만성세균성전립선염모델쥐에서 Ginsenoside 혹은 Urovaxom R 과 Ciprofloxacin 의상승효과 Synergistic Effect between Ginsenoside or Urovaxom R with Ciprofloxacin on Chronic Bacterial Prostatitis Rat Model Yong-Sun Choi, Yong-Hyun Cho, Chang-Hee Han From the Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea Purpose: Chronic bacterial prostatitis (CBP) is one of the most common urological diseases in adult males, for which antibiotic therapy is the gold standard treatment. However, long-term therapy has many side effects and results in antibiotic resistance. For these reasons, a new treatment modality, which can replace the traditional antibiotic therapy, is required. Ginsenoside has various confirmed bacterial clearance effects in the respiratory system and on immune modulation. Urovaxom R also has confirmed effects on immune modulation, with a preventive effect on recurrent urinary tract infection (UTI). Therefore, the anti-bacterial and synergistic effects of ginsenoside and Urovaxom R were evaluated for the treatment of CBP in ananimal model. Materials and Methods: The 60 rats demonstrating CBP were randomly divided into 6 groups; the control, ciprofloxacin, ginsenoside, Urovaxom R, ciprofloxacin with ginsenoside, and ciprofloxacin with Urovaxom R groups. All drug treatments were conducted for 2 weeks. After treatment, the results were analysed microbiologically and histopathologically. Results: The microbiological cultures of the prostate and urine samples and the histological findings of the prostate demonstrated reduced bacterial growth and improved inflammatory responses in all the experimental groups compared with the control group. The ciprofloxacin, and Urovaxom R with ciprofloxacin groups showed statistically significant decreases in bacterial growth and improvements in inflammatory responses compared to the control group (p<0.05). The ginsenoside with ciprofloxacin group showed no statistical significance (p>0.05), but the mean difference was very large. Conclusions: Ginsenoside and Urovaxom R may be effective materials in CBP treatment, and has synergistic effects as a combination treatment. Therefore, the combination therapy of ginsenoside with ciprofloxacin or Urovaxom R with ciprofloxacin will be effective treatments of CBP. (Korean J Urol 2007;48:849-857) Key Words: Ginsenosides, Urovaxom R, Antibiotics, Prostatitis 대한비뇨기과학회지제 48 권제 8 호 2007 가톨릭대학교의과대학비뇨기과학교실 최용선ㆍ조용현ㆍ한창희 접수일자 :2007년 5월 3일채택일자 :2007년 6월 25일 교신저자 : 한창희의정부성모병원비뇨기과경기도의정부시금오동 65-1 480-717 TEL: 031-820-3128 FAX: 031-847-2548 E-mail: urohan@ catholic.ac.kr 서 만성세균성전립선염은남성에서재발성요로감염의 론 가장흔한원인중하나로알려져있으며, 이로인해고통받는환자로인한사회, 경제적비용은매년늘어가고있는추세이다. 만성세균성전립선염은전립선의지속적인병원성세균을특징으로하며, 그원인과병리기전이매우다 849
850 대한비뇨기과학회지 : 제 48 권제 8 호 2007 양하여비뇨기과의사들과환자들에게그진단과치료에어려움을주고있다. 1,2 이런와중에 1980년대중반에등장한 quinolone 계통의약물은전립선조직내로의침투력이매우우수한약제로각광을받았으나, 장기적인관점에서볼때, 치료효과의우수성은아직입증되지않은것으로알려져있다. 3 이러한원인으로는감염으로인한환경의변화와전립선내의석회화로인해세균들이항생제로부터보호받고있기때문이라는의견이있다. 3 이런이유로재발이잦은환자들에게는항생제를장기복용시키거나, 항생제중지후증상이심해지는환자에게는저용량의항생제지속투여를권하게되며, 치료의목적자체를완치에서증상의개선으로전환시키게되었다. 이러한삶의질을개선시키기위한방법의하나로, 항생제약물요법에더불어병합요법이나, 식이요법혹은대증요법을병행하는경우를생각해볼수있으며, 최근인삼에서추출한성분중하나인 ginsenoside가만성염증에서세균의제거에효과가있음을보여주는연구결과가대두되고있어 4-8 본실험에서우리는만성세균성전립선염동물모델을이용하여 ginsenoside가만성세균성전립선염치료에얼마만큼효과가있는지의여부를확인하고자하였다. 또한이미재발성요로감염에예방적으로쓰이고있는 Urovaxom R9,10 을전립선염에광범위하게사용되고있는항생제인 ciprofloxacin 11 과함께사용했을때, 만성세균성전립선염치료에상승효과가있을지여부를확인하고자하였다. 재료및방법 1. 실험동물실험동물은체중 250-350g의 Wistar 수컷흰쥐를일주일간의적응기간을거친뒤사용하였다. 2. 만성세균성전립선염모델흰쥐를이용한만성세균성전립선염모델은 10⁸CFU/ml 의 E. coli를요도에주입하는방법을사용하였다. 12-15 전립선염의주요병원균으로알려진 Escherichia coli Z17(02:K1: H ) 을사용하였으며, 이병원균은 70 o C의배양기내에서배양액인 tryptic soy broth (TSB) 에 24시간배양후주입직전에세균수가 1x10⁸CFU/ml이되도록 TSB에서정량재배양하였다. 16 실험동물 (n=72) 을 Ether를이용하여마취후요도주위를 70% alcohol로소독하였다. 멸균된 polyethylene tube 를실험동물의요도에삽입하고인슐린주사기를사용하여실험동물각각의전립선요도에 Escherichia coli Z17(02:K1: H ) 현탁액 (1x10⁸CFU/ml) 0.2ml씩을주입후마취를 1시간동안유지하여쥐의움직임에의한소변의누출이없도록 하여세균이전립선내로침투할충분한시간을유지하도록하였다. 모델의확인검증을위해서 E. coli 주입후 4주째에전립선조직검사를시행하며, 동시에소변을채취하여 McConkey agar 배양검사를시행하였다. 현미경학적으로만성세균성전립선염은염증세포의침윤및간질섬유화, 선소포의폐쇄를특징으로하므로, 각표본에서조직학적으로만성세균성전립선염을만족하며배양검사에서세균균주수가조직의 gram당 20CFU 이상인것을만성세균성전립선염모델로선택하였다. 3. 실험군 60마리의만성세균성전립선염모델을무작위로 6개군으로나누었다. 1) 대조군 (n=10): E. coli 현탁액주입후 4주째부터 2주일간 1일 2회씩경구위관을이용하여 1cc의 phosphate buffered saline (PBS, ph 7.2) 를투여하였다. 2) Ciprofloxacin 투여군 (n=11): E. coli 현탁액주입후 4 주째부터 2주일간 1일 2회씩경구위관을이용하여 ciprofloxacin (Cycin R, 일동제약, 서울, 한국 ) 2.5mg/kg을증류수 1cc에희석후투여하였다. 3) Ginsenoside 투여군 (n=11): E. coli 현탁액주입후 4주째부터 2주일간 1일 2회씩경구위관을이용하여 ginsenoside ( 비트로시스, 경북, 한국 ) 50mg/kg의농축액을 1cc의증류수에희석후투여하였다. 4) Urovaxom R 투여군 (n=13): E. coli 현탁액주입후 4주째부터 2주일간 1일 2회씩경구위관을이용하여 Urovaxom R (Urovaxom R, 아주약품, 서울, 한국 ) 50mg/kg을증류수 1cc 에희석후투여하였다. 5) Ginsenoside와 ciprofloxacin 병용투여군 (n=13): E. coli 현탁액주입후 4주째부터 2주일간 1일 2회씩경구위관을이용하여 ciprofloxacin 2.5mg/kg을증류수 1cc에희석하고 ginsenoside 50mg/kg의농축액을 1cc 증류수에희석후투여하였다. 6) Urovaxom R 과 ciprofloxacin 병용투여군 (n=13): E. coli 현탁액주입후 4주째부터 2주일간 1일 2회씩경구위관을이용하여 ciprofloxacin 2.5mg/kg을증류수 1cc에희석하여주고 Urovaxom R 50mg/kg 농축액을 1cc의증류수에희석후투여하였다. 4. 조직과표본의검체채취 2주간의실험을마친후, 실험동물들은 ketamine (50mg/ kg) 과 xylazine (12mg/kg) 을이용하여전신마취후전립선을절제하여, 전립선조직을취하였으며, 방광천자를통해소
최용선외 : 만성세균성전립선염모델쥐에서 Ginsenoside 혹은 Urovaxom R 과 Ciprofloxacin 의상승효과 851 변검체를채취하였다. 5. 미생물학검사약물투여후 2주째 (E. coli 현탁액주입후 6주째 ) 실험동물에서얻은전립선조직의일부를 10ml의 PBS에서 15분간초음파처리한후 E.coli 배양검사를시행하였다. 또한, 방광천자를통해채취한소변으로 E. coli 배양검사를시행하였으며, 전립선조직에서의세균균주수 (CFU) 평가는전립선의 gram당 CFU의평균 log± 표준편차로표시하였다. 6. 병리조직학검사각군에서채취한전립선조직을 10% 중성포르말린에서고정하였으며, 이후얻은절편을 Hematoxin-Eosin 염색을시행하여실험군을모르는병리학자 2명에의해만성염증세포의침윤, 선소포변화, 간질섬유화의세가지기준에따라만성세균성전립선염의정도를기술하였다. 각항목정도에따라만성세균성전립선염의증거가없으면 0점, 10% 미만에서 1점, 10-25% 에서 2점, 25-50% 에서 3점, 50-75% 에서 4점 75-100% 에서 5점을기록하여전립선염의정도를기술하였다. 12 7. 통계분석방법모든실험자료는 SPSS R for Microsoft Windows R 를이용하여평균값 ± 표준편차로자료를분석하였고, 각군의감염률과세균수는 Wilcoxon signed rank sum test와 ANOVA 를이용하여분석하였으며, 결과의확인을위해 Turkey 사후검정을시행하였다. 통계적유의수준은 p값이 0.05 미만인경우로한정하였다. 결과미생물학적소견과조직학적소견으로만성세균성전립선염동물모델은 83.3% (72마리중 60마리 ) 에서만들어졌다. 2마리는실험시작직후사망했으며 10마리는전립선염증소견이없는것으로나타났다. 1. 전립선조직과요세균배양의미생물학적자료 60마리중 58마리가실험자료에사용되었다. 2마리는실험중질식및패혈증으로사망하였다. 전립선조직배양검사결과대조군과비교하였을때 ciprofloxacin 투여군 (68.700±13.439, p<0.05), ginsenoside 투여군 (45.778±13.807, p<0.05), Urovaxom R 투여군 (46.111±13.807, p<0.05), ginsenoside와 ciprofloxacin 병용투여군 (82.300±13.439, p<0.05), Urovaxom R 과 ciprofloxacin 병용투여군 (93.100±13.439, p< 0.05) 에서통계학적으로유의한수준의세균수의감소를보였다. Ginsenoside 단독투여군과 ginsenoside와 ciprofloxacin 병용투여군을비교하였을때, 통계적으로유의한정도의세균수차이는없는것으로확인되었다 (36.522±13.807, p> 0.05). Urovaxom R 단독투여군과 Urovaxom R 과 ciprofloxacin 병용투여군을비교하였을때, 통계적으로의미있는세균수의감소결과를확인할수있었다 (46.989±13.807, p<0.05). Table 1. Microbiological data of the prostate tissue and urine culture samples (I) (J) Mean Standard Culture 0 p-value group group difference (I-J) error negative 1 2 68.7000 (*) 13.43868 <0.001 3 45.7778 (*) 13.80694 0.020 4 46.1111 (*) 13.80694 0.018 5 82.3000 (*) 13.43868 <0.001 6 93.1000 (*) 13.43868 <0.001 2 1 68.7000 (*) 13.43868 <0.001 3 22.9222 13.80694 0.564 4 22.5889 13.80694 0.579 5 13.6000 13.43868 0.912 6 24.4000 13.43868 0.465 3 1 45.7778 (*) 13.80694 0.020 2 22.9222 13.80694 0.564 4 0.3333 14.16562 1.000 5 36.5222 13.80694 0.105 6 47.3222 (*) 13.80694 0.014 4 1 46.1111 (*) 13.80694 0.018 2 22.5889 13.80694 0.579 3 0.3333 14.16562 1.000 5 36.1889 13.80694 0.110 6 46.9889 (*) 13.80694 0.015 5 1 82.3000 (*) 13.43868 <0.001 2 13.6000 13.43868 0.912 3 36.5222 13.80694 0.105 4 36.1889 13.80694 0.110 6 10.8000 13.43868 0.966 6 1 93.1000 (*) 13.43868 <0.001 2 24.4000 13.43868 0.465 3 47.3222 (*) 13.80694 0.014 4 46.9889 (*) 13.80694 0.015 5 10.8000 13.43868 0.966 0% (0/10) 60% (6/10) 11% (1/9) 33% (3/9) 80% (8/10) 100% (10/10) *: p<0.05, compare with the control group. Group 1: control, Group 2: ciprofloxacin treatment for 2 weeks, Group 3: ginsenoside treatment for 2 weeks, Group 4: Urovaxom R treatment for 2 weeks, Group 5: ginsenoside with ciprofloxacin treatment for 2 weeks, Group 6: Urovaxom R with ciprofloxacin treatment for 2 weeks
852 대한비뇨기과학회지 : 제 48 권제 8 호 2007 요배양검사상에서는총 28마리에서세균배양을관찰할수없었으며, ciprofloxacin 단독투여군에서 60% (6/10), Ginsenoside 단독투여군에서 11% (1/9), Urovaxom R 단독투여군에서 33% (3/9), ciprofloxacin과 ginsenoside 병용투여군에서 80% (8/10), ciprofloxacin과 Urovaxom R 병용투여군에서 100% (10/10) 로세균배양검사에서음성소견을나타냈다 (Table 1). 2. 전립선조직의조직학적자료치료시행 2주후채취한전립선조직에서염증세포의조직내침윤, 선소포의변화와간질섬유화각각을확인한후이를점수화하여평가하였다 (Fig. 1-6). 조직내염증세포침윤정도는대조군과비교하였을때, ciprofloxacin 투여군 (2.900±0.506, p<0.05), Urovaxom R 투여군 (1.889±0.520, p<0.05), ginsenoside와 ciprofloxacin 병용투여군 (3.800±0.506, p<0.05), Urovaxom R 과 ciprofloxacin 병용투여군 (3.900±0.506, p<0.05) 에서통계학적으로유의한수준의차이를확인할수있었으나, ginsenoside 단독투여군에서는통계적으로유의한차이를확인하지못하였다 (1.444±0.520, p>0.05). 또한 ginsenoside 단독투여군과 ginsenoside와 ciprofloxacin 병용투여군을비교하였을때, 통계적으로유의한차이가있음을확인하였으며 (2.356±0.520, p <0.05), Urovaxom R 단독투여군과 Urovaxom R 과 ciprofloxacin 병용투여군의비교에서도같은결과를확인할수있었다 (2.011±0.520, p<0.05) (Table 2). Fig. 1. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after PBS treatment. The acinar structures are severely shrunken and obliterated. Marked chronic inflammatory cell infiltration and interstitial fibrosis are seen (H&E, Bar=200μm). PBS: phosphate buffered saline. Fig. 3. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after ginsenoside treatment. The acinar structures are moderately atrophied, shrunken and obliterated. Lymphocyte infiltration, with interstitial fibrosis, is clearly seen (H&E, Bar= 200μm). Fig. 2. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after ciprofloxacin treatment. The acinar structures are partially atrophied, and mild lymphocytic infiltration, with partial interstitial fibrosis, is seen (H&E, Bar=200μm). Fig. 4. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after Urovaxom R treatment. The acinar structures are moderately atrophied and obliterated. Chronic lymphocytic infiltration, with moderate interstitial fibrosis, is seen (H&E, Bar= 200μm).
최용선외 : 만성세균성전립선염모델쥐에서 Ginsenoside 혹은 Urovaxom R 과 Ciprofloxacin 의상승효과 853 Table 2. Inflammatory cell infiltration of prostate tissue (I) (J) Mean Standard 0 Significance group group difference (I-J) error 1 2 2.9000 (*) 0.50578 0<0.001 3 1.4444 0.51964 0.077 4 1.8889 (*) 0.51964 0.008 5 3.8000 (*) 0.50578 <0.001 6 3.9000 (*) 0.50578 <0.001 Fig. 5. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after ginsenoside with ciprofloxacin treatment. The acinar structures are slightly atrophied and obliterated. A few chronic lymphocytic infiltrations, with minimal interstitial fibrosis, are seen (H&E, Bar=200μm). 2 1 2.9000 (*) 0.50578 <0.001 3 1.4556 0.51964 0.073 4 1.0111 0.51964 0.387 5 0.9000 0.50578 0.488 6 1.0000 0.50578 0.369 3 1 1.4444 0.51964 0.077 2 1.4556 0.51964 0.073 4 0.4444 0.53314 0.960 5 2.3556 (*) 0.51964 <0.001 6 2.4556 (*) 0.51964 <0.001 4 1 1.8889 (*) 0.51964 0.008 2 1.0111 0.51964 0.387 3 0.4444 0.53314 0.960 5 1.9111 (*) 0.51964 0.007 6 2.0111 (*) 0.51964 0.004 5 1 3.8000 (*) 0.50578 <0.001 2 0.9000 0.50578 0.488 3 2.3556 (*) 0.51964 <0.001 4 1.9111 (*) 0.51964 0.007 6 0.1000 0.50578 1.000 Fig. 6. Prostate section of a rat with chronic bacterial prostatitis obtained 2 weeks after Urovaxom R with ciprofloxacin treatment. The acinar structures are almost normal in appearance. Minimal interstitial fibrosis, with focal lymphocytic infiltrations, is seen (H&E, Bar=200μm). 선소포의변화정도도마찬가지의방법으로측정되었다. 대조군과비교하였을때 ciprofloxacin 투여군 (2.900±0.533, p<0.05), ginsenoside 투여군 (1.778±0.548, p<0.05), Urovaxom R 투여군 (2.111±0.548, p<0.05), ginsenoside와 ciprofloxacin 병용투여군 (3.500±0.533, p<0.05), Urovaxom R 과 ciprofloxacin 병용투여군 (4.000±0.533, p<0.05) 에서통계학적으로유의한수준의선소포변화정도를확인하였다. Ginsenoside 단독투여군과 ginsenoside와 ciprofloxacin 병용투여군도비교하여, 통계적으로유의한차이를확인하였으며 (1.722±0.548, p<0.05), Urovaxom R 단독투여군과 Urovaxom R 과 ciprofloxacin 병용투여군의비교에서도같은결과를확 6 1 3.9000 (*) 0.50578 <0.001 2 1.0000 0.50578 0.369 3 2.4556 (*) 0.51964 <0.001 4 2.0111 (*) 0.51964 0.004 5 0.1000 0.50578 1.000 *: p<0.05, compare with the control group. Group 1: control, Group 2: ciprofloxacin treatment for 2 weeks, Group 3: ginsenoside treatment for 2 weeks, Group 4: Urovaxom R treatment for 2 weeks, Group 5: ginsenoside with ciprofloxacin treatment for 2 weeks, Group 6: Urovaxom R with ciprofloxacin treatment for 2 weeks 인할수있었다 (1.889±0.548, p<0.05) (Table 3). 간질섬유화비교에서는대조군과비교하였을때 ciprofloxacin 투여군 (2.900±0.556, p<0.05), Urovaxom R 투여군 (1.889±0.571, p<0.05), ginsenoside와 ciprofloxacin 병용투여군 (3.500±0.556, p<0.05), Urovaxom R 과 ciprofloxacin 병용투여군 (4.000±0.556, p<0.05) 에서통계학적으로유의한수준의간질섬유화를확인할수있었으나, ginsenoside 단독투여군에서는대조군과비교하였을때, 통계적으로의미있는수치를얻지는못하였다 (1.667±0.571, p>0.05). Gin-
854 대한비뇨기과학회지 : 제 48 권제 8 호 2007 Table 3. Acinar cell structural change of prostate tissue (I) (J) Mean Standard 0 Significance group group difference (I-J) error 1 2 2.9000 (*) 0.53293 <0.001 3 1.7778 (*) 0.54754 0.024 4 2.1111 (*) 0.54754 0.004 5 3.5000 (*) 0.53293 <0.001 6 4.0000 (*) 0.53293 <0.001 2 1 2.9000 (*) 0.53293 <0.001 3 1.1222 0.54754 0.329 4 0.7889 0.54754 0.702 5 0.6000 0.53293 0.868 6 1.1000 0.53293 0.322 3 1 1.7778 (*) 0.54754 0.024 2 1.1222 0.54754 0.329 4 0.3333 0.56176 0.991 5 1.7222 (*) 0.54754 0.031 6 2.2222 (*) 0.54754 0.002 4 1 2.1111 (*) 0.54754 0.004 2 0.7889 0.54754 0.702 3 0.3333 0.56176 0.991 5 1.3889 0.54754 0.132 6 1.8889 (*) 0.54754 0.014 5 1 3.5000 (*) 0.53293 <0.001 2 0.6000 0.53293 0.868 3 1.7222 (*) 0.54754 0.031 4 1.3889 0.54754 0.132 6 0.5000 0.53293 0.935 6 1 4.0000 (*) 0.53293 <0.001 2 1.1000 0.53293 0.322 3 2.2222 (*) 0.54754 0.002 4 1.8889 (*) 0.54754 0.014 5 0.5000 0.53293 0.935 *: p<0.05, compare with the control group. Group 1: control, Group 2: ciprofloxacin treatment for 2 weeks, Group 3: ginsenoside treatment for 2 weeks, Group 4: Urovaxom R treatment for 2 weeks, Group 5: ginsenoside with ciprofloxacin treatment for 2 weeks, Group 6: Urovaxom R with ciprofloxacin treatment for 2 weeks Table 4. Interstitial fibrosis with structural change in prostate tissue (I) (J) Mean Standard 0 Significance group group difference (I-J) error 1 2 2.9000 (*) 0.55570 <0.001 3 1.6667 0.57093 0.055 4 1.8889 (*) 0.57093 0.020 5 3.5000 (*) 0.55570 <0.001 6 4.0000 (*) 0.55570 <0.001 2 1 2.9000 (*) 0.55570 <0.001 3 1.2333 0.57093 0.274 4 1.0111 0.57093 0.493 5 0.6000 0.55570 0.887 6 1.1000 0.55570 0.368 3 1 1.6667 0.57093 0.055 2 1.2333 0.57093 0.274 4 0.2222 0.58576 0.999 5 1.8333 (*) 0.57093 0.026 6 2.3333 (*) 0.57093 0.002 4 1 1.8889 (*) 0.57093 0.020 2 1.0111 0.57093 0.493 3 0.2222 0.58576 0.999 5 1.6111 0.57093 0.070 6 2.1111 (*) 0.57093 0.007 5 1 3.5000 (*) 0.55570 <0.001 2 0.6000 0.55570 0.887 3 1.8333 (*) 0.57093 0.026 4 1.6111 0.57093 0.070 6 0.5000 0.55570 0.945 6 1 4.0000 (*) 0.55570 <0.001 2 1.1000 0.55570 0.368 3 2.3333 (*) 0.57093 0.002 4 2.1111 (*) 0.57093 0.007 5 0.5000 0.55570 0.945 *: p<0.05, compare with the control group, Group 1: control, Group 2: ciprofloxacin treatment for 2 weeks, Group 3: ginsenoside treatment for 2 weeks, Group 4: Urovaxom R treatment for 2 weeks, Group 5: ginsenoside with ciprofloxacin treatment for 2 weeks, Group 6: Urovaxom R with ciprofloxacin treatment for 2 weeks senoside 단독투여군과 ginsenoside와 ciprofloxacin 병용투여군비교에서는통계적으로유의한차이를확인하였으며 (1.833±0.571, p<0.05), Urovaxom R 단독투여군과 Urovaxom R 과 ciprofloxacin 병용투여군의비교에서도마찬가지의결과를확인할수있었다 (2.111±0.571, p<0.05) (Table 4). 이상의결과들을종합해볼때, ginsenoside 단독투여군은다른실험군에비해선소포의변화정도에서는명확한호전을확인할수있었으나, 그외의조직내염증세포침윤의정도와간질섬유화에서는통계적으로유의할만한결과를 얻지는못하였다. 이에비해 Urovaxom R 은단독투여군에서염증세포의침윤, 선소포의변화정도, 간질섬유화의 3가지모든부문에서통계적으로유의한정도의호전을확인할수있었다. 고찰세계적으로만성전립선염증후군은남성에서발생하는비뇨기계질환중가장흔한것중의하나로알려져있으며,
최용선외 : 만성세균성전립선염모델쥐에서 Ginsenoside 혹은 Urovaxom R 과 Ciprofloxacin 의상승효과 855 전체남성인구중에서 50% 정도가적어도한번은이에이환되는것으로알려져있으나, 임상양상이비특이적이며, 아직까지명확히알려진병인론이없어진단과치료에있어서어려움이많은실정이다. 17-19 이러한만성세균성전립선염은비록생명을위협하는중대한질환은아니지만, 발병시수개월동안지속될수있으며, 재발이잦아환자의삶의질에지대한영향을미칠수있다. 그럼에도불구하고아직정확한통계는없는실정이다. 20 만성세균성전립선염의임상적특징은하부요로에서기인한상행감염이라는점이다. 이를기초로저자들은본실험에서만성세균성전립선염실험모델을만들어시행하였으며, 상기실험모델은인간의만성세균성전립선염과발생및경과의유사성이많으므로이를통해향후만성세균성전립선염의자연경과에대해설명이가능할것으로기대된다. 14 저자들은실험모델에서세균을인위적으로요도를통해전립선에주입하여급성혹은아급성전립선염을유발시켰으며, 급성, 아급성시기가지나면서숙주의방어기제에의한세포면역기전에의해세균이사멸되지않으면만성세균성전립선염을유발시킨것으로정의하였다. 만성세균성전립선염을유발하는원인은세균감염이며이중가장흔한것은 E. coli로알려져있다. 만성세균성전립선염의가장적절한치료는보존적치료로서항생제를사용하는것이다. 그러나만성세균성전립선염에서모든항생제치료가효과가있는것은아닌것으로알려져있다. 이는일반적인만성세균성전립선염의치료에사용되는약제는분자무게가가볍고및지용성으로혈장단백질에결합이용이하지않아전립선을싸고있는상피막을통과하기가어렵기때문으로생각한다. 이것이만성세균성전립선염의치료가어려운것이고, 치료시고용량, 장기간의항생제치료가필요한이유이다. 20,21 Fluoroquinolone은세포내액과세포외액에모두침투할수있기때문에전립선염의치료에우수한약제로알려져있다. 이러한이유때문에 fluoroquinolone을이용한약제인 ciprofloxacin은전립선염을유발하는병인에대해항균작용을하는약물로널리이용되고있다. 3 저자들의실험에서도 ciprofloxacin으로치료를시행한모델집단은세균배양에서집락수의의미있는감소와염증소견의개선을확인할수있었다. 그러나장기적인관점에서보았을때, 치료효과는 60% 정도로기대에미치지못하는것으로보고되고있다. 이의이유로 Nickel 등은감염에전립선내의환경의변화와전립선조직내의석회화가감염의원인이되는세균균주들을항생제로부터보호하기때문일것으로언급하였다. Ginsenoside는인삼에서얻어진추출물로, 이미그 antitumor effect에대해서는국내외의많은실험에서그효과가 입증된바있다. 22,23 또한최근들어 myocardial infarction 환자에게있어 myocardial cell regeneration 및항산화작용등의 positive effect와 24,25 chronic bacterial pneumonia 환자에게사용시 bacterial clearance rate의증가 4 등 cell regeneration 및 anti-inflammatory effect가보고되고있으며, 또한최근에는 prostate cancer에서 paclitaxel과함께사용하였을때, synergistic effect가있는것으로보고되었다. 22 Urovaxom R 은 18 Escherichia coli strains에서얻어진 immuno-stimulating component의 bacterial extract로서주로재발성요로감염에예방적으로쓰이고있다. 주로 interleukin-6 (IL-6), IL-10 등을통한 T 세포의면역기전에작용하여항염효과를나타내는것으로알려져있으며, 경구투여시재발성요로감염에효과를나타내는것으로보고되었다. 9,10 저자들은실험을통해전립선조직과요배양검사에서염증의호전이통계학적으로유의하지는않지만 ginsenoside를투여한실험군모델에서대조군모델에비해전립선염증의개선을확인하였으며, 세균배양결과에서도대조군모델에비해실험군모델에서세균의집락수가적게측정됨을확인하였다. 또한, Urovaxom R 을경구투여한실험군모델에서는대조군모델에비해전립선조직의미생물학적지표와조직학적지표가모두통계적으로의미있는개선을확인할수있었다. 이는 Urovaxom R 만을단독으로처리한군과, Urovaxom R 과 ciprofloxacin을병용투여한군을비교하였을때, 병용투여군에서더욱치료효과가좋은것으로확인되어 Urovaxom R 을항생제와함께복용시그상승효과를기대할수있을것으로예상한다. 전술한바와같이항생제의장기복용으로인한경제적부담이나, 항생제내성균의발전, 그리고약제장기복용으로인한부작용등여러원인으로항생제만의단독치료는어느정도의치료한계를가진다. 3 저자들은 ginsenoside와 ciprofloxacin의병용투여, 혹은 Urovaxom R 과 ciprofloxacin의병용투여가이러한항생제단독치료의한계를극복할수있을것이라고생각하였고이를실험을통해알아보고자하였으며, 실험결과 ginsenoside와 ciprofloxacin을병용투여한군에서세균수의의미있는감소와염증정도의개선을확인할수있었으나, 이를 ciprofloxacin 혹은 ginsenoside를단독투여한군과비교하였을때통계적으로의미있는차이는확인할수없었다. 이의이유로는실험에시행한동물의수가적어충분한양의자료가확보되지않았을가능성에무게를둘수있을것이다. 그이유로통계처리과정중확인된 ginsenoside와 ciprofloxacin의병용투여군과 ginsenoside 단독투여군, ciprofloxacin 단독투여군간의평균값의차이가매우높기때문이며, 비록본실험에서는통계적으로의미있는수치는얻지못했지만, 향후충분한실험이
856 대한비뇨기과학회지 : 제 48 권제 8 호 2007 다시행해진다면본실험과는다른조금더의미있는결과를얻을수있을것으로생각한다. 또한 Urovaxom R 단독투여군과 Urovaxom R 과 ciprofloxacin 병용투여군사이에서는통계학적으로의미있는차이를확인할수있었고, 이는만성세균성전립선염모델에서 ginsenoside와 ciprofloxacin, 혹은 Urovaxom R 과 ciprofloxacin의병용투여시상승효과를기대할수있으며, 향후만성세균성전립선염환자들의삶의질개선에효과적인대안이될수있을것으로생각한다. 결 만성세균성전립선염치료모델에있어본실험은 ciprofloxacin의단독투여, Urovaxom R 의단독투여및 ginsenoside 와 ciprofloxacin 혹은 Urovaxom R 과 ciprofloxacin의병용투여를비교해보았을때, ciprofloxacin의단독투여는만성세균성전립선염의치료에효과적이지만, ginsenoside와 ciprofloxacin을병용투여하였을때, 혹은 Urovaxom R 과 ciprofloxacin을병용투여하였을때만성세균성전립선염치료에더욱효과적이었음을확인할수있었으며, 이로인해향후재발의가능성을줄일여지가더높을것으로추측된다. 더나아가 ginsenoside 혹은 Urovaxom R 과 ciprofloxacin의병용투여는장기적인관점에서볼때, 항생제장기복용의필요기간을단축시킴으로써항생제부작용을줄이고세균내성을줄일수있다는점에서임상적으로유용할것으로생각되며이에대해서는향후지속적인연구가필요할것으로생각한다. 론 REFERENCES 1. Pfau A. Prostatitis. A continuing enigma. Urol Clin North Am 1986;13:695-715 2. Nickel JC, Olson ME, Costerton JW. Rat model of experimental bacterial prostatitis. Infection 1991;19(Suppl 3):S126-30 3. Nickel JC. Antibiotics for bacterial prostatitis. J Urol 2000; 163:1407 4. Song ZJ, Johansen HK, Faber V, Hoiby N. Ginseng treatment enhances bacterial clearance and decreases lung pathology in athymic rats with chronic P. aeruginosa pneumonia. APMIS 1997;105:438-44 5. Ahn JY, Song JY, Yun YS, Jeong G, Choi IS. Protection of Staphylococcus aureus-infected septic mice by suppression of early acute inflammation and enhanced antimicrobial activity by ginsan. FEMS Immunol Med Microbiol 2006;46:187-97 6. Park EK, Choo MK, Han MJ, Kim DH. Ginsenoside Rh1 possesses antiallergic and anti-inflammatory activities. Int Arch Allergy Immunol 2004;133:113-20 7. Matsuda H, Samukawa K, Kubo M. Anti-inflammatory activity of ginsenoside ro 1. Planta Med 1990;56:19-23 8. Yu SC, Li XY. Effect of ginsenoside on IL-1 beta and IL-6 mrna expression in hippocampal neurons in chronic inflammation model of aged rats. Acta Pharmacol Sin 2000;21:915-8 9. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents 2002;19:451-6 10. Lee SJ, Kim SW, Cho YH, Yoon MS. Anti-inflammatory effect of an Escherichia coli extract in a mouse model of lipopolysaccharide-induced cystitis. World J Urol 2006;24:33-8 11. Naber KG, Sorgel F, Kees F, Jaehde U, Schumacher H. Pharmacokinetics of ciprofloxacin in young (healthy volunteers) and elderly patients, and concentrations in prostatic fluid, seminal fluid, and prostatic adenoma tissue following intravenous administration. Am J Med 1989;87:57S-9 12. Seo SI, Lee SJ, Kim JC, Choi YJ, Kim SW, Hwang TK, et al. Effects of androgen deprivation on chronic bacterial prostatitis in a rat model. Int J Urol 2003;10:485-91 13. Lee YS, Shin MS, Cho YH. Experimental animal model of bacterial prostatitis. Korean J Urol 2001;42:636-41 14. Nickel JC, Olson ME, Barabas A, Benediktsson H, Dasgupta MK, Costerton JW. Pathogenesis of chronic bacterial prostatitis in an animal model. Br J Urol 1990;66:47-54 15. Cho YH, Lee SJ, Lee JY, Kim SW, Lee CB, Lee WY, et al. Antibacterial effect of intraprostatic zinc injection in a rat model of chronic bacterial prostatitis. Int J Antimicrob Agents 2002;19:576-82 16. Jantos C, Altmannsberger M, Weidner W, Schiefer HG. Acute and chronic bacterial prostatitis due to E-coli. Description of an animal model. Urol Res 1990;18:207-11 17. Moon TD. Questionnaire survey of urologist and primary care physicians' diagnostic and treatment practices for prostatitis. Urology 1997;50:543-7 18. Terai A, Yamamoto S, Mitsumori K, Okada Y, Kurazono H, Takeda Y, et al. Escherichia coli virulence factors and serotypes in acute bacterial prostatitis. Int J Urol 1997;4:289-94 19. Neal DE Jr, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1994;43: 460-5 20. Winningham DG, Nemoy NJ, Stamey TA. Diffusion of antibiotics from plasma into prostatic fluid. Nature 1968;219: 139-43 21. Stamey TA, Meares EM Jr, Winningham DG. Chronic bacterial prostatitis and diffusion of dugs into prostatic fluid. J Urol 1970;103:187-94 22. Xie X, Eberding A, Madera C, Fazli L, Jia W, Goldenberg L, et al. Rh2 synergistically enhances paclitaxel or mitoxantrone in prostate cancer models. J Urol 2006;175:1926-31 23. Kim HS, Lee EH, Ko SR, Choi KJ, Park JH, Im DS. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate
최용선외 : 만성세균성전립선염모델쥐에서 Ginsenoside 혹은 Urovaxom R 과 Ciprofloxacin 의상승효과 857 cancer cells. Arch Pharm Res 2004;27:429-35 24. Tian JM, Li H, Ye JM, Guo WF, Li LY, Wang LP. Effect of ginsenoside Rg2 on chemical myocardial ischemia in rats. Zhongguo Zhong Yao Za Zhi 2003;28:1191-2 25. Cho WC, Chung WS, Lee SK, Leung AW, Cheng CH, Yue KK. Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocininduced diabetic rats. Eur J Pharmacol 2006;550:173-9