Review
article
Evaluation of Efficacy and Safety
of Cystone Syrup in Lower Ureteric
Calculi
Jeyaraman*, SR Prasad**, SK Mitra†
*Consultant Urologist, Professor and Head,
Department of Urology, Madras Medical College, Chennai.
**Medical Advisor,
†
Executive Director,
R&D Center, The Himalaya Drug Company, Bangalore.
Address for correspondence:
Dr SR Prasad, Medical advisor,
R & D Center, The Himalaya Drug Company, Bangalore.
E-mail: [email protected]
After 28-day treatment with Cystone syrup, disappearance of calculi was
noted in 12 patients. A significant symptomatic relief from abdominal pain
and dysuria was reported by patients.
Abstract
The present study was planned
to evaluate the efficacy and safety
of Cystone syrup, a polyherbal
formulation, in lower ureteric
calculi. The prevalence of urinary
calculi is estimated to be 5% in the
general population, with an annual
incidence of as much as 1%.
This study was an open, nonrandomized,
non-comparative,
prospective clinical trial conducted
as per the ethical guidelines of
Declaration of Helsinki. Twentyfive patients having lower ureteric
calculi were included in this study.
Patients with any complication
like severe pain, hematuria or
obstruction requiring immediate
surgery, marked hydronephrosis,
acute renal failure, multiple
ureteral stones, pregnant or
lactating women, women with
childbearing potential without
adequate contraception, and those
with hepatic or renal or cardiac
disease were excluded from the
study.
A thorough history, symptomatic
evaluation and clinical examination
was done for all patients before
treatment and during follow-up
visits every week till the end of
treatment on day 28 along with
recording the occurrence of any
adverse event/s. All the patients
were investigated before and after
treatment for routine urine analysis
with culture and sensitivity,
blood urea, serum creatinine,
sodium, potassium, calcium and
bicarbo-nate, and uric acid levels.
All
patients
also
underwent
abdominal radio imaging and
ultrasound examination at baseline
and at the end of the therapy.
Twenty-five
patients
were
enrolled in the study and all the
subjects completed the study.
On
starting
Cystone
syrup
therapy, a significant (p < 0.0001)
symptomatic relief from abdominal
pain and dysuria was reported by
patients. There was a significant
(p < 0.0001) reduction in the
mean number of pain episodes
from 4.520 ± 0.451 to 1.320 ± 0.298
per day at the end of the therapy.
A significant reduction (p < 0.0001)
in the daytime and night-time
urinary frequency, and tenderness
in KUB area was observed at the
end of treatment. Disappearance
of stones was noted in 12 (48%;
p < 0.001) patients at the end of
the 28-day study period. Therefore,
it may be concluded that Cystone
syrup is clinically safe and
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
33
Review
article
effective in the management of
lower ureteric calculi.
Introduction
The prevalence of urinary
calculi is estimated to be 5% in
the general population, with an
annual incidence of as much as
1%. Men are twice as likely as
women to develop calculi, with
the first episode occurring at an
average age of 30 years. Women
have a bimodal age of onset,
with episodes peaking at 35 and
55 years. Without preventive
treatment, the recurrence rate of
calcium oxalate calculi increases
with time and reaches 50% at
10 years1.
Renal calculi are crystalline
mineral deposits that form in
the kidney. They develop from
microscopic crystals in the loop
of Henle, the distal tubule, or
the collecting duct, and they can
enlarge to form visible fragments.
The process of stone formation
depends on urinary volume;
concentrations
of
calcium,
phosphate, oxalate, sodium and
uric acid ions; concentrations of
natural calculi inhibitors (e.g.,
citrate,
magnesium,
TammHorsfall mucoproteins, bikunin);
and urinary pH2.
Calculi are classified into
five categories based on their
composition:
calcium
oxalate
(70%), calcium phosphate (5-10%)
uric acid (10%), struvite (15-20%)
and cystine (1%)3.
With hydration and pain
control, calculi smaller than
5 mm will pass spontaneously in
approximately 90% of patients.
The rate of passage decreases as
stone size increases; a 1 cm stone
34
has a <10% chance of passing
without surgical intervention4.
Recent studies5 have suggested
that the use of the a1-adrenergic
blocker, tamsulosin, can increase
the chance of spontaneous passage
of ureteric calculi.
Surgical options include extracorporeal shock wave lithotripsy,
ureteroscopic stone extraction and
percutaneous
nephrolithotomy.
Ureteric calculi is a significant
health
problem.
Although,
surgical management has become
increasingly tolerable, medical
prevention of recurrent calculi
is feasible, easily obtained and
greatly desirable.
Twenty-five
patients
were
enrolled in the study and all
the
subjects
completed
the
study. The present study was
planned to evaluate the efficacy
and safety of Cystone syrup, a
polyherbal formulation, in lower
ureteric calculi. Cystone syrup
comprises of extracts of Tribulus
terrestris,
Boerhaavia
diffusa,
Saxifraga ligulata, Cyperus rotundus,
Asparagus
racemosus,
Dolichos
biflorus,
Vetiveria
zizanioides,
Curcuma zedoaria and Trikatu and
powders of Suvarchika, Narasara,
Yuvakshara and Saindhava.
Patients and methods
Inclusion criteria
Patients above 18 years of
age, of either sex, and diagnosed
with
ultrasonographically
or
radiologically, with visible distal
ureteric calculi of 5-10 mm size,
below the common iliac vessels
were included in the study.
Exclusion criteria
Patients with any complication
like severe pain, hematuria or
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
obstruction requiring immediate
surgery, marked hydronephrosis,
acute renal failure, pregnant or
lactating women, women with
childbearing potential without
adequate
contraception,
those
with hepatic or renal or cardiac
disease, and those unwilling
to give informed consent were
excluded from the study.
Study procedure
The study was an open, nonrandomized and non-comparative,
prospective, phase III clinical
trial, conducted at B.R. Speciality
Hospital and Research Centre,
T. Nagar, Chennai, Tamil Nadu,
India between March 2007 to
June 2007 as per the ethical
guidelines of Declaration of
Helsinki. The study protocol, case
report forms (CRFs), regulatory
clearance
documents,
product
related information, and informed
consent forms (in English and
Tamil) were submitted to the
institutional ethics committee and
were approved by the same.
Twenty-five
patients
were
enrolled in the study and all the
subjects completed the study.
The patients who attended the
OPD surgical unit were informed
about the study drug, its effects,
duration of stay in the trial, and
overall plan of the study. The
patients were included in the
clinical study only after written
informed consent was obtained
from them.
The history was noted by
interviewing
each
patient.
Thorough clinical examination
and symptomatic evaluation was
carried out and the details were
noted down in the CRF. Patients
were advised to take 1 teaspoonful
Review
of Cystone syrup, twice a day
after meals for 28 days.
All patients were reviewed
every week till the end of treatment
on day 28, and symptomatic
evaluation and clinical examination
was done along with recording the
occurrence of any adverse event
(either reported or observed).
All patients were investigated
before
and
after
treatment
for
complete
urine
analysis
with culture and sensitivity,
blood urea, serum creatinine,
sodium, potassium, calcium and
bicarbonate, and uric acid levels.
Patients also underwent abdominal
radio imaging and ultrasound
examination at baseline and at the
end of the therapy.
Primary and secondary
end-points
The predefined primary endpoints were the effects on change
in the number and size of stones,
and spontaneous passage of
stone. The predefined secondary
end-points were symptom score
reduction, short- and long-term
safety, and overall compliance to
the drug treatment.
Adverse events
All adverse events, reported
or observed by patients, were
recorded with information about
severity, date of onset, duration
and action taken regarding the
study drug. Relation of adverse
events
to
study
medication
were predefined as “unrelated”
(a reaction that does not follow
a reasonable temporal sequence
from the administration of the
drug), “possible” (follows a
known response pattern to the
suspected drug, but could have
been produced by the patient’s
clinical state or other modes
of therapy administered to the
patient) and “probable” (follows
article
a known response pattern to
the suspected drug that could
not be reasonably explained by
the known characteristics of the
patient’s clinical state).
Patients were allowed to
voluntarily withdraw from the
study if they experienced serious
discomfort during the study or
sustained serious clinical events
requiring
specific
treatment.
For patients withdrawing from
the study, efforts were made to
ascertain the reason for dropout.
Non-compliance (defined as failure
to take <80% of the medication)
was not regarded as treatment
failure, and reasons for noncompliance were noted.
Statistical analysis
One
way
ANOVA
test
followed by Dunnett’s Multiple
Comparison test for evaluation of
symptomatic scores, Fisher’s Exact
test and Paired Student “t” test
Table 1. Reduction in mean symptom score of abdominal pain, dysuria, number of
pain episodes, urinary frequency and tenderness in KUB area with Cystone syrup
treatment (mean ± SEM)
Parameter
Day 0
Day 7
Day 14
Day 21
Day 28
Statistics and
significance
Abdominal
pain
3.053
± 0.143
2.684
± 0.110
1.211
± 0.211#
1.053
± 0.248#
0.474
± 0.221*
FS: –179.5; p<0.0001,
significant
Dysuria
2.080
± 0.163
2.000
± 0.173
1.680
± 0.160
1.480
± 0.201
0.800
± 0.216#
FS: 33.84; p<0.0001,
significant
No. of pain
episodes
4.520
± 0.451
3.240
± 0.226#
2.800
± 0.192#
2.240
± 0.240#
1.320
± 0.298#
R2 = 0.3576; FS = 4.888;
p<0.0001, significant
Urinary
frequency
1.960
± 0.227
1.920
± 0.223
1.760
± 0.210
1.600
± 0.208
0.880
± 0.226#
R2 = 0.6694; FS = 12.61;
p<0.0001, significant
Tenderness
in KUB area
2.160
± 0.180
2.040
± 0.187
1.760
± 0.145
1.440
± 0.183
0.840
± 0.214*
FS: 44.44; p<0.0001,
significant
Statistical analysis was carried out using repeated ANOVA test and Friedman test, followed by Dunnett’s Multiple Comparison test.
#
p<0.01 and *p<0.001 as compared with day 0 value.
Abbreviation: FS: Friedman statistic value
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
35
article
Review
Table 2. Reduction in number of patients with calculi
following Cystone syrup treatment
No. of patients
Present
25
13
Before treatment
After treatment
Absent
0
12*
Results
Statistical analysis was carried out using repeated ANOVA test, followed by Fisher’s exact test.
*p<0.001 as compared with day 0 value
Table 3. Reduction in mean calculi size before and
after treatment with Cystone syrup (mean ± SEM)
Parameter
Calculi size (mm)
Before treatment
After treatment
7.204 ± 0.341
4.040 ± 0.821*
Statistical analysis was carried out using repeated ANOVA test, followed by Paired “t” test.
*p<0.001 as compared with day 0 value.
Abdominal pain (mean symptom score)
3.5
#
3.0
3.053
p<0.01 and *p<0.001 as compared with day 0 value
2.000
2.5
2.0
#
1.5
#
1.211
1.0
1.053
0.5
*
0.474
0.0
Day 0
Day 7
Day 14
Day 21
Day 28
Figure 1. Reduction in mean symptom score of abdominal pain with Cystone syrup treatment
(mean ± SEM).
Dysuria (mean symptom score)
2.5
2.0
#
2.08
p<0.01 as compared with day 0 value
2.00
1.68
1.5
1.48
#
1.0
0.80
0.5
0.0
Day 0
Day 7
Day 14
Day 21
Figure 2. Reduction in mean symptom score of dysuria with Cystone syrup treatment
(mean ± SEM).
36
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
for evaluation of reduction and
passage of stones by comparing
baseline values and end-of-thetreatment values were used.
Day 28
Twenty-five
patients
were
enrolled in the study (19 males
and six females) and all the
subjects completed the study.
The mean age of the patients was
37.2 years. On starting Cystone
syrup therapy, a significant
(p<0.0001)
symptomatic
relief
from
abdominal
pain
and
dysuria was reported by patients
(Table 1; Figs. 1 and 2). There
was a significant (p<0.0001)
reduction in the mean number of
pain episodes from 4.520 ± 0.451
to 1.320 ± 0.298 at the end of
the therapy (Table 1 and Fig. 3).
A significant reduction (p<0.0001)
in the daytime and night time
urinary frequency, and tenderness
in KUB area was observed at the
end of treatment (Table 1; Figs.
4 and 5). The reduction in the
symptoms started appearing from
the day 7 of therapy itself.
Disappearance
of
calculi
(dissolution
or
spontaneous
passage) was noted in 12
(48%; p<0.0001) patients at the
end of the 28-day study period,
as confirmed by X-ray KUB
and
ultrasound
examination
(Table 2 and Fig. 6). The size of
expelled stones varied between
5-8 mm, the average size being
6.08 ± 0.2865 mm. There was
a significant decrease (p<0.001)
in the mean size of the calculi
from 7.204 ± 0.341 mm to 4.040 ±
0.821 mm after 28 days of
treatment with Cystone syrup
(Table 3 and Fig. 7).
No. of pain episodes (mean symptom score)
Review
5.0
4.5
4.0
#
p<0.01 as compared with day 0 value
4.52
#
3.5
#
3.24
3.0
2.80
2.5
#
2.24
2.0
#
1.5
1.32
1.0
0.5
0.0
Day 0
Day 7
Day 14
Day 21
Day 28
Urinary frequency (mean symptom score)
Figure 3. Reduction in mean symptom score of number of pain episodes with Cystone syrup
treatment (mean ± SEM).
2.5
2.0
#
1.96
1.92
1.5
p<0.01 as compared with day 0 value
1.76
1.60
1.0
#
0.88
0.5
0.0
Day 0
Day 7
Day 14
Day 21
Day 28
Tenderness in KUB area (mean symptom score)
Figure 4. Reduction in mean symptom score of urinary frequency with Cystone syrup treatment
(mean ± SEM).
2.5
*p<0.001 as compared with day 0 value
2.0
2.16
2.04
1.76
1.5
1.44
*
1.0
0.84
0.5
0.0
Day 0
Day 7
Day 14
Day 21
Day 28
Figure 5. Reduction in mean symptom score of tenderness in KUB area with Cystone syrup
treatment (mean ± SEM).
article
There was no change in the
biochemical
investigations
of
blood urea, serum creatinine,
sodium, potassium, calcium and
bicarbonate, and uric acid levels,
and urine analysis done between
baseline and day 28 of the
therapy.
There were no recurrences
and clinically significant adverse
events, either reported or observed,
during the study period.
Discussion
The majority of individuals with
nephrolithiasis have small ureteral
stones that pass spontaneously.
However, patients may experience
severe pain during this process,
which significantly alters their
quality-of-life and may limit
their vocational responsibilities.
Therefore, measures to facilitate
stone passage are uniformly
embraced.
The rate of spontaneous passage
with no medical intervention for
a stone of 5 mm or smaller in the
proximal ureter is estimated to be
29-98%, and in the distal ureter,
71-98%. The most important
factors in predicting the likelihood
of spontaneous stone passage are
stone location and stone size6.
Recently, medical expulsion
therapy has been investigated as
a supplement to observation in
an effort to improve spontaneous
stone passage rates, which can be
unpredictable. Because ureteral
edema and ureteral spasm have
been postulated to affect stone
passage, these effects have been
targeted
for
pharmacologic
intervention.
Therefore,
the
primary agents that have been
evaluated for medical expulsion
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
37
Review
25
article
#
p<0.001 as compared with before treatment value
Present
No. of patients
20
Absent
15
*
10
5
0
Before treatment
After treatment
Figure 6. Reduction in number of patients with calculi following Cystone syrup treatment
Mean calculi size (mm)
8
#
p<0.001 as compared with day 0 value
7
6
5
*
4
3
2
1
0
Before treatment
After treatment
Figure 7. Reduction in mean calculi size before and after treatment with Calculi syrup treatment
(mean ± SEM).
therapy are calcium channel
blockers, steroids, nonsteroidal
anti-inflammatory drugs (NSAIDs),
and alpha-1-adrenergic receptor
antagonists.
A
recent
metaanalysis was performed, looking
at studies that compared stone
passage rates in patients who were
given calcium channel blockers
or alpha-1-adrenergic receptor
antagonists versus controls who
did not receive these medications.
The analysis demonstrated a
65% greater chance of passing
a ureteral stone in patients who
received either medication7.
In the present study, disappearance of calculi (dissolution
38
or spontaneous passage) was noted
in 12 patients at the end of the
28-day study period. Other stones
could not be passed out as they
were more than 10 mm in size.
A significant symptomatic relief
from abdominal pain and dysuria
was reported by patients. There
was a significant reduction in the
mean number of pain episodes
from baseline to the end of the
therapy. A significant reduction
in the daytime and night-time
urinary frequency, and tenderness
in KUB area was observed at the
end of treatment. The reduction in
symptoms started appearing from
the Day 7 of therapy itself.
Indian Journal of Clinical Practice | Vol. 18 | No. 7 | December 2007
The beneficial actions of
Cystone syrup might be due
to the synergistic actions of its
ingredients.
Tribulus
terrestris
has long been used empirically
to propel urinary stones. The
diuretic and contractile effects of
Tribulus terrestris indicate that it
has the potential of propelling
urinary stones8. The steroidal
saponin constituents obtained
from Tribulus terrestris were
tested for their antimicrobial and
cytotoxic effects9.
In an investigation, a methanol
extract
obtained
from
roots
of Boerhavia diffusa exhibited
a
significant
spasmolytic
activity in the guinea pig
ileum,
probably
through
a
direct effect on the smooth
muscle10. The hexane extracts of
Cyperus rotundus showed potent
treatment of dysuria11.
In
Ayurveda,
Asparagus
racemosus has been described as a
rasayana herb and has been used
extensively as an adaptogen to
increase the non-specific resistance
of body against a variety of
stresses12. The ethanolic extract
of Asparagus racemosus showed
inhibitory potential on lithiasis
(stone formation) and this plant
extract inhibits stone formation13.
Methanol extract of the roots of
Asparagus racemosus showed
considerable in vitro antibacterial
efficacy against Escherichia coli,
Shigella dysenteriae, Shigella sonnei,
Shigella flexneri, Vibrio cholerae,
Salmonella
typhi,
Salmonella
typhimurium, Pseudomonas putida,
Bacillus subtilis and Staphylococcus
aureus14.
The
chemical
constituents
of the essential oil of Curcuma
zedoaria
(Berg.)
Rosc.
were
Review
analyzed by gas chromatographymass spectrometry (GC-MS). The
essential oil was evaluated for
potential antimicrobial activity
against
Staphylococcus
aureus,
Escherichia
coli,
Pseudomonas
aeruginosa, Vibrio parahaemolyticus,
Salmonella
typhimurium
and
Bacillus cereus. V. parahaemolyticus
was sensitive to the presence of
the essential oil15. The analgesic
activity
of Curcuma zedoaria
rhizomes was proven in a
phytochemical analysis study16.
Soxhlet extracts of seeds of
Dolichos biflorus and Saxifraga
ligulata
showed
in
vitro
antilithiatic/anticalcification
activity17. An in vitro study has
showed the effect of Dolichos
biflorus seeds on crystallization
of calcium phosphate, a major
constituent of ureteric calculi18.
Therefore, the observed clinical
benefits of Cystone syrup might
be due to the synergistic actions
of its ingredients.
Conclusion
Surgery or lithotripsy is the
available treatment option for
calculi and recurrence is the core
issue in the clinical management
of calculi. A drug, which will
article
inhibit calculogenesis, in addition
to high success rates, excellent
safety profile, low side effect
profile, and ease of use, is ideal
for management of calculi.
This study indicates Cystone
syrup to be an effective and safe
treatment in lower ureteric calculi
as it expels the stones and brings
about significant reduction of
symptoms associated with calculi.
The overall compliance of Cystone
syrup was good. No clinically
significant adverse reactions were
reported or observed during the
entire study period.
References
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on ethylene glycol-induced lithiasis in male albino Wistar rats. Methods Find. Exp. Clin. Pharmacol. 2005;27(9):633-638.
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17. Garimella TS, Jolly CI and Narayanan S. In vitro studies on antilithiatic activity of seeds of Dolichos biflorus Linn. and rhizomes
of Bergenia ligulata Wall. Phytother. Res. 2001;15(4):351-355.
18. Peshin A and Singla SK. Anticalcifying properties of Dolichos biflorus (horse gram) seeds. Indian J. Exp. Biol. 1994;32(12):
889-891.
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