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Comparison of Ziziphus jujube
Mill. Syrup versus polyethylene
glycol in children with functional
constipation: a randomized clinical
trial
Fatemeh Keihanian1, Shohreh Maleknejad2, Amin Saeidinia3,4, Soheil Soltanipour5 &
Amir Pirooz2
Functional constipation is a common disorder of the gastrointestinal tract in children without
specic treatment. Ziziphus jujuba has been used in traditional medicine for various diseases such
as constipation. A safe and inexpensive treatment with few side eects can be used as an eective
alternative to current medications. In this study, we sought to compare Ziziphus jujuba syrup (ZS)
with polyethylene glycol (PEG) for the treatment of pediatric functional constipation. A double-blind,
randomized clinical trial was performed on children aged 2–10 years with functional constipation
who were referred to the gastroenterology clinic of the 17-Shahrivar Hospital in Rasht, Iran. Eligible
patients were randomized into two groups: PEG group; 1–5 cc/kg/day (40% w/v solution without
electrolytes; average dose: 0.2–1 g/kg), and ZS group; 1–5 cc/kg/day (average dose: 5–25 mg/kg). All
patients were followed up for three months, every 2 weeks in the rst month, and then monthly for 2
months. At the beginning and end of the study, liver and kidney function tests and blood sugar levels
were checked. Data were analyzed using SPSS software version 19 at a signicance level of 0.05. Out
of 90 eligible children, 32 patients in the PEG group and 30 patients in the ZS group completed the
follow-up visits. The mean age of the subjects was 4.31 ± 1.97 years. There was no signicant dierence
between the two groups in terms of age (P = 0.181), gender (P = 0.218), age at onset of constipation
(P = 0.083), and weight (P = 0.199). The average therapeutic response score in the ZS group improved
prominently compared to the PEG group (P < 0.05). The average number of encopresis and visual
analog scale pain scores signicantly decreased in the ZS group compared to the PEG group (P < 0.05).
Other indices, including frequency of defecation, and medication adherence in the ZS group were
signicantly improved compared to the PEG group (P < 0.05). Only in the PEG group, a few cases
reported self-limiting side eects. ZS can be a treatment choice for functional constipation without
any adverse events or liver or kidney injury in children. However, further studies are necessary to nd
potential side eects.
Keywords Functional constipation, Ziziphus jujube Mill., Polyethylene glycol, Clinical trial
Functional constipation is one of the most frequent complaints in childhood, which is oen dicult to manage1.
It accounts for more than 3% of visits to general pediatricians and 10–25% of pediatric gastroenterology
consultations2,3. Constipation is dened as infrequent and painful defecation, hard or large stools, and fecal
incontinence, usually associated with abdominal pain4,5. In about 95% of children suering from constipation,
no underlying pathological condition is responsible for the development of symptoms6. e global prevalence of
pediatric functional constipation varies from 0.7 to 29.6% (median 12%)7–9. e peak incidence of constipation
1Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
2Pediatric Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran. 3Pharmaceutical
Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
4Department of Pediatric, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad,
Iran. 5Department of Community Medicine, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
email: shohremaleknejad@gmail.com
OPEN
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occurs during toilet training, between the ages of 2 and 4 years10. Genetic susceptibility, insucient uid and
ber intake, immobility, postponing defecation in public places, especially in schools, early or poor toilet training,
and introduction of solids during the process of weaning are some of the predisposing factors for functional
constipation11. e pathophysiology of this disorder is biopsychosocial, lacking an identiable structural or
biochemical etiology12. Withholding behavior is the most common etiology of functional constipation, usually
occurring aer an episode of painful defecation, which leads to a vicious cycle of stool withholding, pain, and
infrequent bowel movements13.
Functional constipation is diagnosed clinically, based on history, physical examination, and the ROME IV
criteria14,15. e delay in diagnosis and intervention leads to more severe functional constipation and a worse
prognosis16,17. Childhood constipation negatively impacts children’s physical, social, emotional, and school
functioning18. Treatment of functional constipation includes a combination of non-pharmacological and
pharmacological options19. Pharmacological treatment of functional constipation with laxatives comprises three
stages: disimpaction, maintenance therapy and nally weaning4.
Laxative drugs mainly include bulking, osmotic, lubricating, and stimulant agents20. Polyethylene glycol
(PEG) 3350 is widely prescribed as the rst-choice drug in pediatrics. Common side eects of PEG include
diarrhea, bloating, atulence, nausea, and abdominal pain3,21.
Lactulose, mineral oil, and magnesium hydroxide are prescribed as the second therapeutic options. However,
they are limited to certain age groups and can cause serious adverse eects22. ey have minimal therapeutic
eects but considerable side eects, while the symptoms tend to recur23. e evidence of non-pharmacological
modalities is weak24. erefore, nding an eective and safe therapeutic option for the treatment of functional
constipation in children is essential.
e trend of using natural-based drugs and complementary and alternative medicine is increasing25.
Ziziphus jujuba is one of the medicinal plants used as an analgesic, anticonvulsant, and anti-constipation in
the folk medicine of dierent countries26–29. Clinical trials on Ziziphus fruit showed anti-inammatory,
antihyperglycemic, and anti-hyperlipidemic eects on type 2 diabetes mellitus patients30.
Medicinally active peptides such as cyclopeptide alkaloids, avonoids, sterols, jujuboside A, jujuboside B,
lauric acid, and triterpenoid saponins have been sequestered and chemically identied from various Ziziphus
species26. It has been considered safe in a wide range of doses31. Despite its laxative eects in traditional
medicines, there are limited investigations in the context of pediatric constipation. A previous study in the adult
population showed appropriate laxative eects32.
Material and methods
Study design and population
A prospective, double-blind, randomized controlled-trial (12-week follow-up) was conducted in the 17-Shahrivar
tertiary referral hospital in Rasht, Iran, from April 2020 to January 2021. Children aged between 2 and 10 years
who referred to the pediatric gastroenterology clinic with functional constipation were included in our study.
e sample size was calculated using the mean scores and standard deviation of the severity of pain based
on the visual analog scale (20 ± 19.9) in the study of Mozaarpur et al.33 by OpenEpi version 3 soware. Aer
calculating the dropout rate up to 10%, with power (1−β) = 0.90, and type I error probability and α = 0.01, a
sample size of 30 was obtained for each group.
Eligibility
Diagnosis of functional constipation was based on the ROME IV criteria aer ruling out organic causes by
history taking, physical examination, and laboratory tests. e physical examination consisted of a thorough
abdominal examination, evaluation of growth parameters, inspection of the perianal region (for ssures, skin
tags, polyps, or any obvious anomalies), and lumbosacral region (for pits, dimples, and creases), and a digital
rectal examination. Each patient was assessed in terms of red ags, abdominal distension, and fecal impaction in
the lower abdominal quadrant and hypogastric region.
Patients with organic causes of constipation (including hypothyroidism, Hirschsprung’s disease, celiac,
diabetes insipidus, cystic brosis, renal, cardiac, and neurological disorders), FTT or weight loss greater than
5%, those with a history of colorectal surgery and medication use in the last 3 months (such as antidepressants,
anticonvulsants, and sedatives), and children with fecal impaction were not eligible for study participation.
Patients with incomplete follow-up visits and those who declined to participate were excluded.
Randomization and blinding
Eligible patients were randomly allocated to PEG or ZS groups, by block randomization with a block size of
four (ratio 1:1). e order of the blocks was randomly determined in the PEG or ZS group, and the subjects
were assigned with the order of admission. A random allocation method was employed to determine sequences
using non-transparent envelopes sealed with random sequences (sequentially numbered, sealed, and opaque
envelopes).
e pediatric gastroenterologist (principal investigator) and patients/parents were both blinded to the
treatment allocation. Another medical practitioner not involved in the data analysis was unblinded to the
treatment groups and was responsible for allocating the drug to each patient and determining the dose. e
statistician was also blinded and used coded trial data in SPSS.
Intervention
In the PEG group, patients received oral PEG solution (Sepidaj Company, Iran) at a dose of 1–5cc/kg/day (0.2–1
g/kg) given as two divided doses. In the ZS group, oral consumption of Ziziphus jujuba syrup at a dose of 1–5cc/
kg/day (5–25mg/kg) was administered similarly in two divided doses. In both groups, treatment was continued
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for a total of 12 weeks. All parents were educated about proper diet, including increased uid intake and dietary
ber, and behavioral modications such as a regular toileting schedule, sitting on the toilet for 5–10min aer
each meal, and considering rewards for appropriate toileting behavior.
PEG and ZS preparation and standards
e plant was identied and authenticated as a Ziziphus jujube Mill. by an academic pharmacognosist. e fruits
of Ziziphus jujuba Mill. were collected from Birjand, Iran, in September 2019. Five kilograms of fruits were
shade dried and coarsely powdered. About 3.3kg of powder was extracted with water and ethanol by percolation
method in the Faculty of Pharmacy, Mashhad, Iran by a pharmacist. Aer the extraction was completed, the
solvent was recovered by distillation and concentrated in vacuo. e formulation of syrup was prepared with
sucrose, distilled water, and sodium benzoate, and the syrup with 10% (v/v) of the extract was provided (the
concentration was 5mg/ml). All microbiologic, stability, and physicochemical tests of syrup were performed,
and total phenolic content and fructose content were determined by the HPLC method in the nal sample
(Supplementary Table S1–3).
PEG was initially prepared as a solution, in which 1cc contains 0.2 g of PEG. e PEG solution and ZS were
packaged in the same dark 250 mL glass bottles. To ensure successful blinding, only the treatment code and lot
number were placed on the outside of each bottle.
Assessment and follow-ups
For each patient, a checklist containing demographic data (age, sex, developmental status, age at onset of
constipation, surgical history) was completed. Frequency of defecation, stool consistency measured through the
Bristol Stool Form Scale, visual analog scale (VAS) pain score, presence of fecal incontinence, and other related
gastrointestinal symptoms (such as nausea, vomiting, atulence, and abdominal pain), and positive ndings in
the physical examination were documented at the rst visit. In addition, we used the scoring system of functional
constipation criteria according to the Karami et al. study34. To determine therapeutic response as a variable, we
calculated scores for the following variables at each visit: painful defecation, blood in stool, stool frequency per
week, number of encopresis per month, and stool consistency. e minimum score was six, and the maximum
was 21. erapeutic response was classied as follows: poor (6–10), moderate (11–15), and good (16–21).
All patients were visited every 2 weeks in the rst month, then monthly for 2 months (a total of 3 months).
Parents were requested to fulll a weekly checklist to record the number of defecations, encopresis, bloody stool,
VAS pain score, and fecal consistency according to the Bristol stool chart. In each visit, symptoms, adherence to
medication, and side eects were controlled. Medication adherence was evaluated based on the 4-item Morisky
scale35. Blood sugar levels and kidney and liver function tests were checked at the beginning and the end of the
trial for each participant. e primary endpoint was the VAS pain score, and the secondary one was adverse drug
events. Parents had access to an on-call physician in case of any complications or side eects.
Ethics declaration
is research was conducted in conformance with the principles stated in the Helsinki Declaration and was
approved by the ethical committee of Guilan University of Medical Sciences (Ethics code: IR.GUMS.REC.1397.157).
e study was also registered in the Iranian Registry of Clinical Trials (IRCT ID: IRCT20131006014915N3)
on 26/09/2018. Written informed consent was obtained from parents or legal guardians of all patients aer
explaining the purpose of the study.
Data analysis
All data were entered into SPSS soware version 19 (SPSS Inc. Chicago, Il, e USA). Descriptive statistics were
expressed as mean, standard deviation, frequency, and percent. e normal distribution of quantitative data
was evaluated by the Shapiro–Wilk test. e independent t-test was applied for normally distributed variables
and the Mann–Whitney test for non-normally distributed variables. For analysis of repetitive quantitative data
during the study follow-ups, the repeated measures ANOVA test was employed. e signicance level was set at
P < 0.05 in all tests.
Results
Forty-eight patients were assigned to the PEG group and 42 to the ZS group. However, during the study, 16
subjects in the PEG group and 12 subjects in the ZS group were excluded. e study owchart is depicted in
Fig.1.
e mean age of the subjects was 4.31 ± 1.97 years and 53.2% of them were females. ere was no statistically
signicant dierence between the two groups regarding the baseline demographic data (P > 0.05). Demographic
characteristics are presented in Table1.
As shown in Table2, baseline clinical manifestations of patients in both groups were not signicantly dierent
(P-value > 0.05).
Laboratory ndings
ere were signicant dierences in hemoglobin (P = 0.026) and TSH (P = 0.023) between ZS and PEG groups.
Other baseline laboratory data are listed in Table3.
Laboratory data at the last follow-up showed signicant dierences in AST (ZS group: 23.60 ± 6.81 vs. PEG
group: 33.35 ± 10.17; P = 0.003) and blood sugar levels (ZS group: 95.90 ± 9.56 vs. PEG group: 84.36 ± 9.40;
P = 0.005) between the two groups. Despite the statistically signicant dierence, it was not clinically relevant
and both of them were in the normal range.
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Characteristics ZS group (n = 30) PEG group (n = 32) P-value
Abdominal distention, n (%) 2 (6.7) 1 (3.1) 0.475
Stool retention on the DRE, n (%) 6 (20) 13 (40.6) 0.068
Abnormal sphincter tone, n (%) 0 1 (3.1) –
Anal ssure, n (%) 7 (23.3) 4 (12.5) 0.217
Tab le 2. Baseline clinical manifestations of patients in the ZS and PEG groups. ZS Ziziphus jujuba syrup, PEG
polyethylene glycol, DRE digital rectal examination.
Characteristics ZS group (n = 30) PEG group (n = 32) P-value
Gender, n (%) Male 12 (40) Male 17 (53.1) 0.218
Female 18 (54.5) Female 15 (46.9)
Age (mean ± S.D) years 4.66 ± 2.36 3.97 ± 1.48 0.181
Age at onset of constipation (mean ± S.D) months 37.40 ± 26.97 27.50 ± 16.19 0.083
Weight (mean ± S.D) kg 19.42 ± 7.83 17.17 ± 5.71 0.199
Familial history, n (%) 5 (16.7) 1 (3.1) 0.084
Tab le 1. Comparison of demographic data in the ZS and PEG groups. ZS Ziziphus jujuba syrup, PEG
polyethylene glycol, S.D standard deviation.
Fig. 1. e study owchart.
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Clinical ndings
As shown in Table4, the therapeutic response in the ZS group was prominently better than the PEG group
at all follow-up visits (P = 0.001). In addition, the frequency of defecation in the ZS group was signicantly
higher than the PEG group at all follow-up intervals (P < 0.05; Fig.2a). e number of encopresis in the ZS
group signicantly decreased compared to the PEG group (P < 0.05; Fig.2b). VAS scores in the ZS group were
signicantly lower than the PEG group at weeks 4, 8, and 12 aer the intervention (P < 0.05; Fig.2c). In terms of
fecal consistency, there was no signicant dierence in the ZS group and PEG group at follow-up intervals (P>
0.05; Fig.2d).
Adverse events
Vomiting and abdominal pain were reported in the rst, second, and third weeks of the intervention in two
cases and in the fourth week in three cases of the PEG group. ere were no drug-related complications in the
ZS group. Improper consumption of the medication was reported in three cases of the PEG group in the second
week, in two cases of the PEG group in the third week, in ve cases of the PEG group and two cases of the ZS
group in the 12th week.
Medication adherence
Medication adherence of the patients at 2, 4, 8, and 12 weeks of follow-up was signicantly better in the ZS group
compared to the PEG group (P < 0.001) (Fig.3).
Discussion
Although pediatric constipation is a common chronic problem, few studies have compared dierent laxatives.
Among children who were referred to pediatric gastroenterologists, 50% would improve and be taken o
laxatives aer 6–12 months. About 10% of patients do well when using laxatives, and 40% will continue to have
symptoms despite using laxatives19. In this trial, we sought to compare the ecacy and safety of ZS and PEG
in children with functional constipation. To the best of our knowledge, this was the rst study to assess the
ecacy of ZS in pediatric functional constipation. Our ndings revealed that the mean therapeutic response
score, frequency of defecation, encopresis, and medication adherence were signicantly better in the ZS group
compared to the PEG group. e average number of encopresis and VAS pain score was signicantly decreased
in the ZS group than in the PEG group.
PEG is one of the choice therapeutic options, but children are not interested in its avor. Despite dierent
options in the treatment of functional constipation, there is limited evidence of their ecacy. Ziziphus jujube
fruit contains betulinic acid, oleanolic acid, maslinic acid, glucose, sitosterol, stigmasterol, desmosterol, resin,
Wee k 2 We ek 4 Wee k 8 Week 12
erapeutic response
PEG group 10.59 ± 1.77 11.09 ± 2.23 11.62 ± 2.73 11.62 ± 2.73
ZS group 13.03 ± 3.54 14.83 ± 3.64 15.10 ± 3.59 16.86 ± 4.56
P-value 0.001 0.001 0.001 0.001
Tab le 4. Comparison of therapeutic response in the ZS and PEG groups in follow-up visits. ZS Ziziphus jujuba
syrup, PEG polyethylene glycol.
Characteristics ZS group (n = 30) PEG group (n = 32) P-value
WBC (mean ± S.D) 7088.18 ± 0.43 1.48 ± 0.26 0.181
Hemoglobin (mean ± S.D) g/dL 11.82 ± 1.07 12.49 ± 1.05 0.026
Platelet (mean ± S.D) 303.05 ± 70.93 297.40 ± 78.90 0.791
Blood sugar (mean ± S.D) mg/dL 94.81 ± 14.54 87.58 ± 12.78 0.081
Sodium (mean ± S.D) 137.42 ± 1.89 138.77 ± 2.68 0.066
Potassium (mean ± S.D) 4.18 ± 0.23 4.33 ± 0.44 0.146
Calcium (mean ± S.D) 9.86 ± 0.62 9.61 ± 0.50 0.147
Phosphorus (mean ± S.D) 4.74 ± 0.82 4.88 ± 0.83 0.581
AST (mean ± S.D) U/L 31.21 ± 7.08 35.72 ± 19.24 0.258
ALT (mean ± S.D) U/L 15.16 ± 5.23 20.14 ± 16.62 0.211
Bun (mean ± S.D) mg/dL 14.85 ± 4.97 15.51 ± 7.30 0.722
Creatinine (mean ± S.D) mg/dL 0.65 ± 0.14 0.59 ± 0.12 0.159
TSH (mean ± S.D) 2.05 ± 0.67 2.96 ± 1.65 0.023
FT4 (mean ± S.D) 9.80 ± 6.50 8.74 ± 5.91 0.562
Tab le 3. Comparison of baseline laboratory data in the ZS and PEG groups. ZS Ziziphus jujuba syrup,
PEG polyethylene glyco, S.D standard deviation, WBC white blood cell, AST aspartate aminotransferase,
ALT Alanine transaminase, TSH thyroid stimulating hormone, FT4 free thyroxine.
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catechol, tannin, essential oil, 13 types of amino acids, selenium, calcium, phosphorus, iron, cAMP, and cGMP31.
Its toxicity has been investigated in mice and doses up to 150g/kg did not show any signs of toxicity. LD50 for
intraperitoneal injection was 14g/kg e LD50 for intraperitoneal injection was 14g/kg36.
In a double-blind clinical trial, the ecacy of Ziziphus jujuba extract for chronic idiopathic constipation
in adults was examined, using both subjective self-reports and objective measurement of transit time. eir
ndings demonstrated that Ziziphus jujuba is eective for the treatment of chronic constipation. e transit time
was markedly improved in the treatment group. Furthermore, most patients expressed their satisfaction with the
treatment based on the severity of symptoms and quality of life questionnaire32.
In this study, we found that the most abundant carbohydrate in standardized ZS is fructose, with 40 g/100
g of dried extract. In an in vivo experimental study on hamsters, the dried extract of Ziziphus jujuba (∼82.4g/
kg of dried jujube) was shown to have high water-soluble carbohydrates (∼77% by weight on a moisture-free
basis). eir results suggested that feeding diets with medium and high doses of water-soluble carbohydrate
concentrate extract (5–15g/kg of diet) signicantly shortened transit time and improved intestinal motility in
comparison with the control group. e fecal moisture content in the group with medium- and high-dose diets
was considerably higher than the control group. It was concluded that a signicant reduction in transit time
decreases water reabsorption in the intestinal lumen, which leads to an increase in moisture retention in feces.
ese changes may have a substantial impact on the intestinal mucosa by reducing exposure to toxic ammonia
and other harmful contents37.
In a clinical trial study on 121 neonates, the eect of Ziziphus Jujuba extract and phototherapy on the
reduction of bilirubin level and also the hospitalization period for neonatal jaundice were examined. Patients were
compared into two groups. In the intervention group, 1cc/kg of Ziziphus Jujuba extract was given orally three
times a day in addition to phototherapy and was compared with another group that received only phototherapy.
is study revealed that administration of Ziziphus Jujuba extract can lead to bilirubin excretion in neonates
owing to laxative eects and increased urine output. ZS is prepared from the extract of a naturally growing
fruit and contains several compounds. Now, we cannot attribute the laxative eect to a particular ingredient. In
Fig. 2. Comparison of clinical ndings at baseline, 2, 4, 8, and 12 weeks of follow-up in the PEG and ZS
groups using the general linear model. (a) Number of defecation; e upper curve, representing the ZS group,
shows an increase in the frequency of defecation with a much faster course. (b) Fecal encopresis; e lower
curve representing the ZS group shows a decrease in the frequency of fecal encopresis over time, but the
upper curve shows an increasing trend despite a good decrease in the rst 4 weeks. (c) VAS pain score; e
lower curve that represents the ZS group indicates a signicant decrease over time. (d) Fecal consistency; e
dierence between the two groups is not statistically signicant.
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a previous study, it was contributed to a form of anthraquinone, as contained in senna and other plant-based
laxatives32. However, according to the analysis of ingredients in our study, it could also be attributed to its high
fructose content and high total phenolic content.
is was the rst clinical trial in evaluating the ecacy of standardized ZS in functional constipation. We also
assessed patients’ medication adherence in each follow-up.
Limitation
e primary limitation of this investigation was the lack of an objective index for assessing the improvement
of constipation, which can be considered in future research by measuring colonic transit time. Long-term drug
safety should also be assessed. We educated all parents about proper diet, behavioral modications, and proper
physical activity. As the study did not include any measurement tools to evaluate these aspects among patients,
this should be considered as another potential limitation.
Conclusion
ZS is a potentially safe and eective therapeutic choice for functional constipation without adverse eects and
can be prescribed for at least 3 months. Further investigations are recommended to assess the long-term ecacy
and safety of the syrup using both subjective and objective methods.
Data availability
e data that support the ndings of this study are available from the corresponding author upon reasonable
request.
Received: 3 August 2024; Accepted: 6 January 2025
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Author contributions
S.M., F.K., A.S., and S.S. designed the study. F.K. and A.S. participated in syrup preparation. S.M. visited the
patients and F.K. allocated the drugs and collected the data. S.S. performed the statistical analysis. A.P. contrib-
uted to data interpretation. F.K., S.M., and A.S. wrote the rst dra of the manuscript. All authors contributed to
revising the manuscript and approved the nal version of the submitted manuscript.
Declarations
Competing interests
e authors declare no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at h t t p s : / / d o i . o r g / 1
0 . 1 0 3 8 / s 4 1 5 9 8 - 0 2 5 - 8 5 8 0 1 - w .
Correspondence and requests for materials should be addressed to S.M.
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