CAJ | 학술논문

目的研究5-氨基水杨酸(5-ASA)对硫嘌呤类药物骨髓抑制的影响及其机制，探讨中国炎症性肠病(IBD)患者合用5-ASA时所需硫嘌呤类药物的剂量。方法回顾性分析服用硫嘌呤类药物IBD患者的临床资料，检测硫嘌呤甲基转移酶(TPMT)活性和红细胞6-硫鸟嘌呤核苷酸(6-TGN)浓度。前瞻性研究中先予患者硫唑嘌呤(AZA) 50 mg/d治疗4周，继而加用5-ASA 3 g/d治疗4周，检测第4、8周末红细胞6-TGN浓度。结果回顾性分析AZA/6-巯嘌呤(6-MP) +5-ASA组45例、AZA/6-MP组94例患者，两组骨髓抑制发生率分别为46.7％和16.0％，多因素回归分析显示合用5-ASA为增加骨髓抑制的惟一独立危险因素(OR= 3.45，95％CI：1.31～9.04)。TPMT活性在AZA/6-MP+ 5-ASA组和AZA/6-MP组之间差异无统计学意义(t=-0.351，P=0.734)。AZA/6-MP+5-ASA组6-TGN浓度显著高于AZA/6-MP组（中位浓度为384.9 pmol/8×108 RBC比286.4 pmol/8×108 RBC，F=29.15，P=0.00）。8例患者完成前瞻性研究，予AZA 50mg/d 4周后，7例患者6-TGN浓度＜230 pmol/8×108 RBC；加用5-ASA 4周后，7例患者6-TGN浓度≥230 pmol/8×108 RBC，其中3例6-TGN浓度≥420 pmol/8×108 RBC，2例发生骨髓抑制。结论当中国IBD患者合用5-ASA治疗时，采用常规推荐剂量的AZA/6-MP时骨髓抑制的发生概率增加，其机制可能与红细胞内6-TGN浓度升高有关，降低AZA剂量有可能在保持疗效的同时降低骨髓抑制发生率。
목적 연구5-안기수양산(5-ASA)대류표령류약물골수억제적영향급기궤제，탐토중국염증성장병(IBD)환자합용5-ASA시소수류표령류약물적제량。방법 회고성분석복용류표령류약물IBD환자적림상자료，검측류표령갑기전이매(TPMT)활성화홍세포6-류조표령핵감산(6-TGN)농도。전첨성연구중선여환자류서표령(AZA) 50 mg/d치료4주，계이가용5-ASA 3 g/d치료4주，검측제4、8주말홍세포6-TGN농도。결과 회고성분석AZA/6-구표령(6-MP) +5-ASA조45례、AZA/6-MP조94례환자，량조골수억제발생솔분별위46.7％화16.0％，다인소회귀분석현시합용5-ASA위증가골수억제적유일독립위험인소(OR= 3.45，95％CI：1.31～9.04)。TPMT활성재AZA/6-MP+ 5-ASA조화AZA/6-MP조지간차이무통계학의의(t=-0.351，P=0.734)。AZA/6-MP+5-ASA조6-TGN농도현저고우AZA/6-MP조（중위농도위384.9 pmol/8×108 RBC비286.4 pmol/8×108 RBC，F=29.15，P=0.00）。8례환자완성전첨성연구，여AZA 50mg/d 4주후，7례환자6-TGN농도＜230 pmol/8×108 RBC；가용5-ASA 4주후，7례환자6-TGN농도≥230 pmol/8×108 RBC，기중3례6-TGN농도≥420 pmol/8×108 RBC，2례발생골수억제。결론 당중국IBD환자합용5-ASA치료시，채용상규추천제량적AZA/6-MP시골수억제적발생개솔증가，기궤제가능여홍세포내6-TGN농도승고유관，강저AZA제량유가능재보지료효적동시강저골수억제발생솔。
Objective To evaluate the effect and mechanism of 5-aminosalicylic acid (5-ASA) on bone marrow suppression caused by thiopurines, and to explore the proper dosage of thiopurines when combined with 5-ASA for inflammatory bowel diseases (IBD) patients.Methods The clinical data of IBD patients who took thiopurines were retrospectively analyzed. Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) concentration were tested.In prospective study, patients firstly treated with azathioprine (AZA) of 50 mg/d for 4 weeks, then combined with 5-ASA of 3 g/d for another 4 weeks.The concentration of 6-TGN in red blood cells (RBC) was analyzed at the end of 4th and 8th week.Results In retrospective study, there were 45 cases in AZA/6-mercaptopurine (MP) combined with 5-ASA group, 94 patients were in AZA/6-MP.alone group.The incidence of bone marrow suppression in these two groups were 46.7％ and 16.0％, respectively.Multivariates regression analysis indicated co-administration of 5-ASA was the only risk factor of increasing bone marrow suppression incidence (OR=3.45,95％ CI 1.31 ～ 9.04).There was no significant difference of TPMT activity between AZA/6-MP combined with 5-ASA group and AZA/6-MP alone group(t=-0.351 ,P=0.734).The 6-TGN concentration was significantly higher in AZA/6-MP combined with 5-ASA group than that of AZA/6-MP alone group (the median concentration was 384.9 pmol/8× 108 RBC and 286.4 pmol/8× 108 RBC,F=29.15,P=0.00).Prospective study was completed in 8 patients.After treated with AZA of 50 mg/d for 4 weeks, the 6-TGN concentration of 7 patients was lower than 230 pmol/8 × 108 RBC.After added with 5-ASA of 3 g/d for another 4weeks, the 6-TGN concentration of 7 patients was over 230 pmol/8 × 108 RBC, three patients of those was even higher than 420 pmol/8 × 108 RBC, and bone marrow suppression occurred in 2 patients.Conclusions The incidence of bone marrow suppression increased in Chinese IBD patients treated with recommended routine dossage of AZA/6-MP when conbined with 5-ASA.The mechanism may be related with the increased concentration of 6-TGN in RBC.To reduce the AZA dosage may possibly keep the efficacy while decrease the incidence of bone marrow suppression.