SILDENAFIL IS SAFE AND EFFECTIVE FOR THE TREATMENT OF LOWER URETERIC STONE WITH NO MAJOR SIDE EFFECT Affiliation

KC SR, Timilsina BR, Upadhyay HP, Devkota G, Shah R, Lamichhane N. Sildenafil is Safe and Effective for the Treatment of Lower Ureteric Stone with no Major Side Effect. BJHS 2018;3(3)7: 560-564. * Corresponding Author Dr Sudeep Raj KC Lecturer Department of Urology College of Medical Science, Teaching Hospital, Nepal Email: sudeeprkc786@gmail.com ORCID ID: https://orcid.org/0000-0002-6584-3768 ORA 90 ABSTRACT


INTRODUCTION
Urolithiasis is one of the most common disease of the urinary tract.Prevalence of urinary stones in a life me is approximately 1% to 15%.Peak age of incidence is 30 years.Male are more commonly affected than female about 2 to 3 1 mes.At the me of presenta on 20 % of the calculi are found in the ureter, among which 70% are located in the 2 distal third of the ureter.Spasm induced by ureter due to stone will interfere with its expulsion.So, by reducing spasm and gaining normal peristal c ac vity the stone expulsion chance increases.
Fi y percentage of the ureteric calculi will pass spontaneously in me but size of the calculi is the key factor for its success.Calculi less than 5 mm in size will pass spontaneously and decreases significantly as the size increases.There is only 20% chance of stone expulsion if stone size is greater than 8 3 mm in size.
Most commonly used agents for medical expulsion therapy is alpha-1 adrenergic blocker.
Many studies have proven that tamsulosin increases the stone expulsion rate and decreases the expulsion me.So, it 4,5 is extensively used.Nowadays, phosphodiesterase-5 (PDE5) inhibitors has shown some promise in stone expulsion.Phosphodiesterases are enzymes that regulate intracellular cyclic nucleo de metabolism cyclic guanosine monophosphate [cGMP], cyclic adenosine monophosphate [cAMP]) which helps in the relaxa on and contrac on of the muscles.Some of the studies have shown that phosphodiesterase-5 relax 6 muscles of the lower ureter.
Sildenafil, a PDE5 inhibitor, causes local release of NO, causes increased levels of cGMP which further causes 7 relaxa on of the smooth muscles of ureter.Sildenafil is drug which is used in erec le dysfunc on(ED) and some mes even in lower urinary tract symptoms due to benign enlargement of prostate (BEP), its role in distal ureteric calculi has not been well prac ced in Nepal.On the other hand, tamsulosin is well accepted and used widely in our part of the world.This study is aimed to analyse the safety and efficacy of Sildenafil in distal ureteric calculi and also to compare the efficacy of Sildenafil with placebo group.

METHODOLOGY
This is a quasi-experimental study performed in College Of Medical Science, Chitwan, Nepal, from February 2017 to February 2018 and ethical clearance was taken from ins tu onal review board.Inclusion criteria were pa ent over 16 years presented to outpa ent department in the department of urology, <10 mm calculi located in distal ureter confirmed with NCCT, CT Urography or USG.Exclusion criteria were pa ent with history of heart diseases, high or low blood pressure, ac ve pep c ulcer, urinary tract infec on which was confirmed with urine culture and sensi vity, severe pain not controlled with NSAIDS, acute or chronic renal failure, single func oning kidney, congenital ureteric anomalies, calculi in bilateral ureter, mul ple calculi in the ureter, calculi in mid and proximal ureter, risk factor to priapism (e.g.sickle cell anaemia, mul ple myeloma or leukaemia) Sample size for treatment group was calculated using the formula, Where, p1=prevalence in treatment group= 67.3%, p =prevalence in comparison group= 40.4%, p= (p +p )/2,1: r=required ra o (1:1).
The level of significance was kept at α= 0.05, the power was kept at 1-β=0.8,Z value was taken single sided as the alterna ve hypothesis is set as use of sildenafil is be er than no treatment.Sample size for comparison group was calculated as (r*n).Sample size in each group was calculated to be 47 a er taking non response rate as 10%, which was then increased to 50.Hence total sample size was taken as 100.
100pa ent were divided into two groups Group A and Group B with the help of lo ery method.In group A we had pa ent on placebo and in group B we had pa ent receiving sildenafil 50 once daily for the period of two weeks.Both group of pa ent received tab diclofenac 50 mg for three days then as per requirement by the pa ent for colicky pain.Pa ent were asked to drink plenty of water and filter urine with thin net to look for stone whether or not it is excreted.Pa ent were asked to follow up in OPD on weekly basis and whenever required.The record for analgesic use, adverse effect of the drugs, and number of hospital visit for pain and expulsion me for stone were recorded.Data were collected and filled in proforma.Data were analyzed by using the SPSS16.0.Discrete variables were evaluated by chi-square test and con nuous variables by unpaired Student t-test.All sta s cal tests were based on two-tailed probability, and a p-value <0.05 was considered sta s cally significant.
Expulsion of stone was confirmed with the help of history by asking pa ent to pass urine through filter and reconfirmed with USG.In some pa ent who s ll showed hydronephrosis in USG scan were subjected to NCCT to confirm expulsion.Side effect of drugs were also recorded like headache, postural hypertension, backache and gastri s.
Primary objec ve of this study was to check for stone expulsion and secondary objec ve was to check for number of colicky pain, analgesic required and drug side effect.Pa ent who failed for stone expulsion were subjected to surgery.

RESULTS
Group A (placebo group) included 29 male and 19 female with mean age of 30.93 ± 13.94, while group B (sildenafil group) included 29 male and 18 female with mean age of 29.08± 12.0.No sta s cal difference were observed in pa ent age between two groups P=0.49 neither with regards to sex difference p=0.576 using chi square test.
Mean stone size was 6.85±1.56mmrange from 4.5to 10mm in group A and.7.01± 1.70mm range from 4.5 to 10 mm for group B. There was no difference between the average diameter of the stone between two group p=0.642 using independent t test.
The stone expulsion rate was 41.7% (20 out of 48) for group A and 74.5 %( 35out of 47) for group B. The stone expulsion rate is sta s cally significant for the treatment group.P=0.001.
Group B showed a sta s cally significant advantage in term of the stone expulsion rate (p value <0.001) and mean expulsion me (P=0.008i.e. p value <0.05) so there is sta s cally significant difference between the two groups.Table (1).The Kaplan-Meier curve showed that the stone passage rate was significantly higher in the sildenafil citrate group vs the placebo group (P =0.028; figure 3) Studying the factor predic ng stone passage with univariable analysis showed that pa ent receiving sildenafil citrate was the only factor that significantly affected the stone passage.Cox propor onal hazard model showed that pa ent receiving sildenafil citrate was the only independent factor that had significant impact on stone passage with HR1.68(95% CI 0.96-2.96;P=0.046)

Table 1: Different Parameters between the Two Groups
In the sildenafil citrate group pa ent reported with headache with was treated with acetaminophen, 3 pa ent complained of unnecessary erec on.It was iden fied that all pa ent who expelled their stones did that within 14 days of oral Sildenafil 50mg treatment start.Total of 40 pa ent failed on MET in both group were subjected to URS a er 15days of treatment plan.

DISCUSSION
Large volume of distal ureteric calculi will pass spontaneously.Some of the impacted stone and even the stone that pass can cause some complica ons like hydronephrosis, 8 complicated urinary tract infec on and renal dysfunc on; which requires treatment as per complica on.EDU urolithiasis guideline state that stone size more than 10mm in size requires URS, but for smaller stone size less then Although URS is preferred op on by most of the surgeon; there are many disadvantage like requirement of 10 general or regional anaesthesia need for hospital admission, and there are many local complica ons like trauma to the ureter, ureter avulsion and in late run stricture.Nowadays with the availability of sophis cated instrument like flexible ureterorenoscopy and use of narrow calibre instrument 11 these rate have decreased significantly.
ESWL is also a safe method of treatment for ureteral stone, which is used since late 1980.Pa ent who are subjected to ESWL does not require hospitaliza on, general or regional anaesthesia, and even returned to work immediately a er the procedure.Main drawback of this procedure is they are In our study where sildenafil was used as a drug of choice and have slightly be er result than placebo.
Sildenafil citrate significantly improve the stone expulsion rate compared to placebo group with not much of side effect.

CONCLUSION
PDE5 inhibitor is the effec ve treatment op on in distal ureteric calculi compared with placebo group with high expulsion rate and be er mean expulsion me.Compared to placebo PDE5 inhibitor decreases incidence of colicky pain and the amount of analgesic required.However high quality trails and mul centre study with large number of sample size needs to be conducted to support the conclusion of our study.

RECOMMENDATION
Sildenafil citrate can be used as a drug for medical expulsion therapy for distal ureteric calculi with minimal side effect.However high quality trails and mul centre study with large number of sample size needs to be conducted.

LIMITATION OF STUDY
Limita on of this study is small number of sample size and one centre study.

Figure 3 :
Figure 3: Kaplan-Meier curve comparing the rate of spontaneous passage of ureteric stones in both groups

Figure 2 :
Figure 2: Percent of Expulsion in two groups Pa ent in group B had lower VAS (visual analogue scale) 3.49±1.300than that of pa ent in group A who had 6.77± 1.308(p<0.0001).Table (1)Stone PassesThe mean number of analgesic use during therapy was 7.56 ± 1.62 for group A and 3.48±1.10for group B (figure 5), showing significantly less analgesic use in group B, (P<0.0001)

9 10mm
both URS and ESWL is preferred.Choice of treatment further depends upon pa ent choice and availability of theKC