Urolithiasis (2014) 42:541–547 DOI 10.1007/s00240-014-0708-6
ORIGINAL PAPER
Comparative evaluation of efficacy of use of naftopidil and/or celecoxib for medical treatment of distal ureteral stones Jian Lin Lv · Qing Lai Tang
Received: 6 February 2014 / Accepted: 5 August 2014 / Published online: 20 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract We performed a randomized, prospective study to assess the possible role of combined a1D-receptor antagonist naftopidil and nonsteroidal anti-inflammatory hormones celecoxib for the spontaneous expulsion of distal ureteral stones. Patients were randomized to one of the three treatment groups. Treatment group 1 patients received naftopidil 50 mg/day, group 2 patients received naftopidil 50 mg/day plus celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h), and group 3 patients received celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h). All patients were instructed to drink at least 2 L of fluids daily. Pain descriptions were recorded by the patients using the visual analog scale. All patients were followed up for 2 weeks. A total of 105 patients provided consent and 103 patients completed the study. Stone expulsion was observed in 29 patients in group 1 (29 of 35, 82.86 %), 33 patients in group 2 (33 of 35, 94.29 %) and 20 patients in group 3 (20 of 33, 60.61 %). A statistically significant difference was noted with Chi-square testing for stone expulsion rate between groups 1 and 3, and groups 2 and 3 (P = 0.04 and P = 0.000, respectively). Kaplan– Meier curves were plotted to access the expulsion rate of each group over time. A significant difference was shown for the expulsion rate between the group 3 and the other two groups. (P a1A > a1B [7–10]. Numerous clinical trials have been performed to investigate the efficacy of the a1A/D selective a-blocker tamsulosin for distal ureteral stones [11–15]. Current tamsulosin represents a non-invasive and cost-effective alternative to interventional approaches [15, 16]. Naftopidil is a specific a1D receptor antagonist [17–19]. Compared with tamsulosin, naftopidil had a greater selectivity for a1D subtype, with approximately 3- and 17-fold higher potency for a1D than for a1A and a1B, respectively [18]. According to the above, it is expected that naftopidil could also
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542
be used as a medical expulsive agent with higher efficacy and lower side effects for distal ureteral stones than tamsulosin. Nevertheless, a1 receptor-mediated pain-relieving effects have not been clearly observed. Obstruction of the urinary tract at any level eventually results in an elevation of ureteral pressure, which usually eventually causes pain. Rising pressure in the renal pelvis, due to the obstructive calculus, stimulates the local synthesis and release of prostaglandins [20]. Understanding of the mechanism of prostaglandin action during renal colic and obstruction related to the presence of ureteral stones suggested the possible role of NSAIDs in MET, because these drugs would reduce inflammation and edema at the site of the stone. In ureteral obstruction, the increase in PG synthesis is secondary to the activation of COX, thromboxane, and prostacyclin synthesis. Celecoxib is a selective inhibitor of cyclo-oxygenase-2 non-steroidal anti-inflammatory drug. In this study, we performed a randomized, prospective study to assess the possible role of combined a1D-receptor antagonist naftopidil and nonsteroidal anti-inflammatory hormones celecoxib for the relief of ureteral colic and in facilitating the spontaneous expulsion of distal ureteral stones.
Materials and methods A total of 105 patients with distal ureteral stones were included in the study from September 2012 to September 2013. All the patients underwent evaluation including blood and urine analyses, urine culture and biochemical test. The distal ureteral stones were initially diagnosed by abdominal ultrasound and plain abdominal X-ray for kidney, ureter and bladder (KUB). IVU (intravenous urogram) or unenhanced CT scan is performed when necessary. Stone size was registered as the maximum diameter measured on a plain abdominal film. After local ethical committee approval and informed consent from each subject, those patients with ureteral stone (9≤ mm >4 mm) were included in the study. The exclusion criteria were: multiple stones, history of distal ureteral surgery, renal colic for more than 24 h, urinary tract infection, severe hydronephrosis, voiding dysfunction, hypotension, cardiovascular and cerebrovascular diseases, hepatic and renal dysfunction, pregnancy, diabetes and ulcer disease. Also, subjects with a history of hypersensitivity to naftopidil and subjects receiving treatment with cardiovascular drugs, other nonsteroidal anti-inflammatory drugs (NSAIDs), a receptor antagonists or calcium antagonists were excluded from the study. Also, individuals who withdrew from the study or were lost to follow-up were excluded from this study.
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Urolithiasis (2014) 42:541–547
Patients were randomized to one of the three treatment groups. Treatment group 1 patients received naftopidil 50 mg/day, group 2 patients received naftopidil 50 mg/ day plus celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h), and group 3 patients received celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h). All patients were instructed to drink at least 2 L of fluids daily. Pain descriptions were recorded by the patients using the visual analog scale (VAS). The patients were advised to filter their urine, and those who had passed their stones were asked to stop taking the medication. All patients were followed up for 2 weeks. Ultrasonography and KUB were performed on days 7 and 14. The stone expulsion rate and time, the number of pain episodes and requirements for pain medication were recorded. The potential side effects of naftopidil and celecoxib were also documented during the treatment period. At the end of the follow-up period, patients who failed to expel the stone were scheduled to undergo ESWL or ureteroscopy. Discrete variables were presented as counts (or frequencies) and were evaluated by the Chi-square or Fisher exact test. Continuous variables with normal distribution were presented as mean ± standard deviation (SD) and were compared by Student’s t test. Kaplan–Meier curves were plotted to describe time to stone expulsion in patients in each group, and the differences between the curves were assessed using log-rank analysis. The Cox proportional hazards regression model was applied to estimate the effects of different variables on stone expulsion, including age, sex, stone size and therapy. STATA Version 8.0 was used for all the analyses. All statistical tests were based on two-tailed probability. A P value of 0.05 was considered to be statistically significant. The sample size was enough to achieve a statistical power of 95 % at 5 % type I error.
Results A total of 105 patients provided consent and 103 patients completed the study. Two patients were excluded from the analysis because they withdrew their consent before the first dose of medication, leaving 59 men and 44 women available for analysis. No statistically significant differences were observed with regard to patient age, gender distribution or the stone side (right or left). Average stone size for groups 1, 2 and 3 was 6.89 ± 1.25, 7.05 ± 1.49 and 7.33 ± 1.19 mm, respectively. ANOVA did not reveal any statistically significant difference in size among the groups (P = 0.376) (Table 1).
Urolithiasis (2014) 42:541–547 Table 1 Demographic information and results of three groups
543 Parameter
Group 1
Group 2
Group 3
P Value
No. Mean 1 age ± SD (years) No. male/female Mean stone size ± SD (mm) Ureteral stone side (L/R)
35 31.40 ± 3.94 20/15 6.9 ± 1.30 19/16
35 33.20 ± 5.28 21/14 7.1 ± 1.50 18/17
33 33.75 ± 5.24 18/15 7.3 ± 1.2 16/17
0.115 0.902 0.376 0.892
Expulsion rate (%)
82.86 (29 of 35)
94.29 (33 of 35)
60.61 (20 of 33)
0.002
Fig. 1 Kaplan–Meier curves for the expulsion rate of each group over time (a significant difference was shown for the expulsion rate between the group 3 and the other two groups. P
ORIGINAL PAPER
Comparative evaluation of efficacy of use of naftopidil and/or celecoxib for medical treatment of distal ureteral stones Jian Lin Lv · Qing Lai Tang
Received: 6 February 2014 / Accepted: 5 August 2014 / Published online: 20 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract We performed a randomized, prospective study to assess the possible role of combined a1D-receptor antagonist naftopidil and nonsteroidal anti-inflammatory hormones celecoxib for the spontaneous expulsion of distal ureteral stones. Patients were randomized to one of the three treatment groups. Treatment group 1 patients received naftopidil 50 mg/day, group 2 patients received naftopidil 50 mg/day plus celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h), and group 3 patients received celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h). All patients were instructed to drink at least 2 L of fluids daily. Pain descriptions were recorded by the patients using the visual analog scale. All patients were followed up for 2 weeks. A total of 105 patients provided consent and 103 patients completed the study. Stone expulsion was observed in 29 patients in group 1 (29 of 35, 82.86 %), 33 patients in group 2 (33 of 35, 94.29 %) and 20 patients in group 3 (20 of 33, 60.61 %). A statistically significant difference was noted with Chi-square testing for stone expulsion rate between groups 1 and 3, and groups 2 and 3 (P = 0.04 and P = 0.000, respectively). Kaplan– Meier curves were plotted to access the expulsion rate of each group over time. A significant difference was shown for the expulsion rate between the group 3 and the other two groups. (P a1A > a1B [7–10]. Numerous clinical trials have been performed to investigate the efficacy of the a1A/D selective a-blocker tamsulosin for distal ureteral stones [11–15]. Current tamsulosin represents a non-invasive and cost-effective alternative to interventional approaches [15, 16]. Naftopidil is a specific a1D receptor antagonist [17–19]. Compared with tamsulosin, naftopidil had a greater selectivity for a1D subtype, with approximately 3- and 17-fold higher potency for a1D than for a1A and a1B, respectively [18]. According to the above, it is expected that naftopidil could also
13
542
be used as a medical expulsive agent with higher efficacy and lower side effects for distal ureteral stones than tamsulosin. Nevertheless, a1 receptor-mediated pain-relieving effects have not been clearly observed. Obstruction of the urinary tract at any level eventually results in an elevation of ureteral pressure, which usually eventually causes pain. Rising pressure in the renal pelvis, due to the obstructive calculus, stimulates the local synthesis and release of prostaglandins [20]. Understanding of the mechanism of prostaglandin action during renal colic and obstruction related to the presence of ureteral stones suggested the possible role of NSAIDs in MET, because these drugs would reduce inflammation and edema at the site of the stone. In ureteral obstruction, the increase in PG synthesis is secondary to the activation of COX, thromboxane, and prostacyclin synthesis. Celecoxib is a selective inhibitor of cyclo-oxygenase-2 non-steroidal anti-inflammatory drug. In this study, we performed a randomized, prospective study to assess the possible role of combined a1D-receptor antagonist naftopidil and nonsteroidal anti-inflammatory hormones celecoxib for the relief of ureteral colic and in facilitating the spontaneous expulsion of distal ureteral stones.
Materials and methods A total of 105 patients with distal ureteral stones were included in the study from September 2012 to September 2013. All the patients underwent evaluation including blood and urine analyses, urine culture and biochemical test. The distal ureteral stones were initially diagnosed by abdominal ultrasound and plain abdominal X-ray for kidney, ureter and bladder (KUB). IVU (intravenous urogram) or unenhanced CT scan is performed when necessary. Stone size was registered as the maximum diameter measured on a plain abdominal film. After local ethical committee approval and informed consent from each subject, those patients with ureteral stone (9≤ mm >4 mm) were included in the study. The exclusion criteria were: multiple stones, history of distal ureteral surgery, renal colic for more than 24 h, urinary tract infection, severe hydronephrosis, voiding dysfunction, hypotension, cardiovascular and cerebrovascular diseases, hepatic and renal dysfunction, pregnancy, diabetes and ulcer disease. Also, subjects with a history of hypersensitivity to naftopidil and subjects receiving treatment with cardiovascular drugs, other nonsteroidal anti-inflammatory drugs (NSAIDs), a receptor antagonists or calcium antagonists were excluded from the study. Also, individuals who withdrew from the study or were lost to follow-up were excluded from this study.
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Urolithiasis (2014) 42:541–547
Patients were randomized to one of the three treatment groups. Treatment group 1 patients received naftopidil 50 mg/day, group 2 patients received naftopidil 50 mg/ day plus celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h), and group 3 patients received celecoxib 200 mg (Take two capsules (400 mg) by mouth immediately, then take one capsule (200 mg) by mouth every 12 h). All patients were instructed to drink at least 2 L of fluids daily. Pain descriptions were recorded by the patients using the visual analog scale (VAS). The patients were advised to filter their urine, and those who had passed their stones were asked to stop taking the medication. All patients were followed up for 2 weeks. Ultrasonography and KUB were performed on days 7 and 14. The stone expulsion rate and time, the number of pain episodes and requirements for pain medication were recorded. The potential side effects of naftopidil and celecoxib were also documented during the treatment period. At the end of the follow-up period, patients who failed to expel the stone were scheduled to undergo ESWL or ureteroscopy. Discrete variables were presented as counts (or frequencies) and were evaluated by the Chi-square or Fisher exact test. Continuous variables with normal distribution were presented as mean ± standard deviation (SD) and were compared by Student’s t test. Kaplan–Meier curves were plotted to describe time to stone expulsion in patients in each group, and the differences between the curves were assessed using log-rank analysis. The Cox proportional hazards regression model was applied to estimate the effects of different variables on stone expulsion, including age, sex, stone size and therapy. STATA Version 8.0 was used for all the analyses. All statistical tests were based on two-tailed probability. A P value of 0.05 was considered to be statistically significant. The sample size was enough to achieve a statistical power of 95 % at 5 % type I error.
Results A total of 105 patients provided consent and 103 patients completed the study. Two patients were excluded from the analysis because they withdrew their consent before the first dose of medication, leaving 59 men and 44 women available for analysis. No statistically significant differences were observed with regard to patient age, gender distribution or the stone side (right or left). Average stone size for groups 1, 2 and 3 was 6.89 ± 1.25, 7.05 ± 1.49 and 7.33 ± 1.19 mm, respectively. ANOVA did not reveal any statistically significant difference in size among the groups (P = 0.376) (Table 1).
Urolithiasis (2014) 42:541–547 Table 1 Demographic information and results of three groups
543 Parameter
Group 1
Group 2
Group 3
P Value
No. Mean 1 age ± SD (years) No. male/female Mean stone size ± SD (mm) Ureteral stone side (L/R)
35 31.40 ± 3.94 20/15 6.9 ± 1.30 19/16
35 33.20 ± 5.28 21/14 7.1 ± 1.50 18/17
33 33.75 ± 5.24 18/15 7.3 ± 1.2 16/17
0.115 0.902 0.376 0.892
Expulsion rate (%)
82.86 (29 of 35)
94.29 (33 of 35)
60.61 (20 of 33)
0.002
Fig. 1 Kaplan–Meier curves for the expulsion rate of each group over time (a significant difference was shown for the expulsion rate between the group 3 and the other two groups. P
