Download Evaluation of Efficacy and Safety of Cystone Syrup in Lower Ureteric

Clinical
Study
Evaluation of Efficacy and Safety
of Cystone Syrup in Lower Ureteric
Calculus
Abstract
The present study evaluated the efficacy
and safety of Cystone syrup, a polyherbal
formulation, in lower ureteric calculus.
The incidence of urolithiasis is high in
developing countries, and in the northern
and north-western regions of India.
The study was an open, non-randomized,
non-comparative, prospective clinical trial
conducted as per the ethical guidelines
of Declaration of Helsinki. Twenty-five
patients having lower ureteric calculi were
included in this study. Patients with any
complication like severe pain, hematuria
or obstruction requiring immediate surgery,
hydronephrosis, acute renal failure, multiple
ureteric stones, pregnant or lactating
women, women with childbearing potential
without adequate contraception, hepatic/
renal/cardiac disease were excluded.
A thorough history and clinical
examination was done before treatment
and during follow-up visits every week
till the end of treatment on day 28 along
with recording of adverse events. All
patients were investigated before and after
the treatment for routine urine analysis
with culture and sensitivity and blood
urea, serum creatinine, sodium, potassium,
calcium, bicarbonate and uric acid levels.
All patients also underwent abdominal
radio imaging and ultrasound examination
at baseline and at the end of the therapy.
All 25 patients enrolled completed the
study. On starting Cystone syrup therapy,
a significant (p < 0.0001) symptomatic
relief of abdominal pain and dysuria
was reported. There was a significant
(p < 0.0001) reduction in the mean number
of pain episodes from 2.72 ± 1.339 to 0.92
± 0.8622 per day at the end of the therapy.
A significant reduction (p < 0.0001) in the
daytime and night time urinary frequency
was observed at the end of treatment.
Disappearance of stones was noted in 11
(44%, p < 0.001) patients at the end of
the 28-day study period. It was concluded
that Cystone syrup is clinically safe and
effective in the management of lower
ureteric calculus.
MG Shekar Kumaran*
SR Prasad**
SK Mitra†
Introduction
Urolithiasis affects 1-5% of population.
The incidence is higher in developing
countries, including India. It has been
hypothesized that the main source of
dietary proteins being cereals, unlike
meat in western countries, is an important
etiological factor1. The northern and northwestern regions of India can be described
as an endemic stone-forming belt due to a
dietary pattern rich in cereals and pulses2.
Urolithiasis is a consequence of complex
physicochemical processes and the major
contributory factors are urinary super
saturation, crystallization, calculogenesis
and matrix formation. The sequence of
events in the formation of any urinary
stone can be: Urinary saturation, super
saturation, nucleation, crystal growth,
crystal aggregation, crystal retention and
stone formation3.
Kidney stones smaller than 4 mm in
diameter are most likely to be flushed out
in urine without any medical intervention,
except occasional analgesics and anti
spasmodics that enable the patient to
endure the episode, which may last several
days. Kidney stones >5 mm in diameter
are less likely to be flushed out in urine
on their own. If the stone is larger than
Urolithiasis is a consequence
of complex physicochemical
processes and the major
contributory factors are
urinary super saturation,
crystallization, calculogenesis
and matrix formation.
*Laparscopic Surgeon and
Consultant Urologist,
Shree Sai Hospitals,
Choolaimedu, 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 - 562 123, India
E-mail: dr.prasad@
himalayahealthcare.com
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007
31
Clinical
Study
10 mm in diameter, it has to be either
removed by surgery or by lithotripsy.
Medical therapies using calcium
channel blockers or a-adrenergic
blockers to ease urinary stone
passage have been reported, but are
not generally used. Drugs with high
success rates, excellent safety profile,
low side effect profile, and ease of use,
have become the leading candidates in
medical therapy and should be used
as first-line therapy in the treatment
of a distal ureteral stone4.
The present study was planned
to evaluate the efficacy and safety
of Cystone syrup, a polyherbal
formulation, in lower ureteric
urolithiasis. Cystone syrup comprises
of extracts of Tribulus terrestris,
Boerhaavia diffusa, Saxifraga
ligulata, Cyperus rotundus, Asparagus
racemosus, Dolichos biflorus, Vetiveria
zizanioides, Curcuma zedoaria, Trikatu
and powders of Suvarchika, Narasara,
Yuvakshara and Saindhava.
Patients and methods
Inclusion criteria
Patients above 18 years, of either
sex, diagnosed ultrasonographically
or radiologically with visible distal
ureteric calculi of 4 mm size or larger,
below the common iliac vessels.
Exclusion criteria
Patients with severe pain, hematuria
or obstruction requiring immediate
surgery, marked hydronephrosis, acute
renal failure, pregnant or lactating
women, women with childbearing
potential without adequate
contraception, hepatic or renal or
cardiac disease, and those unwilling to
give informed consent.
Procedure
The study was an open, nonrandomized and non-comparative,
prospective, phase III clinical trial,
32
conducted at Shree Sai Hospitals,
Chennai, India from December 2006 to
May 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,
Hindi and Tamil) were approved by
the institutional ethics committee and
were approved by the same.
The OPD patients were informed
about the study drug, its effects,
duration of stay in the trial and overall
plan of the study. A written informed
consent was obtained. 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 one teaspoonful of Cystone
syrup, twice a day after meals for
28 days.
All patients were followed up
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/s (either reported
or observed).
All patients were investigated
before and after treatment for complete
urine analysis followed by culture and
sensitivity and 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-
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007
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 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 for evaluation of
reduction and passage of stones by
comparing baseline values and end-ofthe-treatment values were used.
Results
Twenty-five patients were enrolled
in the study (8 males and 17 females)
Clinical
Study
Table 1. Reduction in mean symptom score of
upper abdominal pain with Cystone syrup treatment
Parameter
Day 0
Day 7
Day 14
Day 21
Table 2. Reduction in mean symptom score of
dysuria with Cystone syrup treatment
Day 28
Parameter
Day 0
Day 7
Day 14
Day 21
Day 28
Mean
2.360
2.160
1.360*
1.200*
1.000*
Mean
1.120
1.120
0.6400
0.4800
0.4400*
Std. error
0.1137
0.1108
0.1514
0.1633
0.1732
Std. error
0.2332
0.2332
0.1720
0.1306
0.1424
[Upper abdominal pain (mean
symptom score)]
2.5
*p < 0.001 as compared with day 0 value
2.0
*
1.5
*
*
1.0
0.5
0.0
Day 0
Day 7
Day 21
Day 14
Day 28
Figure 1. Reduction in mean symptom score of upper abdominal
pain with Cystone syrup treatment (mean ± SEM).
Friedman test: Friedman statistic: 39.58; p < 0.0001; significant
Dunnett’s multiple comparison test: *p < 0.05 as compared with day 0 value
Dysuria (mean symptom score)
Friedman test: Friedman statistic: 66.90; p < 0.0001; significant
Dunnett’s multiple comparison test: *p < 0.001 as compared with day 0 value
*p < 0.05 as compared with day 0 value
1.4
1.2
1.0
0.8
*
0.6
0.4
0.2
0.0
Day 0
Day 7
Day 14
Day 21
Day 28
Figure 2. Reduction in mean symptom score of dysuria with
Cystone syrup treatment (mean ± SEM).
Table 3. Reduction in number of pain episodes with
Cystone syrup treatment
Table 4. Reduction in mean symptom score of day
time urinary frequency with Cystone syrup treatment
Parameter
Day 0
Day 7
Day 14
Day 21
Parameter
Day 0
Day 7
Day 14
Day 21
Day 28
Mean
2.720
2.160
1.520*
1.000** 0.9200**
Mean
5.400
5.280
4.760*
4.760*
4.720*
Std. error
0.2678
0.1600
0.1428
0.1633
Std. error
0.3367
0.3241
0.2400
0.2023
0.1873
Day 28
0.1724
Friedman test: Friedman statistic: 73.18; p < 0.0001; significant
Dunnett’s multiple comparison test: *p < 0.01 and **p < 0.001 as compared with
day 0 value
*p < 0.01 and **p < 0.001 as compared with day 0 value
2.5
2.0
*
1.5
**
1.0
**
0.5
0.0
5.8
Daytime urinary frequency
(No. of times)
No. of pain episodes scor
3.0
Repeated measure of ANOVA: R = 0.2341; F = 7.335; p < 0.0001, significant
Dunnett’s multiple comparison test: *p < 0.01 as compared with day 0 value
2
5.6
5.4
5.2
Day 7
Day 14
Day 21
Day 28
Figure 3. Reduction in number of pain episodes with Cystone
syrup treatment (mean ± SEM).
and all the su bjects 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 (Tables 1
*
5.0
*
*
4.8
4.6
4.4
4.2
4.0
Day 0
*p < 0.01 as compared with day 0 value
Day 0
Day 7
Day 14
Day 21
Day 28
Figure 4. Reduction in mean symptom score of daytime urinary
frequency with Cystone syrup treatment (mean ± SEM).
and 2; Figs. 1 and 2). There was a
significant (p < 0.0001) reduction in
the mean number of pain episodes
from 2.72 ± 0.2678 to 0.92 ± 0.1724
at the end of the therapy (Table 3 and
Fig. 3). A significant reduction (p <
0.0001) in the daytime and night time
urinary frequency was observed at
the end of treatment (Tables 4 and 5;
Figs. 4 and 5). The reduction in the
symptoms started appearing right from
the day 14 of therapy.
Disappearance of calculi
(dissolution or spontaneous passage)
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007
33
Clinical
Study
Table 5. Reduction in mean symptom score of night time
urinary frequency with Cystone syrup treatment
Table 6. Reduction in mean calculus size with
Cystone syrup treatment
Parameter
Day 0
Day 7
Day 14
Day 21
Day 28
Parameter
Mean
1.640
1.360*
1.240**
1.280**
1.240**
Mean
Std. error
0.1514
0.1137
0.1327
0.1083
0.1046
Std. error
Repeated measure of ANOVA: R = 0.1914; F = 5.679; p < 0.0001, significant
Dunnett’s multiple comparison test: *p < 0.05 and **p < 0.01 as compared with
day 0 value
1.8
*p < 0.05 and **p < 0.01 as compared with day 0 value
1.6
*
1.4
**
**
**
Day 14
Day 21
Day 28
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Day 0
Day 7
Figure 5. Reduction in mean symptom score of night time urinary
frequency with Cystone syrup treatment (mean ± SEM).
was noted in 11 (44%; p < 0.001)
patients at the end of the 28-day
study period, as confirmed by X-ray
KUB and ultrasound examination
(Table 6 and Figs. 6 and 7). The size
of expelled stones varied between
5-12 mm, the average size being 7
mm. There was a significant decrease
(p < 0.001) in the mean size of the
calculus from 8.80 ± 0.55 mm to 6.08
± 1.06 mm after 28 days of treatment
with Cystone syrup (Table 7 and
Fig. 8).
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.
10
9
8
7
6
5
4
3
2
1
0
There were no recurrences and
clinically significant adverse events,
either reported or observed, during the
study period.
Discussion
Recent advances in endoscopic
stone management have allowed
kidney stones to be treated using
minimally invasive techniques, which
have increased success rates and
decreased treatment-related morbidity.
These advances include shock wave
lithotripsy (SWL), ureteroscopy and
percutaneous nephrostolithotomy.
Although these approaches are less
invasive than traditional open surgical
approaches, they are expensive and
have inherent risks5.
Recently, medical expulsion therapy
Present
Absent
Before treatment
25
0
After treatment
14
11
Fisher’s exact test: p < 0.0002; significant
34
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007
6.08
0.5477
1.064
t = 4.327; df = 24; p < 0.0002; significant
Before treatment
After treatment
Figure 6. Reduction in mean calculus size with Cystone syrup
treatment (mean ± SEM).
Table 7. Improvement in number of patients with calculi
with Cystone syrup treatment
Parameter
After treatment
8.80
Paired ‘t’ test: t = 4.327; df = 24; p < 0.0002; significant
Calculus size
(mean symptom score)
Night time urinary frequency
(No. of times)
2
Before treatment
(MET) 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
MET are calcium channel blockers,
steroids, nonsteroidal anti-inflammatory
drugs (NSAIDs), and α 1-adrenergic
receptor antagonists6.
Although success has been shown
with calcium channel blockers with
or without steroids and/or NSAIDs,
α-blockers, with their high success rates,
excellent safety profile, low side effect
profile, and ease of use, have become
the leading candidate in MET4.
In the present study, disappearance
of calculi (dissolution or spontaneous
passage) was noted in 11 patients at
the end of the 28-day study period.
A significant symptomatic relief from
abdominal pain and dysuria was
reported by patients. There was a
Clinical
Study
Before treatment
Before treatment
Before treatment
Before treatment
Patient No. 1
Patient No. 3
Patient No. 5
Patient No. 7
After treatment
Before treatment
After treatment
Before treatment
After treatment
Before treatment
After treatment
Before treatment
Before treatment
Patient No. 2
Patient No. 4
Patient No. 6
After treatment
After treatment
After treatment
After treatment
Patient No. 8
After treatment
Patient No. 9
Figure 7. Ultrasound images of patients with lower ureteral stones before and after treatment with Cystone syrup.
indicate that it has the
*p < 0.0002 as compared with
25
before treatment
potential of propelling
7
urinary stones . The
20
steroidal saponin
15
constituents obtained
*
from T. terrestris
10
were tested for their
antimicrobial and
5
cytotoxic effects8.
In an investigation,
0
Before treatment
After treatment
a methanol extract
Present
Absent
obtained from roots of
B. diffusa exhibited a Figure 8. Improvement in number of patients with calculi with
significant spasmolytic Cystone syrup treatment.
No. of patients
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 was observed
at the end of treatment. The reduction
in symptoms started appearing from
the day 14 of therapy itself.
The beneficial actions of Cystone
syrup might be due to the synergistic
actions of its ingredients. T. terrestris
has long been used empirically to
propel urinary stones. The diuretic
and contractile effects of T. terrestris
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007
35
Clinical
Study
activity in the guinea pig ileum,
probably through a direct effect on
the smooth muscle9.
The hexane extracts of C. rotundus
showed potent treatment of dysuria10.
In Ayurveda, A. 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 stresses 11. The ethanolic extract
of A. racemosus showed inhibitory
potential on lithiasis (stone formation)
and this plant extract inhibits stone
formation12.
Methanol extract of the roots of
A. 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 aureus13.
The chemical compositions of
the essential oil of C. zedoaria
(Berg.) Rosc. were analyzed by gas
chromatography-mass spectrometry
(GC-MS). The essential oil was
evaluated for potential antimicrobial
activity against S. aureus, E. coli,
Pseudomonas aeruginosa, Vibrio
parahaemolyticus, S. typhimurium and
Bacillus cereus. V. parahaemolyticus
was sensitive to the presence of the
essential oil14.
The analgesic activity of C.
zedoaria rhizomes was proven in a
phytochemical analysis study15.
Soxhlet extracts of seeds of
D. biflorus and S. ligulata showed
in vitro antilithiatic/anticalcification
activity16. An in vitro study has showed
the effect of D. biflorus seeds on
crystallization of calcium phosphate, a
major constituent of kidney stone17.
Therefore, the observed clinical
benefits of Cystone syrup might be
due to the synergistic actions of its
ingredients.
36
Conclusion
Surgery or lithotripsy is the
available option in urolithiasis and
recurrence is the core issue in the
clinical management of urolithiasis. A
drug, which will inhibit calculogenesis,
in addition to high success rates,
excellent safety profile, low side effect
profile, and ease of use, is ideal for
management of urolithiasis.
This study indicates Cystone syrup
to be an effective and safe treatment
in lower ureteric calculus as it expels
the stones and brings about significant
reduction of symptoms associated with
urolithiasis. The overall compliance of
Cystone syrup was good. No clinically
significant adverse reactions were
reported or observed during the entire
study period.
References
1. Polinsky MS, Kaiser BA and Balurate
HJ. Urolithiasis in childhood. Pediatr.
Clin. North Am. 1987;3:683-704.
2. Teotia M and Teotia SPS. Kidney and
bladder stones in India. Postgraduate
Med. 1977;53:41-48.
3. Nabi G, Cook J, N’Dow J and
McClinton S. Outcomes of stenting
after uncomplicated ureteroscopy:
Systematic review and metaanalysis. BMJ 2007;334:572.
4. Lipkin M and Shah O. The use of
alpha-blockers for the treatment
of nephrolithiasis. Rev. Urol.
2006;8(Suppl. 4):S35-S42.
5. Segura JW, Preminger GM, Assimos
DG, et al. Ureteral stones clinical
guidelines panel summary report on
the management of ureteral calculi.
J. Urol. 1997;158:1915-1921.
Zea mays. J. Ethnopharmacol. 2003;
85(2-3):257-260.
8. Bedir E, Khan IA and Walker
LA. Biologically active steroidal
glycosides from Tribulus terrestris.
Pharmazie 2002;57(7):491-493.
9. Borrelli F, Ascione V, Capasso R, Izzo
AA, Fattorusso E and TaglialatelaScafati O. Spasmolytic effects of
nonprenylated rotenoid constituents
of Boerhaavia diffusa roots. J. Nat.
Prod. 2006 June;69(6):903-906.
10. Ngamrojanavanich N, Manakit
S, Pornpakakul S and Petsom A.
Inhibitory effects of selected Thai
medicinal plants on Na+,K+-ATPase.
Fitoterapia 2006;77(6):481-483.
11. Bopana N and Saxena S. Asparagus
racemosus: Ethnopharmacological
evaluation and conservation needs.
J. Ethnopharmacol. 2007;110(1):1-15.
12. Christina AJ, Ashok K, Packialakshmi
M, Tobin GC, Preethi J and Murugesh
N. Antilithiatic effect of Asparagus
racemosus willd on ethylene glycolinduced lithiasis in male albino
Wistar rats. Methods Find. Exp. Clin.
Pharmacol. 2005;27(9):633-638.
13. Mandal SC, Nandy A, Pal M and
Saha BP. Evaluation of antibacterial
activity of Asparagus racemosus
willd. root. Phytother. Res. 2000;14(2):
118-119.
14. Lai EY, Chyau CC, Mau JL, Chen
CC, Lai YJ, Shih CF and Lin LL. Antimicrobial activity and cytotoxicity
of the essential oil of Curcuma
z e d o a r i a . Am. J. Chin. Med.
2004;32(2):281-290.
15. Navarro Dde F, de Souza MM, Neto
RA, Golin V, Niero R, Yunes RA, Delle
Monache F and Cechinel Filho V.
Phytochemical analysis and analgesic
properties of Curcuma zedoaria
grown in Brazil. Phytomed. 2002;
9(5):427-432.
6. Hollingsworth JM, Rogers MAM,
Kaufman SR, et al. Medical therapy
to facilitate urinary stone passage:
A meta-analysis. Lancet 2006;368:
1171-1179.
16. 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.
7. Al-Ali M, Wahbi S, Twaij H and
Al-Badr A. Tribulus terrestris:
Preliminary study of its diuretic and
contractile effects and comparison with
17. Peshin A and Singla SK. Anticalcifying
properties of Dolichos biflorus (horse
gram) seeds. Indian J. Exp. Biol.
1994;32(12):889-891.
Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007