ORIGINAL ARTICLE

A Systematic Review on Vitex negundo (NIRPROMP

formulations) for the Treatment of Acute Cough of
Mild to Moderate Severity in Pediatric Patients
Daisy-Mae Alegado-Bagaoisan,1 Mary Christine R. Castro2 and Jaime M. Purificacion1
1
Institute of Herbal Medicine, National Institutes of Health, University of the Philippines Manila, Philippines
2
Nutrition Center of the Philippines, Madrigal Business Park, Ayala Alabang, Philippines

ABSTRACT

Objective. The aim of this systematic review was to evaluate the efficacy and safety of Vitex negundo (lagundi)
for the treatment of acute cough of mild to moderate severity among pediatric patients.

Methods. A systematic review of randomized controlled trials (RCTs) comparing lagundi to placebo for acute
cough of mild to moderate severity in children and adolescents aged two to twenty one years in ambulatory
settings was performed. Authors of unpublished clinical trials with existing patent numbers were contacted and
permission was obtained to access and include their studies in this review.

Results. Seven studies were included, with a total of 308 participants. Lagundi increased the peak exploratory flow
rate (PEFR) at the end of therapy compared with placebo but this was not statistically significant (p=0.36). The increase
in PEFR was consistent with the results of the mechanistic isolated tissue studies that showed bronchodilating
effect of lagundi. Studies using lagundi syrup showed decrease in the frequency of cough by 44–71%.

Conclusion. Lagundi therapy in acute cough of mild to moderate severity among pediatric patients has a
bronchodilating effect and decreases the frequency and duration of coughing, with no serious adverse effects.

Key Words: Vitex negundo, lagundi, cough

Introduction

Cough is the most common symptom in primary care

in which patients seek medical consultation, and persistent
cough among children is normally the reason for a child
to be referred to a physician and pulmonologist.1 On the
average, normal children cough 11 times per day when they
are well and this increases in frequency and severity when
there is presence of upper respiratory tract infections.2 Cough
can either be acute or chronic. Acute cough is a recent onset
of cough lasting less than 3 weeks while chronic cough last
greater than 8 weeks. Cough can also either be specific or
non-specific, recurrent, or post-viral. Specific cough is a
cough in which there is a clearly identifiable cause. Non-
specific cough is a persistently dry cough with no other
associated respiratory symptoms. The majority of cough
cases is due to a non-serious etiology and may spontaneously
Corresponding author: Daisy-Mae O. Alegado-Bagaoisan, RPh resolve by itself.3 On the other hand, recurrent cough is a
Institute of Herbal Medicine repeated cough (with episodes of ≥2/year) not associated
National Institutes of Health
University of the Philippines Manila
with head colds lasting more than 7-14 days while post-viral
623 Pedro Gil St., Ermita, Manila 1000, Philippines cough is a cough that starts with an upper respiratory tract
Email: dabagaoisan@up.edu.ph infection but the duration is greater than 3 weeks.4

36 ACTA MEDICA PHILIPPINA VOL. 54 NO. 1 2020

 Lagundi for Non Bacterial Cough in Children

Description of the intervention diltiazem-like Ca++ entry blocking constituents which partly
Vitex negundo Linn Family Verbenaceae (lagundi) explains its bronchodilating effect.14
is a woody, erect, branched shrub 2-5 meters in height, Plant extracts tend to exhibit numerous pharmacological
and bears tri- or penta-foliate leaves, and with bluish- actions with multiple mechanisms, which are activated by
purple colored flowers. Lagundi is generally used for several different types of compounds.  There is considerable
the treatment of coughs, asthma symptoms, and other ethnomedical and pharmacological evidence15,16 that Vitex
respiratory problems. It has been recognized by the negundo possesses analgesic and anti-inflammatory,17-22
Philippine Department of Health as an effective clinically antihistaminic, antibacterial,23-26 antioxidant,27 and broncho-
proven medicinal plant in the treatment of respiratory dilating28,29 potential.  
complaints like cough and asthma.5
An in-vivo study on the antitussive effects of an Why it is important to do this review
n-butanol fraction of Vitex negundo on sulphur-dioxide- Lagundi is extremely relevant in primary care because
induced cough performed in mice showed that the if proven efficacious it will justify the use of lagundi in
butanolic extracts of Vitex negundo demonstrated significant children with mild to moderate cough by improving a child’s
inhibition of cough reflex in a dose-dependent manner. quality of life such as better school performance and ability
The antitussive activity of a 250 mg/kg dose at 30 minutes to play free from worries produced by difficult coughing.
was less than those of higher doses at all time points, while A systematic review evaluating the efficacy and
the highest inhibition of cough reflex was achieved at safety of lagundi for reducing cough symptoms of mild to
1000 mg/kg dose of the extract at 60 minutes.6 moderate severity among pediatric patients would be useful.
Isolation studies on the phytochemistry of Vitex Most studies have small sample sizes and combining them
negundo conducted by Dayrit (1987) showed the in a systematic review would give more meaningful results.
presence of several isolates identified as B-sitosterone
from the hexane fraction, and casticin, chrysophenol D, METHODS
luteolin, and alpha-hydroxybenzoic acid from the ethyl
acetate fraction.7 A joint study with Kazuro Yamasaki Literature Search
of Hiroshima University School of Medicine, using cats’ Electronic search was done in various search engines
trachea, revealed that the inhibition of histamine release namely the Cochrane Central Register of Controlled Trials
was mostly found in the ethyl acetate fraction.   (CENTRAL) (The Cochrane Library, 1950 to February
An in-vitro test done by Tigno in 1993 on isolated 2016), PubMed (2004 to February 2016), MEDLINE (1950
compounds from Vitex negundo showed that the activities to February 2016), HERDIN, Philippine Index Medicus
were found in the iridoid and flavonoid fractions of the and Google Scholar. We also searched the Philippine
plant extract. Specifically, the fractions that contain the Herbs and Supplements Research Database (www.herbs.ph).
iridoids agnuside, lagundinin, and 2’-parahydroxybenzoyl Manual search for relevant articles on lagundi
mussaenosidic acid, and the flavonoids casticin and as antitussive agent available at the Department of
chrysophenol D were found to have anti-inflammatory Pharmacology and Toxicology, College of Medicine,
potential. The anti-inflammatory action of lagundi is partly University of the Philippines Manila and at the University
explained by its ability to inhibit chemotaxis, phagocytosis, of the Philippines Manila Medical Library was done.
and complement activation, both via the alternative and The database of the Philippine National Library was also
classical pathway.8 Yunos et al9 and Jana et al10 established searched. We also searched databases of complementary
the anti-inflammatory property of Vitex negundo extracts in and alternative medicine literature and clinical trial
acute and subacute inflammation. Anti-inflammatory and registries. Authors of unpublished clinical trials with
pain suppressing activities of fresh leaves are attributed to existing patent numbers were contacted and permission
prostaglandin synthesis inhibition,11 and to antihistamine, was obtained to access and include their studies in this
membrane stabilizing, and anti-oxidant activities.12 review. (Appendices I – IV )
Patel et al in 2009 utilizing normotensive anesthetized
rats showed that the lagundi extract stabilized mast cells Eligibility Criteria
showing inhibitory effects on immediate hypersensitivity We included randomized controlled trials among
reactions and exhibited anti-eosinophilic activity which participants aged two to twenty-one years with acute cough of
was considered the underlying mechanism involved in the mild to moderate severity given Vitex negundo (NIRPROMP
anti-asthmatic effect of Vitex negundo.13 formulations). We excluded studies that included participants
Khan, Shah et al in 2015 explored the mechanism with a chronic cough lasting more than three weeks.
underlying the effectiveness of Vitex negundo in hyperactive Only randomized controlled trials (RCTs) comparing
respiratory disorders using crude extract of the leaves Vitex negundo with placebo were included in this review.
and found that Vitex negundo possesses a combination of Studies comparing Vitex negundo to other pharmaceutical
papaverine-like phosphodiesterase inhibitors (PPE) and preparations for cough or asthma were excluded.

VOL. 54 NO. 1 2020 ACTA MEDICA PHILIPPINA 37

Lagundi for Non Bacterial Cough in Children

Types of outcome measures Measures of treatment effect

Five studies contributed data for the analysis of
Primary outcomes the reduction of cough (207 participants). For the peak
1. Improvement in PEFR function. exploratory flow rate (PEFR) improvement outcome, four
2. Reduction in frequency of cough studies (146 participants) contributed data. Mean difference
and standard deviation were used for continuous outcomes.
Secondary outcomes
1. Difficulty of breathing Dealing with missing data
2. Difficulty of expectoration We contacted the authors of the unpublished clinical
3. Change in the character of phlegm trials for clarifications on the missing data. Data for the
4. Change in the color of phlegm reduction of the frequency of cough in the included studies
were collapsed into two groups to standardize and create a
Selection of studies uniform category on all included studies. Missing data were
The review authors merged and eliminated duplicates handled to predict and determine the impact of worst case
from the retrieved records identified through electronic and best case scenarios.
database search and other sources. Two authors (DAB,
JMP) independently extracted and entered data into Review Assessment of heterogeneity
Manager 5.3 (Revman 2013). A third author (MCC) Included studies were first assessed for clinical
resolved disagreements by consensus. (Figure 1) heterogeneity by comparing the participants (age range,
inclusion criteria), intervention (preparation and dosage),
and outcomes (measurement, reporting). A meta-analysis
Records identified Additional records using the fixed effects model was conducted for studies that
through database identified through reported similar methods of measuring outcomes. Statistical
search (n=7) other sources (n=7)
heterogeneity of the studies was conducted during the
meta-analysis using the Chi-square test for heterogeneity
at a 5% level of significance. The I2 statistic was used to
Records after duplicates measure impact of statistical heterogeneity. 
removed (n=13)
RESULTS
Records screened (n=13) Records excluded (n=3) Description of studies

Full-text articles Full-text articles Included studies

assessed for excluded, with All the seven included studies were randomized, double-
eligibility (n=10) reasons (n=3) blind clinical trials comparing efficacy of Vitex negundo L. to
placebo for acute cough in patients aged 2 to 21 years old
in ambulatory settings in the Philippines. The total number
Studies included in
qualitative synthesis
of subjects enrolled in the seven studies was 308.   Five of
(n=7) the studies included patients 17 years and below, while two
studies included patients up to 21 years of age.  
Six of the studies utilized Vitex negundo syrup while
Studies included in one study used Vitex negundo tablets.   Among the six
quantitative synthesis studies that used the syrup preparation, four studies used
(meta-analysis) (n=7) 45 mg/kg/day in 3 divided doses, one study used 30 mg/
kg/day and one study explored both a 15 mg/kg/day and
Figure 1. Selection of Studies Flow Diagram. 30-mg/kg/day dose.   The single study that provided Vitex
negundo in tablet form used 300 mg tablets 3x a day for
Risk of bias in included studies children less than 10 years of age and 600 mg tablets 3x a
Two authors (DAB, JMP) determined the risk of bias day for children 10 years old and above.  In all the studies,
for the included studies by assessing random sequence placebo preparations that were similar to the intervention
generation, allocation concealment, blinding, selective in form and concentration were given.
reporting, and other sources of bias, and recorded the
assessment in the 'Risk of bias' tables in Review Manager Excluded studies
5.3 (Revman 2013). We ranked the studies as low risk, Three studies were excluded namely 1) Chu in 1988
unclear risk, and high risk of bias. because the study evaluated the effects of lagundi tablet

38 ACTA MEDICA PHILIPPINA VOL. 54 NO. 1 2020

 Lagundi for Non Bacterial Cough in Children

Figure 2. Risk of bias graph about risk of bias item presented as percentages across
all included studies.

vs theophylline in bronchial asthma; 2) Dyseng in 1996 kg/day) and high dose (30 mg/kg/day) in 3 divided doses.
because the study evaluated the effect of lagundi tablet However, in the Phase II trial done in 1994, lagundi syrup
vs placebo for chronic cough in former smokers and was given in one dose only at 15 mg/kg/dose (0.25 ml/kg/
3) Lagundi Technology Transfer Document (TTD) Phase dose). In the Phase III clinical trial done from January to
I (1993) of the National Integrated Research Program on December 1996, September to December 1997 and January
Medicinal Plants (NIRPROMP) because this is a single to December 1998, lagundi syrup was given at a dose of
blind randomized control trial between lagundi syrup vs 15 mg/kg/dose given 3x daily (45 mg/kg/day).  
placebo and bromhexine. Clinical parameters (frequency of cough and difficulty
of expectoration) were obtained in 4 studies namely, (a.)
Risk of bias in included studies Phase II July-December 1993, (b.) Phase III 1996, (c.) Phase
Most RCTs were evaluated to be of good quality with III 1997 and (d.) Phase III 1998. Difficulty of breathing as
a low risk of selection bias, performance and detection clinical parameter was obtained in all the Phase III studies
bias. Four studies presented incomplete outcome data as (Phase III 1996, Phase III 1997 and Phase III 1998).
participants dropped out of the study. (Figure 2) Frequency of cough, difficulty of expectoration, color and
character of phlegm, and difficulty of breathing were not
Effects of interventions obtained in 3 studies (Maramba et al 1989, Phase II 1993
and Phase II 1994). Efficacy evaluation was done using
Data and Analyses (Appendix V) a visual cough severity and cough relief scales and by the
physician using objective parameters and global assessment
Descriptive Analysis of Included Studies at the end of the patient’s follow-up.
In this systematic review, except for the study done Peak Expiratory Flow Rate (PEFR) as an objective
by Maramba et al 1989 where randomization sequence clinical parameter was obtained in all patients of 6 studies
was done by a statistician not affiliated with the study, all (Phase II 1993, Phase II July-December 1993, Phase II
the other six studies used a table of random numbers for 1994, and all Phase III studies namely (a.) 1996, (b.) 1997
randomization and this was verified with the authors of the and (c.) 1998) except in the study by Maramba et al in 1989
studies. In the Maramba et al 1989 study, lagundi tablet wherein PEFR was done only in cooperative participants.
was given at 300 mg/tablet 3x a day for children less than All outcomes were adequately reported in all the 7 studies.
10 years old and 600 mg/tablet 3x a day for children 10 All patients who dropped out from the study were not
years old and above. Patients in the placebo arm received included in the final analysis. A total of 37 patients were
matching tablets on the same regimen. Two follow-up visits dropped from the study; 1 participant was lost to follow-up
were done at 3-day intervals. Lagundi syrup was given in and 2 developed acute tonsillitis (Maramba et al 1989); 14
the other six studies. In the Phase II studies done in 1993, subjects dropped out and 1 showed no medical improvement
lagundi syrup prepared as 300 mg/5 mL was given at a dose requiring standard medical therapy (Phase II 1993); 19
of 30 mg/kg/day or 10 mg/kg/dose administered 3x a day. subjects dropped out from (Phase II July-December
In another Phase II study done in July-December 1993, 1993); 1 participant from the placebo group dropped out
lagundi syrup was given in two dose levels: low dose (15 mg/ (Phase III 1996).

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Lagundi for Non Bacterial Cough in Children

There was some heterogeneity among the studies in terms were analyzed. Medical studies have shown that drugs in
of outcome measurement, thus data abstraction was not done liquid form exhibit a higher rate of bioavailability compared
due to heterogeneity in outcome reporting. While all seven to the same drug of equivalent dose formulated in tablets or
studies measured peak expiratory flow rates at baseline and capsule because of the large surface area and high dissolution
follow-up visits, one study was only able to measure PEFR in rate of the liquid preparation. Liquid preparations also have
cooperative patients. Vitex negundo increased mean PEFR of faster absorption rate, higher optimization rate and is more
subjects at the end of therapy compared to placebo (MD 10.22, easily digestible.30 The body does not need to break down a
95% CI -11.58 to 32.02; participants=146; studies=6; I2=0%), liquid formulation thereby allowing more of the V. negundo
but this effect was not statistically significant (p-value=0.36). syrup preparation to be absorbed into the system. The liquid
The four studies that reported mean PEFR at the end of extracts take 1-4 minutes to assimilate in contrast to tablet or
therapy showed low heterogeneity (I2=0%) (Analysis 1). capsule which take 20-30 minutes just to break down, before
Although the result was not statistically significant, the the body can even start to assimilate them.31
increase in PEFR values effected by Vitex negundo treatment The frequency of coughing was significantly decreased by
reinforced the results of clinical and experimental studies the first follow-up in the lagundi group.  However, patients
tending to show bronchodilating property of lagundi. who received placebo also had significant improvement but
Frequency of cough was not measured in a standard only by the second follow-up, which suggests that, the usual
way.  Visual analog scales (VAS) were used to rate frequency, course of non-bacterial respiratory tract infection (ex. viral
cough severity and cough relief in 3 of the 7 studies.   One etiology) among the study population would last for 6 days in
study used a 4 to 5-point scale.  Furthermore, outcomes were 94-100% of patients as evaluated by the patients themselves
not stratified according to age group.   When all missing and the physician.  For younger children, the administration
data were imputed to have good outcomes, Vitex negundo of lagundi was no better than the placebo with regard to
significantly decreased cough frequency by 60% compared to the clinical parameters used because of the actual difficulty
placebo. (OR 0.41, 95% CI 0.11 to 1.47; participants=207; in assessing clinical improvement because of their inability
studies=5; I2=41%) (p-value=0.17) (Analysis 2). However, to express by themselves their clinical symptoms.  
when all missing data were imputed to have poor outcomes, There was no statistically significant difference noted
the effect size was smaller (33%) and not statistically in response to therapy based on subjective parameters, but
significant. (OR 0.67, 95% CI 0.35 to 1.30; participants=207; there were more patients with acute mild to moderate cough
studies=5; I2  = 0%) (p-value=0.24) (Analysis 3). We expect treated with lagundi who improved. At the same time, more
the true value of the odds ratio of cough reduction comparing patients treated with lagundi showed improvement in the
Vitex negundo to placebo in this sample to be between 0.41 color and character of their phlegm.
and 0.67. It is significant to note that 2 of the studies (Phase
III 1997 and 1998) had missing cough data at the end of Potential biases in the review process
therapy for more than 25% of the treatment group. These One of the review authors participated as co-investigator
studies were still included in the analysis. For the reduction in four of the seven included studies. The four studies are
of cough outcome, low heterogeneity (I2=0%) was also seen (a.) NIRPROMP TTD Phase II (1994), (b.) NIRPROMP
among the five studies included for the 'worst case scenario' TTD Phase III (1996, 1997 and 1998).
(all missing data imputed with poor outcomes). When the
missing data was imputed with good outcomes ('best case Agreements and disagreements with other studies
scenario'), there was moderate heterogeneity (I2=41%).  or reviews
When we limited the analysis to V. negundo syrup and There were no other systematic reviews on lagundi for
excluded the only study that used the tablet preparation, the treatment of acute cough of mild to moderate severity
V. negundo reduced cough frequency by at least 44% (not that has been published or searched by the authors.
statistically significant, p=0.11) (Analysis 4) to at most 71%
(statistically significant, p=0.006) (Analysis 5). Conclusions

DISCUSSION Lagundi therapy in acute cough of mild to moderate

severity among pediatric patients has a bronchodilating
There was a consistent increase in PEFR values effected effect and decreases the frequency and duration of coughing,
by lagundi treatment that reinforces the results of clinical with no serious adverse effects.
and experimental studies tending to show bronchodilating
property of lagundi. Bronchodilation may be a favorable Limitation of the study
characteristic of a cough preparation since some of these The number of participants was small in the included
acute cough have associated bothersome bronchospasm. clinical studies. The age group of the pediatric patients
There was a statistically significant (p=0.006) reduction included in the study should be the same across all the
in cough frequency when studies using only V. negundo syrup clinical studies done.

40 ACTA MEDICA PHILIPPINA VOL. 54 NO. 1 2020

 Lagundi for Non Bacterial Cough in Children

14. Patel JI, Shah SK, Deshpasde SS, Shah GB. Evaluation of
Recommendations antiasthmatic activity of leaves of Vitex negundo. Asian J Pharm Clin
A large scale clinical trial should be conducted that Res. 2009; 2(1):81-6.
utilize standardized objective and subjective measures. 15. Ladda PL, Magdum CS. et al. Vitex negundo Linn: Ethnobotany,
Objective measures of cough frequency such as automated Phytochemistry and Pharmacology- A review. Int J Adv Pharm
Biol Chem. 2012; 1(1):111-20.
cough frequency monitors and software32 are now already 16. Tandon VR. Medicinal uses and biological activities of Vitex negundo.
available.   For patient important outcomes, the Leicester Nat Prod Rad. 2005; 4(3):162-5.
Cough Questionnaire (LCQ) or Cough-specific Quality 17. Chattopadhyay P, Hazarika S, Dhiman S, Upadhyay A, Pandey
of life questionnaire (CQlQ)33-35 which has been validated A, Karmakar S, et al. Vitex negundo inhibits cyclooxygenase-2
inflammatory cytokine-mediated inflammation on carrageenan-
for use in acute cough can be employed. induced rat hind paw edema. Pharmacognosy Research. 2012;
4(3):134–7.
Statement of Authorship 18. Dharmasiri MG, Jayakody JR, Galhena G, Liyanage SS, Ratnasooriya
All authors participated in data collection and analysis, WD. Anti-inflammatory and analgesic activities of mature fresh
leaves of Vitex negundo. J Ethnopharmacol. 2003; 87(2-3):199–206.
and approved the final version submitted. 19. Gupta RK, Tandon VR. Antinociceptive activity of Vitex-negundo
Linn leaf extract. Indian J Physiol Pharmacol. 2005; 49(2):163–70.
Author Disclosure 20. Kulkarni RR, Virkar AD, Priscilla D’mello. Antioxidant and
Dr. Purificacion was involved in 4 studies which were antiinflammatory activity of Vitex negundo. Indian J Pharm Sci.
2008; 70(6):838–40.
included in the analysis. 21. Tandon VR, Gupta RK. Vitex negundo Linn (VN) leaf extract as
an adjuvant therapy to standard anti-inflammatory drugs. Indian J
Funding Source Med Res. 2006; 124(4):447–50.
This paper was funded by the authors. 22. Vinuchakkaravarthy T, Kumaravel KP, Ravichandran S, Velmurugan
D. Active compound from the leaves of Vitex negundo L. shows
anti-inflammatory activity with evidence of inhibition for secretory
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APPENDICES
Appendix I. PUBMED search strategy Appendix III. CENTRAL search strategy
1. Vitex negundo (160) 1. Vitex negundo (4)
2. Cough (43200) 2. Cough (216)
3. Lagundi (2) 3. Lagundi (2)
4. 1 and 2 (1) 4. 1 and 2 (1)
5. 2 and 3 (0) 5. 2 and 3 (1)
6. 1 and 2 and 3 (0) 6. 1 and 2 and 3 (1)

Appendix II. Philippine Index Medicus search strategy Appendix IV. HERDIN search strategy
1. Vitex negundo (0) 1. Vitex negundo (24)
2. Cough (14) 2. Cough (194)
3. Lagundi (0) 3. Lagundi (27)
4. 1 and 2 (0) 4. 1 and 2 (7)
5. 2 and 3 (0) 5. 2 and 3 (7)
6. 1 and 2 and 3 (0) 6. 1 and 2 and 3 (6)

Appendix V. Data and Analyses

Analysis 1. Forest Plot of Comparison of Included Studies for PEFR at End of Therapy.

Analysis 2. Forest Plot of Comparison of Included Studies for Reduction in frequency of cough, best case (FE model).

Analysis 3. Forest Plot of Comparison of Included Studies for Reduction in frequency of cough, worst case.

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 Lagundi for Non Bacterial Cough in Children

Analysis 4. Forest Plot of Comparison of Included Studies, V. negundo syrup only for Reduction in frequency of cough, best case.

Analysis 5. Forest Plot of Comparison of Included Studies, V. negundo syrup only for Reduction in frequency of cough, worst case.

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