++?
Wang et al. [49], 2017++++++++
Hosseini et al. [48], 2018++++++++
Nejatbakhsh et al. [37], 2017++++++++
Chan et al. [7], 2006++++++++
Chan et al. [50], 2016++++++++
Murali et al. [55], 2006????++++
Rouhi et al. [56], 2006--------
Boskabady et al. [57], 2007?????+--
Thomas et al. [59], 2007?????+??
Watson et al. [60], 2008????+++?
Smith et al. [63], 2015++--++--
Kong et al. [64], 2017++++++++
Koshak et al. [65], 2017----+++-
Power et al. [66], 2017++++++++
Yugandhar et al. [67], 2018++++++++
Manarin et al. [68], 2019++++++++
Hsu et al. [52], 2005++++++++

+Low risk of bias, ?unclear risk of bias, -high risk of bias..


References

  1. Wang L, Cheng L, Yuan Q, Cui X, Shang H, Zhang B, et al. Adverse drug reactions of Shuanghuanglian injection: a systematic review of public literatures. J Evid Based Med. 2010;3(1):18-26.
    Pubmed CrossRef
  2. Rawat S, Jugran AK, Bhatt ID, Rawal RS. Hedychium spicatum: a systematic review on traditional uses, phytochemistry, pharmacology and future prospectus. J Pharm Pharmacol. 2018;70(6):687-712.
    Pubmed CrossRef
  3. Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): a systematic review. Pharmacogn Rev. 2011;5(9):103-10.
    Pubmed KoreaMed CrossRef
  4. Babayigit A, Olmez D, Karaman O, Bagriyanik HA, Yilmaz O, Kivcak B, et al. Ginseng ameliorates chronic histopathologic changes in a murine model of asthma. Allergy Asthma Proc. 2008;29(5):493-8.
    Pubmed CrossRef
  5. Yue GG, Chan BC, Kwok HF, To MH, Hon KL, Fung KP, et al. Screening for anti-inflammatory and bronchorelaxant activities of 12 commonly used Chinese herbal medicines. Phytother Res. 2012;26(6):915-25.
    Pubmed CrossRef
  6. Hofmann D, Hecker M, Völp A. Efficacy of dry extract of ivy leaves in children with bronchial asthma--a review of randomized controlled trials. Phytomedicine. 2003;10(2-3):213-20.
    Pubmed CrossRef
  7. Chan CK, Kuo ML, Shen JJ, See LC, Chang HH, Huang JL. Ding Chuan Tang, a Chinese herb decoction, could improve airway hyper-responsiveness in stabilized asthmatic children: a randomized, double-blind clinical trial. Pediatr Allergy Immunol. 2006;17(5):316-22.
    Pubmed CrossRef
  8. Kim KI, Shin S, Lee N, Lee BJ, Lee J, Lee H. A traditional herbal medication, Maekmoondong-tang, for cough: a systematic review and meta-analysis. J Ethnopharmacol. 2016;178:144-54.
    Pubmed CrossRef
  9. Zhang Y, Qi D, Gao Y, Liang C, Zhang Y, Ma Z, et al. History of uses, phytochemistry, pharmacological activities, quality control and toxicity of the root of Stephania tetrandra S. Moore: a review. J Ethnopharmacol. 2020;260:112995.
    Pubmed CrossRef
  10. Yang T, He J, Yan Y, Lian WW, Xia CY, Xu JK, et al. Euphorbia ebracteolata Hayata (Euphorbiaceae): a systematic review of its traditional uses, botany, phytochemistry, pharmacology, toxicology, and quality control. Phytochemistry. 2021;186:112736.
    Pubmed CrossRef
  11. Yadav V, Krishnan A, Vohora D. A systematic review on Piper longum L.: bridging traditional knowledge and pharmacological evidence for future translational research. J Ethnopharmacol. 2020;247:112255.
    Pubmed CrossRef
  12. Zhang C, Li J, Wu Z, Wang H, Que C, Zhao H, et al. Efficacy and safety of Anluohuaxian in the treatment of patients with severe Coronavirus disease 2019- a multicenter, open label, randomized controlled study: a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):495.
    Pubmed KoreaMed CrossRef
  13. Hashempur MH, Mosavat SH, Heydari M, Shams M. Medicinal plants' use among patients with dyslipidemia: an Iranian cross-sectional survey. J Complement Integr Med. 2018;16(3):/j/jcim.2019.
    Pubmed CrossRef
  14. Moghimi Sarani E, Ghorbannezhad F, Meshkibaf MH, Shakibaee M, Mosavat SH. Evaluation of the effect of alkaloid berberine on the positive and negative symptoms of the patients with schizophrenia: a double-blind randomized placebo-controlled clinical trial. Trad Integr Med. 2022;7(3):287-93.
    CrossRef
  15. Ou-Yang SH, Jiang T, Zhu L, Yi T. Dioscorea nipponica Makino: a systematic review on its ethnobotany, phytochemical and pharmacological profiles. Chem Cent J. 2018;12(1):57.
    Pubmed KoreaMed CrossRef
  16. Namazi N, Larijani B, Ayati MH, Abdollahi M. The effects of Nigella sativa L. on obesity: a systematic review and meta-analysis. J Ethnopharmacol. 2018;219:173-81.
    Pubmed CrossRef
  17. Miraj S, Alesaeidi S, Kiani S. A systematic review of the relationship between dystemprament (sue Mizaj) and treatments and management of diseases (Ilaj and Eslah-e-Mizaj). Electron Physician. 2016;8(12):3378-84.
    Pubmed KoreaMed CrossRef
  18. Ji T, Ji WW, Wang J, Chen HJ, Peng X, Cheng KJ, et al. A comprehensive review on traditional uses, chemical compositions, pharmacology properties and toxicology of Tetrastigma hemsleyanum. J Ethnopharmacol. 2021;264:113247.
    Pubmed KoreaMed CrossRef
  19. He Y, Zhu L, Ma J, Wong L, Zhao Z, Ye Y, et al. Comprehensive investigation and risk study on pyrrolizidine alkaloid contamination in Chinese retail honey. Environ Pollut. 2020;267:115542.
    Pubmed CrossRef
  20. Chen G, Chen Y, Chen Z, Gao S, Zhang P, Zhang H, et al. Sanao decoction for asthma: protocol of a systematic review. Medicine (Baltimore). 2019;98(18):e15313.
    Pubmed KoreaMed CrossRef
  21. Jiang S, Cui H, Wu P, Liu Z, Zhao Z. Botany, traditional uses, phytochemistry, pharmacology and toxicology of Ilex pubescens Hook et Arn. J Ethnopharmacol. 2019;245:112147.
    Pubmed CrossRef
  22. Chen Z, Zhang C, Gao F, Fu Q, Fu C, He Y, et al. A systematic review on the rhizome of Ligusticum chuanxiong Hort. (Chuanxiong). Food Chem Toxicol. 2018;119:309-325.
    Pubmed CrossRef
  23. Khorasanchi Z, Shafiee M, Kermanshahi F, Khazaei M, Ryzhikov M, Parizadeh MR, et al. Crocus sativus a natural food coloring and flavoring has potent anti-tumor properties. Phytomedicine. 2018;43:21-7.
    Pubmed CrossRef
  24. Chen PY, Wang J, Lin YC, Li CC, Tsai CW, Liu TC, et al. 18-Carbon polyunsaturated fatty acids ameliorate palmitate-induced inflammation and insulin resistance in mouse C2C12 myotubes. J Nutr Biochem. 2015;26(5):521-31.
    Pubmed CrossRef
  25. Huntley AL, Thompson Coon J, Ernst E. The safety of herbal medicinal products derived from Echinacea species: a systematic review. Drug Saf. 2005;28(5):387-400.
    Pubmed CrossRef
  26. Wang Y, Chen S, Wang P, Tan C, Zhang C, Shi Z, et al. Comparison of clinical effectiveness of acupuncture and a Western drug on allergic rhinitis: study protocol for a randomized controlled trial. J Tradit Chin Med. 2014;34(3):254-60.
    Pubmed CrossRef
  27. Clark CE, Arnold E, Lasserson TJ, Wu T. Herbal interventions for chronic asthma in adults and children: a systematic review and meta-analysis. Prim Care Respir J. 2010;19(4):307-14.
    Pubmed KoreaMed CrossRef
  28. Huntley A, Ernst E. Herbal medicines for asthma: a systematic review. Thorax. 2000;55(11):925-9.
    Pubmed KoreaMed CrossRef
  29. Arnold E, Clark CE, Lasserson TJ, Wu T. Herbal interventions for chronic asthma in adults and children. Cochrane Database Syst Rev;200(1):CD005989.
    Pubmed CrossRef
  30. Ernst E. Frankincense: systematic review. BMJ. 2008;337:a2813.
    Pubmed KoreaMed CrossRef
  31. Shergis JL, Wu L, Zhang AL, Guo X, Lu C, Xue CC. Herbal medicine for adults with asthma: a systematic review. J Asthma. 2016;53(6):650-9.
    Pubmed CrossRef
  32. Singh BB, Khorsan R, Vinjamury SP, Der-Martirosian C, Kizhakkeveettil A, Anderson TM. Herbal treatments of asthma: a systematic review. J Asthma. 2007;44(9):685-98.
    Pubmed CrossRef
  33. Chan PH, To CY, Chan EY, Li H, Zhang X, Chow PY, et al. A randomized placebo-controlled trial of traditional Chinese medicine as an add-on therapy to oral montelukast in the treatment of mild persistent asthma in children. Complement Ther Med. 2016;29:219-28.
    Pubmed CrossRef
  34. Houssen ME, Ragab A, Mesbah A, El-Samanoudy AZ, Othman G, Moustafa AF, et al. Natural anti-inflammatory products and leukotriene inhibitors as complementary therapy for bronchial asthma. Clin Biochem. 2010;43(10-11):887-90.
    Pubmed CrossRef
  35. Salem AM, Bamosa AO, Qutub HO, Gupta RK, Badar A, Elnour A, et al. Effect of Nigella sativa supplementation on lung function and inflammatory mediatorsin partly controlled asthma: a randomized controlled trial. Ann Saudi Med. 2017;37(1):64-71.
    Pubmed KoreaMed CrossRef
  36. Urata Y, Yoshida S, Irie Y, Tanigawa T, Amayasu H, Nakabayashi M, et al. Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial. Respir Med. 2002;96(6):469-74.
    Pubmed CrossRef
  37. Nejatbakhsh F, Karegar-Borzi H, Amin G, Eslaminejad A, Hosseini M, Bozorgi M, et al. Squill Oxymel, a traditional formulation from Drimia Maritima (L.) Stearn, as an add-on treatment in patients with moderate to severe persistent asthma: a pilot, triple-blind, randomized clinical trial. J Ethnopharmacol. 2017;196:186-92.
    Pubmed CrossRef
  38. Fleming PS, Koletsi D, Pandis N. Blinded by PRISMA: are systematic reviewers focusing on PRISMA and ignoring other guidelines? PLoS One. 2014;9(5):e96407.
    Pubmed KoreaMed CrossRef
  39. Lin J, Yang D, Huang M, Zhang Y, Chen P, Cai S, et al. Chinese expert consensus on diagnosis and management of severe asthma. J Thorac Dis. 2018;10(12):7020-44.
    Pubmed KoreaMed CrossRef
  40. Changizi Ashtiyani S, Shamsi M, Cyrus A, Bastani B, Tabatabayei SM. A critical review of the works of pioneer physicians on kidney diseases in ancient Iran: Avicenna, Rhazes, Al-akhawayni, and Jorjani. Iran J Kidney Dis. 2011;5(5):300-8.
    Pubmed
  41. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev. 2019;10:ED000142.
    Pubmed KoreaMed CrossRef
  42. Marín-Martínez F, Sánchez-Meca J. Weighting by inverse variance or by sample size in random-effects meta-analysis. Educ Psychol Meas. 2010;70(1):56-73.
    CrossRef
  43. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11(2):193-206.
    Pubmed CrossRef
  44. Somes GW. The generalized Mantel-Haenszel statistic. Am Stat. 1986;40(2):106-8.
    CrossRef
  45. Simmonds M. Quantifying the risk of error when interpreting funnel plots. Syst Rev. 2015;4:24.
    Pubmed KoreaMed CrossRef
  46. Sterne JAC, Egger M. Regression methods to detect publication and other bias in meta-analysis. In: Rothstein HR, Sutton AJ, Borenstein M, editors. Publication bias in meta-analysis: prevention, assessment and adjustments. Chichester: John Wiley & Sons; 2005. p. 99-110.
    Pubmed KoreaMed CrossRef
  47. Gjerdevik M, Heuch I. Improving the error rates of the Begg and Mazumdar test for publication bias in fixed effects meta-analysis. BMC Med Res Methodol. 2014;14:109.
    Pubmed KoreaMed CrossRef
  48. Hosseini SA, Zilaee M, Shoushtari MH, Ghasemi Dehcheshmeh M. An evaluation of the effect of saffron supplementation on the antibody titer to heat-shock protein (HSP) 70, hsCRP and spirometry test in patients with mild and moderate persistent allergic asthma: a triple-blind, randomized placebo-controlled trial. Respir Med. 2018;145:28-34.
    Pubmed CrossRef
  49. Wang X, Tian Z, Gao F, Zhang X, Liu J, Li Z. Traditional Chinese medicine as an adjunctive therapy to oral montelukast for treating patients with chronic asthma. Medicine (Baltimore). 2017;96(51):e9291.
    Pubmed KoreaMed CrossRef
  50. Chan PH, To CY, Chan EY, Li H, Zhang X, Chow PY, et al. A randomized placebo-controlled trial of traditional Chinese medicine as an add-on therapy to oral montelukast in the treatment of mild persistent asthma in children. Complement Ther Med. 2016;29:219-28.
    Pubmed CrossRef
  51. Wong EL, Sung RY, Leung TF, Wong YO, Li AM, Cheung KL, et al. Randomized, double-blind, placebo-controlled trial of herbal therapy for children with asthma. J Altern Complement Med. 2009;15(10):1091-7.
    Pubmed CrossRef
  52. Hsu CH, Lu CM, Chang TT. Efficacy and safety of modified Mai-Men-Dong-Tang for treatment of allergic asthma. Pediatr Allergy Immunol. 2005;16(1):76-81.
    Pubmed CrossRef
  53. Wen MC, Wei CH, Hu ZQ, Srivastava K, Ko J, Xi ST, et al. Efficacy and tolerability of anti-asthma herbal medicine intervention in adult patients with moderate-severe allergic asthma. J Allergy Clin Immunol. 2005;116(3):517-24.
    Pubmed CrossRef
  54. Chang TT, Huang CC, Hsu CH. Clinical evaluation of the Chinese herbal medicine formula STA-1 in the treatment of allergic asthma. Phytother Res. 2006;20(5):342-7.
    Pubmed CrossRef
  55. Murali PM, Rajasekaran S, Krishnarajasekar OR, Perumal T, Nalini K, Lakshmisubramanian S, et al. Plant-based formulation for bronchial asthma: a controlled clinical trial to compare its efficacy with oral salbutamol and theophylline. Respiration. 2006;73(4):457-63.
    Pubmed CrossRef
  56. Rouhi H, Ganji F, Nasri H. Effects of ginger on the improvement of asthma [The evaluation of its' treatmental effects]. Pak J Nutr. 2006;5(4):373-6.
    CrossRef
  57. Boskabady MH, Alizadeh M, Jahanbin B. Bronchodilatory effect of Carum copticum in airways of asthmatic patients. Therapie. 2007;62(1):23-9.
    Pubmed CrossRef
  58. Hoang BX, Shaw DG, Levine S, Hoang C, Pham P. New approach in asthma treatment using excitatory modulator. Phytother Res. 2007;21(6):554-7.
    Pubmed CrossRef
  59. Thomas M, Sheran J, Smith N, Fonseca S, Lee AJ. AKL1, a botanical mixture for the treatment of asthma: a randomised, double-blind, placebo-controlled, cross-over study. BMC Pulm Med. 2007;7:4.
    Pubmed KoreaMed CrossRef
  60. Watson RR, Zibadi S, Rafatpanah H, Jabbari F, Ghasemi R, Ghafari J, et al. Oral administration of the purple passion fruit peel extract reduces wheeze and cough and improves shortness of breath in adults with asthma. Nutr Res. 2008;28(3):166-71.
    Pubmed CrossRef
  61. Kelly-Pieper K, Patil SP, Busse P, Yang N, Sampson H, Li XM, et al. Safety and tolerability of an antiasthma herbal Formula (ASHMI) in adult subjects with asthma: a randomized, double-blinded, placebo-controlled, dose-escalation phase I study. J Altern Complement Med. 2009;15(7):735-43.
    Pubmed KoreaMed CrossRef
  62. Park CS, Kim TB, Lee JY, Park JY, Lee YC, Jeong SS, et al. Effects of add-on therapy with NDC-052, an extract from Magnoliae Flos, in adult asthmatic patients receiving inhaled corticosteroids. Korean J Intern Med. 2012;27(1):84-90.
    Pubmed KoreaMed CrossRef
  63. Smith LJ, Kalhan R, Wise RA, Sugar EA, Lima JJ, et al; American Lung Association Asthma Clinical Research Centers. Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial. JAMA. 2015;313:2033-43.
    Pubmed KoreaMed CrossRef
  64. Kong L, Zhang H, Cao Y, Le J, Wu J, Liu B, et al. The anti-inflammatory effects of invigorating kidney and supplementing Qi Chinese herbal formulae in asthma patients. Evid Based Complement Alternat Med. 2017;2017:3754145.
    Pubmed KoreaMed CrossRef
  65. Koshak A, Koshak E, Heinrich M. Medicinal benefits of Nigella sativa in bronchial asthma: a literature review. Saudi Pharm J. 2017;25(8):1130-6.
    Pubmed KoreaMed CrossRef
  66. Power S, Williams M, Semprini A, Munro C, Caswell-Smith R, Pilcher J, et al. RCT of the effect of berryfruit polyphenolic cultivar extract in mild steroid-naive asthma: a cross-over, placebo-controlled study. BMJ Open. 2017;7(3):e013850.
    Pubmed KoreaMed CrossRef
  67. Yugandhar P, Rao KM, Sengupta K. A novel herbal composition containing extracts of Boswellia serrata gum resin and Aegle marmelos fruit alleviates symptoms of asthma in a placebo controlled double-blind clinical study. Phytother Res. 2018;32(1):140-50.
    Pubmed CrossRef
  68. Manarin G, Anderson D, Silva JME, Coppede JDS, Roxo-Junior P, Pereira AMS, et al. Curcuma longa L. ameliorates asthma control in children and adolescents: a randomized, double-blind, controlled trial. J Ethnopharmacol. 2019;238:111882.
    Pubmed CrossRef
  69. Qasemzadeh MJ, Sharifi H, Hamedanian M, Gharehbeglou M, Heydari M, Sardari M, et al. The effect of Viola odorata flower syrup on the cough of children with asthma: a double-blind, randomized controlled trial. J Evid Based Complementary Altern Med. 2015;20(4):287-91.
    Pubmed CrossRef
  70. Silva BM, Andrade PB, Ferreres F, Domingues AL, Seabra RM, Ferreira MA. Phenolic profile of quince fruit (Cydonia oblonga Miller) (pulp and peel). J Agric Food Chem. 2002;50(16):4615-8.
    Pubmed CrossRef
  71. Huang WY, Zhang HC, Liu WX, Li CY. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. 2012;13(2):94-102.
    Pubmed KoreaMed CrossRef
  72. Smruthi R, Divya M, Archana K, Ravi M. The active compounds of Passiflora spp and their potential medicinal uses from both in vitro and in vivo evidences. J Adv Biomed Pharm Sci. 2021;4(1):45-55.
    CrossRef
  73. Dong Y, Jia G, Hu J, Liu H, Wu T, Yang S, et al. Determination of alkaloids and flavonoids in Sophora flavescens by UHPLC-Q-TOF/MS. J Anal Methods Chem. 2021;2021:9915027.
    Pubmed KoreaMed CrossRef
  74. Liu H, Lu X, Hu Y, Fan X. Chemical constituents of Panax ginseng and Panax notoginseng explain why they differ in therapeutic efficacy. Pharmacol Res. 2020;161:105263.
    Pubmed CrossRef
  75. Ghahari S, Alinezhad H, Nematzadeh GA, Tajbakhsh M, Baharfar R. Chemical composition, antioxidant and biological activities of the essential oil and extract of the seeds of Glycine max (Soybean) from North Iran. Curr Microbiol. 2017;74(4):522-31.
    Pubmed CrossRef
  76. Sharma V, Katiyar A, Agrawal RC. Glycyrrhiza glabra: chemistry and pharmacological activity. In: Mérillon JM, Ramawat K, editors. Sweeteners: Pharmacology, Biotechnology, and Applications. Cham: Springer; 2018. p. 87-100.
    CrossRef
  77. Topcagic A, Cavar Zeljkovic S, Karalija E, Galijasevic S, Sofic E. Evaluation of phenolic profile, enzyme inhibitory and antimicrobial activities of Nigella sativa L. seed extracts. Bosn J Basic Med Sci. 2017;17(4):286-94.
    Pubmed KoreaMed CrossRef
  78. Mittal P, Gupta V, Goswami M, Thakur N, Bansal P. Phytochemical and pharmacological potential of Viola odorata. Int J Pharm. 2015;2(5):215-20.
  79. Ude C, Schubert-Zsilavecz M, Wurglics M. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet. 2013;52(9):727-49.
    Pubmed CrossRef
  80. Huang HC. Sowing the seeds of health: is the era of food prescriptions coming? J Chin Med Assoc. 2014;77(6):273-4.
    Pubmed CrossRef
  81. Chen L, Mehrabi Nasab E, Athari SS. Effect of loaded glycyrrhizic acid on PLGA nano-particle on treatment of allergic asthma. Iran J Allergy Asthma Immunol. 2022;21(1):65-72.
    Pubmed CrossRef
  82. Derakhshan AR. Natural treatments for fissure in Ano used by traditional Persian scholars, Razi (Rhazes) and Ibn Sina (Avicenna). J Evid Based Complementary Altern Med. 2017;22(2):324-33.
    Pubmed KoreaMed CrossRef
  83. Ghasemzadeh A, Jaafar HZ, Rahmat A. Antioxidant activities, total phenolics and flavonoids content in two varieties of Malaysia young ginger (Zingiber officinale Roscoe). Molecules. 2010;15(6):4324-33.
    Pubmed KoreaMed CrossRef