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1 Tamsulosin 0.2 mg 의단기간투여가요로결석배출에미치는영향 : 다기관, 전향적, 무작위배분에의한연구 Effect of Tamsulosin 0.2 mg on the Short-Term Treatment of Urinary Stones: Multicenter, Prospective, Randomized Study Korean Journal of Urology Vol. 50 No. 6: , June 2009 DOI: /kju Dong Il Kang, Won Yeol Cho 1, Tae Hyo Kim 1, Jae Min Chung 2, Jisung Park 3, Jang Ho Yoon, Sang Don Lee 3 From the Department of Urology, Inje University College of Medicine, 1 Dong-A University College of Medicine, 2 Kosin University College of Medicine, 3 Pusan National University School of Medicine, Busan, Korea Purpose: We evaluated the effect of tamsulosin for the short-term treatment of urinary stones. Materials and Methods: Two hundred forty-seven patients who were diagnosed with urinary stones were enrolled in this prospective, randomized multicenter study. The treatment and extracorporeal shock wave lithotripsy (ESWL) group (Group 1, n=115) was given diclofenac sodium 100 mg plus tamsulosin 0.2 mg for 1 week. The control and SWL group (Group 2, n=92) was given diclofenac sodium for 1 week. The treatment and no SWL group (Group 3, n=19) was treated the same as Group 1. The control and no SWL group (Group 4, n=21) was given diclofenac sodium only. Patients in Groups 3 and 4 did not want to take SWL treatment. The size of the stone, expulsion rate according to stone location and ESWL machines, changes in pain score, and distance of stone migration when expulsion of the stone failed were compared among the groups. Results: There were no differences in the 4 groups in sex or stone size. The stone expulsion rate of lower ureter stones in group 1 (59.6%) was significantly higher than in group 2 (30.8%) (p=0.01). The distance of stone migration in group 3 was longer than that in group 4 (5.63±5.48 cm compared with 0.33±0.68 cm; p=0.002). Although the difference was not significant in the SWL groups, the distance of stone migration in group 1 was longer than that in group 2 (7.08±6.9 cm compared with 5.46±7.4 cm; p>0.05). There were no significant differences in changes on the pain scale among the groups. Conclusions: These results suggest that adjunctive medical therapy for 1 week with tamsulosin after SWL increases the stone expulsion rate of lower ureteral stones and increases the distance of stone migration in case of failure of stone expulsion. (Korean J Urol 2009;50: ) Key Words: Urinary calculi, Lithotripsy, Tamsulosin 인제대학교, 1 동아대학교, 2 고신대학교, 3 부산대학교의과대학비뇨기과학교실 강동일ㆍ조원열 1 ㆍ김태효 1 ㆍ정재민 2 박지성 3 ㆍ윤장호ㆍ이상돈 3 Received:March 5, 2009 Accepted:May 27, 2009 Correspondence to: Sang Don Lee Department of Urology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Beomeo-ri, Mulgeum-eup, Yangsan , Korea TEL: FAX: lsd@pusan.ac.kr This study was supported by research funds from Astellas Phama Korea, Inc. C The Korean Urological Association, 2009 서론요로결석의치료법은과거개복수술에서최소침습적인치료방법인체외충격파쇄석술과내시경적제거술, 경피적방법등으로발달되어왔다. 1,2 최근요로결석의자연배출을시도하는데있어약물을이용하여배출을촉진하고, 통증을경감시킨다는보고가있다. 3 요로결석의배출에관여하는요인으로는결석요인 ( 결석의위치, 크기, 모양 ) 과요관요인 ( 요관점막의부종, 요관평활근의수축 ) 이있다. 4 그러나크기가작은요관결석에있어서환자가통증이심하지않거나전신적인염증의소견 586

2 Dong Il Kang, et al:the Effect of Tamsulosin for the Short-Term Treatment of Urinary Stones 587 이없을경우수술없이주의깊게지켜보면서자연적인배출을기다리는방법도있다. 5 약물을이용하여배출을촉진하는방법은주로요관폐색으로인한요관의상태를변화시켜요로결석의배출을쉽게하기위한것이다. 요로결석으로인한요관폐색시요관의정상적인연동운동은약화되고요관수축의정도가강해져요의정체나역류가일어난다. 6,7 이에요로결석으로인한비정상적인요관의반응을감소시켜원활한요의흐름을이해하려는연구가진행되었다. 현재요로결석의효과적인배출및통증억제를위해사용되고있는약물은 hydroxyprogesterone을포함한호르몬, 프로스타글란딘합성억제제, 칼슘통로길항제, 알파1차단제, 스테로이드등이다. 4, 년요로결석의가이드라인에따르면결석의배출에있어알파차단제가다른약제보다더우수하여권장하고있다. 11 이에저자들은요로결석환자에있어서쇄석을시행한경우와대기요법을시행한경우하부요관에밀집된알파아드레날린수용체 1A, 1D에대한차단효과가있는 tamsulosin 0.2 mg의단기간투여가요로결석치료에미치는영향을다기관, 전향적, 무작위배분연구를통하여알아보고자하였다. 대상및방법 2007년 7월부터 2007년 12월까지 6개월동안요로결석 ( 신장및요관결석 ) 으로진단받은환자 247명을대상으로다기관 (4개대학병원 ), 전향적, 무작위배분에의한연구를 시행하였다. 급성요통이있으며이때 4 mm 이상의요로결석이진단된경우를대상으로하였으며, 무기능신, 보존적요법으로해결되지않는심한통증, 다발성결석, 심한수신증, 임신, 혈중크레아티닌이 2.5 mg/dl 이상인경우, 이전에요관수술력이있는경우, 요로협착및요관부목을삽입한경우는제외하였다. 1군은쇄석+diclofenac sodium 100 mg (p.o)+tamsulosin 0.2 mg, 2군은쇄석+diclofenac sodium 100 mg (p.o), 3군은 1주일간관찰+diclofenac sodium 100 mg (p.o)+tamsulosin 0.2 mg, 4군은 1주일간관찰+diclofenac sodium 100 mg (p.o) 으로나누었다. 3, 4군의경우환자가쇄석을유보하기를원하는경우에만시행하였다. 결석의위치는미국비뇨기과학회에서제시한요로결석의임상지침에따라, 영상학적검사에서신석, 요관신우이행부로부터천골하부변연까지위치한경우를상부요관결석, 천골하부변연에서방광요관이행부까지위치한경우를하부요관결석으로분류하였다. 12 체외충격파쇄석기는각각 Compact Delta II, Dornier Medtech, Germany; E-3000, Medispec, USA; Sonolith R Praktis, EDAP TMS, Germany를사용하였다. 결석의위치에따른각군간의결석의크기, 1주일동안배출률, 통증의변화, 결석의비배출시결석의이동거리및쇄석기종류에따른배출률을비교하였다. 통증의정도는 visual analogue pain scale을이용하여 0점에서 10점으로세분화해서시술전및시술 1주일후에측정하여그변화를측정하였다. 통계는 Student's t-test, Fisher s exact test, chi-square test, ANOVA를이용하였고, p값이 0.05 미만일때통계학적으로의미있다고하였다. 분석은 SPSS software, window 11.5 version (SPSS, Chicago, USA) 을사용하였다. Table 1. Demographic data of groups (A) and hospitals (B) (A) SWL Observation SWL+Tam SWL-Tam +Tam -Tam (n=115) (n=92) (n=19) (n=21) Mean age±sd (years) 51.08± ± ± ± Sex (male:female) 73:42 59: a 12:7 12: b Mean stone size±sd (cm) 0.73± ± ± ± SWL: shock wave lithotripsy, Tam: tamsulosin, : chi-square test a, Fisher s exact test b and Student's t-test (B) Hospitals A (n=68) B (n=55) C (n=64) D (n=60) Mean age±sd (years) 52.67± ± ± ± Sex (male:female) 41:27 31:24 45:19 39: a Mean stone size±sd (cm) 0.66± ± ± ± : chi-square a and ANOVA

3 588 Korean Journal of Urology vol. 50, , June 2009 Table 2. Expulsion rate and distance of stone migration SWL Observation Total SWL+Tam SWL-Tam +Tam Tam +Tam Tam (n=115) (n=92) (n=19) (n=21) (n=134) (n=113) Expulsion rates (%) Total 58/115 (50.4) 36/92 (39.1) >0.05 9/19 (47.4) 8/21 (38.1) >0.05 a 67/134 (50.0) 44/113 (38.9) >0.05 Renal 6/18 (33.3) 8/19 (42.1) >0.05 a 6/18 (33.3) 8/19 (42.1) >0.05 a Upper ureter 24/50 (48.0) 16/34 (47.1) >0.05 3/9 (33.3) 1/11 (9) >0.05 a 27/59 (45.8) 17/45 (37.8) >0.05 Lower ureter 28/47 (59.6) 12/39 (30.8) /10 (60) 7/10 (70) >0.05 a 34/57 (59.6) 19/49 (38.8) >0.05 Distance of stone migration (cm) 7.08± ±7.4 > ± ± a 6.72± ± SWL: shock wave lithotripsy, Tam: tamsulosin, a : Fisher s exact test Table 3. Expulsion rate according to SWL machines SWL machines Electro- Electro- Spark magnetic conductive gap +Tam 33/55 (60.0%) 11/26 (42.3%) 14/34 (41.2%) a -Tam 15/34 (44.1%) 12/29 (41.4%) 9/29 (31.0%) a b b b SWL: shock wave lithotripsy, a : chi-square test, b : Fisher's exact test Fig. 1. Changes in pain score. SWL: shock wave lithotripsy, Tam: tamsulosin. 결과전체 247명의환자중남자는 156명, 여자는 91명이었다. 쇄석을시행한군은 207명 (1군 115명, 2군 92명 ) 이었으며, 대기요법을시행한군은 40명 (3군 19명, 4군 21명 ) 이었다. 연령분포는 18-79세였으며, 쇄석군간에는차이는없었으나비쇄석군과병원간비교에서는차이가있었다. 결석의크기는 1군 0.73±0.3 mm, 2군 0.82±0.05 mm, 3군 0.51±0.11 mm, 4군 0.47±0.08 mm로쇄석군과비쇄석군각각에서차이는없었으며병원간의비교에서도차이가없었다 (Table 1). 배출률의비교에있어서는쇄석군에있어서하부요관결석에서 1군에서 59.6% (28/47), 2군의경우 30.8% (12/36) 에서통계학적으로의미있는차이를보였으나 (p=0.01), 그외의경우에서는쇄석군이나대기요법군에서 tamsulosin의복용에따른배출률의차이는보이지않았다 (Table 2). 결석의비배출시결석의이동거리의비교에서는 3군에서 5.63± 5.48 cm, 4군에서 0.33±0.68 cm로의미있는차이를보였다 (p=0.002) (Table 2). 쇄석군의비교에서는통계학적인차이를보이지않지만 tamsulosin을투여한군에서이동거리는길었다 (+tam: tam=7.08:5.46, p>0.05) (Table 2). Tamsulosin 투여여부에따라비교한쇄석기간의비교에서배출률에는차이가없었으며 (+tam: p=0.145, tam: p=0.545), 각각의쇄석기에서도 tamsulosin 투여군과비투여군의결석의배출률에있어통계학적으로차이가없었다 (Table 3). 통증의변화나통증의횟수에있어서도각각의군에서유의한차이는없었다 (Fig. 1). 고 본연구는요로결석의배출에영향을미치는 tamsulosin 의효과에대한첫국내다기관연구이다. 쇄석을시행한하부요관결석에서 tamsulosin 0.2 mg을단기간투여한경우배출률이높게나타났다. 또한결석이배출되지않은경우에 tamsulosin을투여한쇄석군이나대기요법군모두에서요석의이동거리가증가하였다. 요로결석을치료하기위한방법은다양하다. 개복수술, 체외충격파쇄석술, 내시경적치료 ( 요관경하배석술, 경피 찰

4 Dong Il Kang, et al:the Effect of Tamsulosin for the Short-Term Treatment of Urinary Stones 589 적신쇄석술 ) 를비롯하여결석의크기가작을경우대기요법도적용할수있다. 11 체외충격파쇄석술의경우합병증이없는상부요로결석에서 1차적치료방법이다. 11 최근요로결석의치료에있어통증조절과결석의배출을쉽게하기위하여체외충격파쇄석술과내과적배출치료 (medical expulsive therapy; MET) 를병행하는시도가있어왔다. 12,13 이러한병합치료의시도는요관의생리학적기능및관련된약제에대한연구가활발히진행되면서이루어졌다. 14,15 현재요로결석의효과적인배출및통증억제를위해사용되고있는약물은여러종류가사용되고있으나 2007 년 AUA/EAU 요로결석의가이드라인에서는알파차단제를권장하고있다. 4,8-11 Progesterone의요로결석의치료효과에대한생각은정상임산부에서의요관확장에서기인한다. 이후여러연구를통해 progesterone은요관의연동운동에영향을미치며, 요관을확장한다는것이증명되었다. 16,17 그러나소수의연구만진행되었으며임상에서의적용은제한적이다. 18 프로스타글란딘합성억제제는프로스타글란딘 E2 가요관폐색에의해신장및요관에서생성되어 GFR을증가시키고, 신우내압력을증가시키며, 이로인해요로결석의이동을억제시킨다는기전에의해요로결석의치료에적용되고있다. 19,20 임상적으로는 diclofenac sodium 및 indomethacin이결석으로인한통증치료에효과적이다. 21,22 프로스타글란딘억제제는신우내압력을감소시키며, 결석에의한부분적인부종과염증을억제하며, 요관의평활근을이완시킨다. 칼슘통로길항제는결석에의해야기된요관평활근의경련을억제한다. 그러나 tamsulosin과의비교연구에서는배출시간및배출률에서효과가떨어진다. 23,24 요관전체에는알파, 베타아드레날린수용체가분포하며, 주로알파아드레닐린수용체가많이분포한다. 특히하부요관에있어알파1 아드레날린수용체가높은밀도로분포해있으며그중에서도알파아드레날린수용체 1D가방광근과하부요관의수축에가장많은영향을끼친다. 14,25 약물에대한요관압및요관연동운동의빈도와속도에대한연구에서알파아드레날린수용체길항제가요관압을감소시켜요석으로인한요관압의증가와평활근의비협조적인연동운동을방지하여원활한요석의배출이가능하다고보고하였다. 26 본연구에서쇄석군의경우하부요관결석에서 tamsulosin의투여가배출률에있어의미있는결과를나타내고, 결석이배출이안된경우에있어서도결석의이동거리가증가한이유를설명할수있다. 비쇄석군의경우에서는유의할만한결과를얻을수없었는데이는충분한환자수를가지지못한것과짧은관찰기간 (1주일) 으로인한것으로판단된다. 그러나대기요법을시행한국내의여러연구에서는 tamsulosin 0.2 mg을 4주간관찰한결과에서 유의할만한결과를가졌다. 27,28 본연구에서는결석이배출되지않은환자들에서 1주일간의결석의이동거리를비교하였다. 쇄석을한군에서는 tamsulosin을사용한군과아닌군이각각 7.08 cm, 5.45 cm로통계학적인차이는없었지만이동거리는길었다. 또한대기요법군과전체환자를대상으로한비교에서는통계학적으로의미있게이동거리가길었다 (p=0.002, p=0.045). 장기간의추적관찰기간이가지는장점이외에도 tamsulosin의단기간사용시에도충분한이득이있음을제시하는결과라고여겨진다. Kim 등 12 은체외충격파쇄석술과약물요법을병행한연구에서상부요관석의경우 tamsulosin을투여한군이쇄석횟수가유의하게적으며또한 1회쇄석후결석배출결과에서도 44% 로 tamsulosin 비투여군 (33%) 보다높음을제시하고있다. 본연구에서통증완화에대한결과는모든비교군에서통계학적으로유의하지않다. 이는저자들의경우에는환자의주관적인통증점수변화 (visual analogue pain score) 를측정하였으며, 또한 diclofenac sodium을지속적으로사용한것에기인한것으로생각한다. Tamsulosin의통증완화에대한연구는이견이있다. Han 등의연구에서는상부및하부요관결석에서 tamsulosin을사용한군이아닌군보다유의하게진통제투여가적었다고하였으나다른연구에서는차이가없다고보고하고있다. 23,27-29 이것은각연구에서통증에대한차이를비교하는항목이진통제사용량, 응급실내원횟수등다른기준에의한것으로판단된다. 본연구에서는다양한쇄석기종류간의효과도분석하였다. 사용한기종은전기폭발형식 (Spark gap) 의 Compact Delta II, 전기자장형식 (electromagnetic) 의 E-3000, 전기수압식의변형 (electroconductive) 인 Sonolith R Praktis의세가지기종을사용하였다. 이전의연구에서는쇄석기종류간의직접적인비교는되어있지않지만, 전기자장식, 압전기식에서시행되었으며, 비교군보다 tamsulosin 투여군이효과가있다고하였다. 29,30 본연구에서는 tamsulosin을투여한군과그렇지않은군모두통계학적으로차이가없었다. Kobayashi 등 30 의전기자장형식의쇄석기를이용한연구에서 tamsulosin을투여한군과투여하지않은군에서결석의배출시간은줄일수있지만배출률에는차이가없다고보고하고이는쇄석기의결석분쇄능력의향상때문인것으로판단하였다. 결론본연구를통하여 tamsulosin 0.2 mg의단기간사용에서결석의이동거리증가와체외충격파쇄석시하부요관결석

5 590 Korean Journal of Urology vol. 50, , June 2009 의배출률을향상시키는장점이있음을확인할수있었다. 향후결석의크기나결석의위치, 약물의종류와용량에대한대규모및다양한연구가이루어진다면결석환자들의치료비용및편익에도움이되며, 또한 tamsulosin의사용이결석치료의한방법으로자리매김할것으로생각한다. REFERENCES 1. Kwon YU, Lee SI, Jeong TY. Treatment of upper and mid ureter stones: comparison of semirigid ureteroscopic lithotripsy with holmium: YAG laser and shock wave lithotripsy. Korean J Urol 2007;48: In BH, Kim JC, Hwang TK. Percutaneous nephrolithotomy followed by extracorporeal shock wave lithotripsy in the treatment of staghorn calculi. Korean J Urol 2002;43: Morita T, Wada I, Suzuki T, Tsuchida S. Characterization of alpha-adrenoceptor subtypes involved in regulation of ureteral fluid transport. Tohoku J Exp Med 1987;152: Porpiglia F, Destefanis P, Fiori C, Fontana D. Effectiveness of nifedipine and deflazacort in the management of distal ureter stones. Urology 2000;56: Hubner WA, Irby P, Stoller ML. Natural history and current concepts for the treatment of small ureteral calculi. Eur Urol 1993;24: Crowley AR, Byrne JC, Vaughan ED Jr, Marion DN. The effect of acute obstruction on ureteral function. J Urol 1990;143: Travaglini F, Bartoletti R, Gacci M, Rizzo M. Pathophysiology of reno-ureteral colic. Urol Int 2004;72(Suppl 1): Mikkelsen AL, Meyhoff HH, Lindahl F, Christensen J. The effect of hydroxyprogesterone on ureteral stones. Int Urol Nephrol 1988;20: Ozcan S, Yilmaz E, Buyukkocak U, Basar H, Apan A. Comparison of three analgesics for extracorporeal shock wave lithotripsy. Scand J Urol Nephrol 2002;36: Porpiglia F, Ghignone G, Fiori C, Fontana D, Scarpa RM. Nifedipine versus tamsulosin for the management of lower ureteral stones. J Urol 2004;172: Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, et al guideline for the management of ureteral calculi. J Urol 2007;178: Kim TH, Oh SY, Moon YT. The effect of tamsulosin on expulsion of ureteral stones after extracorporeal shock wave lithotripsy. Korean J Urol 2008;49: Porpiglia F, Destefanis P, Fiori C, Scarpa RM, Fontana D. Role of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stones. Urology 2002;59: Sigala S, Dellabella M, Milanese G, Fornari S, Faccoli S, Palazzolo F, et al. Evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn 2005; 24: Davenport K, Timoney AG, Keeley FX. A comparative in vitro study to determine the beneficial effect of calcium-channel and alpha(1)-adrenoceptor antagonism on human ureteric activity. BJU Int 2006;98: Kumar D. In vitro effects of steroids on human female ureter. Am J Obstet Gynecol 1962;83: Guyer PB, Delany D. Urinary tract dilatation and oral contraceptives. Br Med J 1970;4: Mikkelsen AL, Meyhoff HH, Lindahl F, Christensen J. The effect of hydroxyprogesterone on ureteral stones. Int Urol Nephrol 1988;20: Al-Waili NS. Prostaglandin synthetase inhibition with indomethacin rectal suppositories in the treatment of acute and chronic urinary calculus obstruction. Clin Exp Pharmacol Physiol 1986; 13: Ahmad M, Chaughtai MN, Khan FA. Role of prostaglandin synthesis inhibitors in the passage of ureteric calculus. J Pak Med Assoc 1991;41: Laerum E, Ommundsen OE, Grønseth JE, Christiansen A, Fagertun HE. Oral diclofenac in the prophylactic treatment of recurrent renal colic. A double-blind comparison with placebo. Eur Urol 1995;28: Ou YC, Hwang TI, Yang CR, Chang CL, Chang CH, Wu HC. Use of indomethacin in the prophylaxis of ureteral colic following extracorporeal shock wave lithotripsy. Scand J Urol Nephrol 1992;26: Dellabella M, Milanese G, Muzzonigro G. Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. J Urol 2005;174: Choi NY, Ahn SH, Han JH, Jang IH. The effect of tamsulosin and nifedipine on expulsion of ureteral stones after extracorporeal shock wave lithotripsy. Korean J Urol 2008;49: Malin JM Jr, Deane RF, Boyarsky S. Characterisation of adrenergic receptors in human ureter. Br J Urol 1970;42: Davenport K, Timoney AG, Keeley FX Jr. Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res 2007;35: Kim JW, Cho DY, Lee JG. Effect of tamsulosin on the expected treatment of upper and lower ureteral stones. Korean J Urol 2007;48: Han MC, Park YY, Shim BS. Effect of tamsulosin on the expectant treatment of lower ureteral stones. Korean J Urol 2006;47: Han MC, Jeong WS, Shim BS. Additive expulsion effect of tamsulosin after shock wave lithotripsy for upper ureteral stones. Korean J Urol 2006;47: Kobayashi M, Naya Y, Kino M, Awa Y, Nagata M, Suzuki H, et al. Low dose tamsulosin for stone expulsion after extracorporeal shock wave lithotripsy: efficacy in Japanese male patients with ureteral stone. Int J Urol 2008;15:495-8

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untitled 요관결석의기대요법에서 Tamsulosin 및 Dichlozid 의효과 Effect of Tamsulosin and Dichlozid on the Expected Treatment of Ureteral Calculi Woon Yong Yoon, Tae Yoong Jeong, Sang Ik Lee, Dong Jun Kim From the Department of