Evaluation of Efficacy and Safety of Cystone Syrup in ... Cystone Syrup in Lower Ureteric Calculus ... the treatment for routine urine analysis ... The Himalaya Drug Company,

31Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007

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

MG Shekar Kumaran*SR Prasad**

SK Mitra†

AbstractThe 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 his tory and cl inical 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.

IntroductionUrolithiasis 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 north-western 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.

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*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, IndiaE-mail: [email protected]

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32 Indian Journal of Clinical Practice l Vol. 18 l No. 4 l September 2007

10 mm in diameter, it has to be either removed by surgery or by lithotripsy.

Medical therapies using calcium channel blockers or a-adrenergic b lockers to ease ur inary s tone 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 fo rmula t ion , in lower u re te r i c urolithiasis. Cystone syrup comprises of extracts of Tribulus terrestris, Boerhaav ia d i f f u sa , Sax i f raga ligulata, Cyperus rotundus, Asparagus racemosus, Dolichos biflorus, Vetiveria zizanioides, Curcuma zedoaria, Trikatu and powders of Suvarchika, Narasara, Yuvakshara and Saindhava.

Patients and methods

Inclusion criteriaPatients 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 p o t e n t i a l w i t h o u t a d e q u a t e contraception, hepatic or renal or cardiac disease, and those unwilling to give informed consent.

ProcedureThe study was an open, non-

randomized and non-comparative, prospective, phase III clinical trial,

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 r ad io imag ing and u l t r a sound examination at baseline and at the end of the therapy.

Primary and secondary end-points

The predefined primary end- points 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 eventsAll 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 non-compliance were noted.

Statistical analysisOne 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-of-the-treatment values were used.

ResultsTwenty-five patients were enrolled

in the study (8 males and 17 females)

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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

Table 1. Reduction in mean symptom score of upper abdominal pain with Cystone syrup treatment

Parameter Day 0 Day 7 Day 14 Day 21 Day 28Mean 2.360 2.160 1.360* 1.200* 1.000*Std. error 0.1137 0.1108 0.1514 0.1633 0.1732Friedman test: Friedman statistic: 66.90; p < 0.0001; significantDunnett’s multiple comparison test: *p < 0.001 as compared with day 0 value

Table 2. Reduction in mean symptom score of dysuria with Cystone syrup treatment

Parameter Day 0 Day 7 Day 14 Day 21 Day 28Mean 1.120 1.120 0.6400 0.4800 0.4400*Std. error 0.2332 0.2332 0.1720 0.1306 0.1424Friedman test: Friedman statistic: 39.58; p < 0.0001; significantDunnett’s multiple comparison test: *p < 0.05 as compared with day 0 value

Figure 1. Reduction in mean symptom score of upper abdominal pain with Cystone syrup treatment (mean ± SEM).

*p < 0.001 as compared with day 0 value

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Figure 2. Reduction in mean symptom score of dysuria with Cystone syrup treatment (mean ± SEM).

*

and al l 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 (Tables 1

Table 3. Reduction in number of pain episodes with Cystone syrup treatment

Parameter Day 0 Day 7 Day 14 Day 21 Day 28Mean 2.720 2.160 1.520* 1.000** 0.9200**Std. error 0.2678 0.1600 0.1428 0.1633 0.1724Friedman test: Friedman statistic: 73.18; p < 0.0001; significantDunnett’s multiple comparison test: *p < 0.01 and **p < 0.001 as compared with day 0 value

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 Day 28Mean 5.400 5.280 4.760* 4.760* 4.720*Std. error 0.3367 0.3241 0.2400 0.2023 0.1873Repeated measure of ANOVA: R2 = 0.2341; F = 7.335; p < 0.0001, significantDunnett’s multiple comparison test: *p < 0.01 as compared with day 0 value

3.0

2.5

2.0

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0.5

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*p < 0.01 and **p < 0.001 as compared with day 0 value

No.

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ain

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Day 7 Day 14 Day 21 Day 28

Figure 3. Reduction in number of pain episodes with Cystone syrup treatment (mean ± SEM).

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Figure 4. Reduction in mean symptom score of daytime urinary frequency with Cystone syrup treatment (mean ± SEM).

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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.

D i s a p p e a r a n c e o f c a l c u l i (dissolution or spontaneous passage)

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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.

There were no recurrences and clinically significant adverse events, either reported or observed, during the study period.

DiscussionRecent 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

(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 α1-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

Table 5. Reduction in mean symptom score of night time urinary frequency with Cystone syrup treatment

Parameter Day 0 Day 7 Day 14 Day 21 Day 28Mean 1.640 1.360* 1.240** 1.280** 1.240**Std. error 0.1514 0.1137 0.1327 0.1083 0.1046Repeated measure of ANOVA: R2 = 0.1914; F = 5.679; p < 0.0001, significantDunnett’s multiple comparison test: *p < 0.05 and **p < 0.01 as compared with day 0 value

Table 6. Reduction in mean calculus size with Cystone syrup treatment

Parameter Before treatment After treatmentMean 8.80 6.08Std. error 0.5477 1.064Paired ‘t’ test: t = 4.327; df = 24; p < 0.0002; significant

Figure 5. Reduction in mean symptom score of night time urinary frequency with Cystone syrup treatment (mean ± SEM).

*p < 0.05 and **p < 0.01 as compared with day 0 value1.8

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t = 4.327; df = 24; p < 0.0002; significant109876543210

Cal

culu

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Figure 6. Reduction in mean calculus size with Cystone syrup treatment (mean ± SEM).

After treatment

Table 7. improvement in number of patients with calculi with Cystone syrup treatment

Parameter Present AbsentBefore treatment 25 0After treatment 14 11Fisher’s exact test: p < 0.0002; significant

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indicate that it has the potential of propelling urinary stones7. The s t e r o i d a l s a p o n i n constituents obtained f rom T . t e r re s t r i s were tested for their a n t i m i c r o b i a l a n d cytotoxic effects8.

In an investigation, a methanol extract obtained from roots of B. diffusa exhibited a significant spasmolytic

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

Figure 7. Ultrasound images of patients with lower ureteral stones before and after treatment with Cystone syrup.

*p < 0.0002 as compared with before treatment

25

20

15

10

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No.

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atie

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Before treatment

Figure 8. Improvement in number of patients with calculi with Cystone syrup treatment.

After treatment

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Present Absent

Before treatment After treatmentPatient No. 1









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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 stresses11. 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 p u t i d a , B a c i l l u s s u b t i l i s a n d 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.

ConclusionSurgery or l i thotripsy 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.

References1. 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 meta- analysis. 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.

6. Hollingsworth JM, Rogers MAM, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: A meta-analysis. Lancet 2006;368: 1171-1179.

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

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 Taglialatela-Scafati 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 glycol-induced 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. Anti-microbial activity and cytotoxicity of the essential oil of Curcuma zedoar ia. 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.

16. Garimella TS, Jolly CI and Narayanan S. In vitro studies on antilithiatic activity of seeds of Dolichos biflorus Linn. and rhizomes of Bergenia l igulata Wall. Phytother. Res. 2001;15(4):351-355.

17. Peshin A and Singla SK. Anticalcifying properties of Dolichos biflorus (horse gram) seeds. Indian J. Exp. Biol. 1994;32(12):889-891.

Evaluation of Efficacy and Safety of Cystone Syrup in ... Cystone Syrup in Lower Ureteric Calculus ... the treatment for routine urine analysis ... The Himalaya Drug Company,

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