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민도준,양동원,민창기,김완욱,이상헌,박성환,김동욱,이종욱,조철수,민우성,김범생,김호연,김춘추 대한조혈모세포이식학회 2001 대한조혈모세포이식학회지 Vol.6 No.1
배경: 기존의 치료에 불응하고 예후가 불량한 자가면역질환 환자들에게 최근 고용량 면역억제 및 조혈모 세포이식이 새로운 치료방법으로 대두되고 있다. 저자들은 다발성 경화증(multiple sclerosis, MS) 및 류마티스 관절염(rheumatoid arthritis, RA) 등 2명의 자가면역질환 환자들에서 자가조혈모세포 이식을 시행하였다. 방법: 말초혈액 조혈모세포 가동화를 위하여 cyclophosphamide (4 g/㎡) 및 granulocyte colony stimulating factor (10 g/kg/day)를 투여하였고, CD34+ 세포를 분리·채집 하였다, 이식 전처치로 MS 환자에서 BEAM 및 antihymocyte globulin (ATG) (3.75 mg/kg), RA 환자에서 fludarabine (180 mg/㎡), ATG (10 mg/kg)와 busulfan (8 mg/kg)을 투여하였다. 결과: 호중구 수가 500/㎕ 이상으로 회복되는 기간은 MS 환자에서 9일, RA 환자에서 15일이었다. 혈소판이 20.000/㎕ 이상으로 회복되는 가간은 RA 환자에서 9일 이었고, MS 환자에서는 혈소판 감소증이 발생하지 않았다. 비혈액학적 독성으로 MS 환자에서 WHO 1도의 오심 및 점막염이 관찰되었다. MS 환자는 이식 6개월 후까지 시력감소가 남아있었으나, 이식전에 관찰되던 감각이상 및 운동장애 등의 신경학적 이상 소견은 더 이상 관찰되지 않았다. RA 환자는 이식 1개월 후 관절 증상 및 검사소견의 호전을 보였다. 결론: 불응성 자가면역질환 환자에서 고용량 면역억제 및 조혈모세포이식은 적은 독성으로 높은 치료효과를 기대할수 있으며, 향후 이 시술의 임상적 의의를 규명하기 위하여 전향적이고 장기적인 연구가 필요할 것으로 사료된다. Background: High-dose immunosuppressive therapy followed by autologous hemathpoietic stem cell transplantation (HSCT) has been proposed as a new approach to treat severe, refractory autoimmune diseases. We describe two patients with refractory autoimmune diseases (one multiple sclerosis 〔MS〕and one rheumatoid arthritis〔RA〕) who underwent T-cell-depleted autologous peripheral bleed stem cell transplantation for the first time in Korea. Methods: We mobilized autologous stem cells with cyclophisphamide (4 g/㎡) and granulocyte colony-stimulating factor (10 ㎍/kg/day). Stem cells were enriched ex vivo using CD34-positive immunoselection and reinfused after high-dose chemotherapy with BEAM and antithymocyte globulin (ATG) (3.75 mg/kg) in MS, or fludarabine (180 mg/㎡), ATG (10 mg/kg) and busulfan (8 mg/kg) in RA. Results: The engraftment with an absolute nerutrophil count greater than 500㎕ occurred on day 9 in MS and 15 in RA, respectively. The time to nontransfused platelet count greater than 2.000/㎕ was 9 day in RA. MS patient did not show ant episode of thrombocytopenia. Regimen-related non-hematopoietic toxicity was minimal. For 6 months since HSCT, them patient with MS had been free from previously existed sensory and motor abnormalities except decreased visual acuity. Then patient with RA and only one tender joint and two mildly swollen joints with improvement in laboratory parameters at one month after HSCT. Conclusion: These results underscore the feasibility and potential efficacy of intensive immunosuppression followed by autologous HSCT for treatment of intractable autoimmune diseases. The durability of remission, however, remains to be clarified.
민도준,노대근,민준기,홍연식,이상헌,박성환,조철수,김호연 大韓免疫學會 1996 大韓免疫學會誌 Vol.18 No.3
Objectives: Anti-Ro antibody is one of the prominent anti-nuclear antibodies in patients with systemic lupus erythematosus(SLE). This study was designed to determine whether this antibody reacts with certain antigenic determinants and to evaluate the frequency and clinical associations of anti-Ro antibody in patients with SLE. Method: Double immunodiffusion(DID) were used to detect anti-Ro antibody with sera from 151 patients with SLE. Western .blot analysis was done in 57 patients who were positive for anti-Ro antibody in DID to find out the major antigenic determinant of Ro antigen. We evaluated the presence of anti-Ro antibody and associations with clinical features in SLE. Result: 1) Anti-Ro by DID were positive in 56% (84 of 151 cases) of patients with SLE. 2) Photosensitivity(59% versus 27%, P=0.0001), cutaneous lesion of all types (80% versus 58%, P=0.004), malar rash (67% versus 49%, P=0.025), leukopenia (38% versus 22%, P=0.036) were closely associated with anti-Ro positivity. But there was no significant difference between anti-Ro positive and negative patients in other clinical findings such as sicca complex, thrombocytopenia and nephritis 3) In Western blot analysis, 38 of 57 Ro positive sera had antibodies to the 60-kD and the 52-kD peptide, 8 cases of them revealed antibody to the 60-kD peptide without concomitant antibody to the 52-kD, and only one had isolated presence of antibody to 52-kD peptide. Ten of immunodiffusion defined anti-Ro sera were not reactive with the Ro proteins by Western blot analysis. Conclusions: In patients with SLE, the presence of anti-Ro antibody is closely associated with photosensitive cutaneous lesion and leukopenia, and the major antigenic determinant of anti-Ro sera in SLE is 60-kD peptide.
자가조혈모세포이식을 이용한 불응성 류마티스 관절염의 치료
민도준 ( Do June Min ),민창기 ( Chang Ki Min ),양동원 ( Dong Won Yang ),윤종현 ( Chong Hyeon Yoon ),김완욱 ( Wan Uk Kim ),이상헌 ( Sang Heon Lee ),김동욱 ( Dong Wook Kim ),이종욱 ( Jong Wook Lee ),조철수 ( Chul Soo Cho ),김호연 ( 대한류마티스학회 2002 대한류마티스학회지 Vol.9 No.1
Objective: To investigate the safety and efficacy of immunoablation and subsequent autologous hematopoietic stem cell transplantation (HSCT) in refractory rheumatoid arthritis (RA). Methods: Three patients with severe, refractory RA were treated. We mobilized autologous hematopoietic stem cells (HSCs) with cyclophosphamide (Cy) and granulocyte colony-stimulating factor. HSCs were collected and enriched ex vivo using CD34-positive immunoselection. Two different immunoablative conditioning regimens were employed; fludarabine-Cy-anti-thymoayte glonulin (ATG) in patients whose disease activity was transiently ameliorated in response to Cy used in stem cell mobilization, or fludarabine-busulfan-ATG in those who didn`t show any response to that. Results: Median time to engraftment with an absolute neutrophil count greater than 500/μl and nontransfused platelet count greater than 20,000/μl was 15 days (range 12-16) and 9 days (range 7-13), respectively. Regimen-related toxicity was minimal. Two patients were markedly improved at 2 or 3 months after HSCT, repectively. In another patient, disease activity was transiently subsided, but relapsed at 2 months after HSCT, which led to reinstitution of anti-rheumatic medications. This resulted in subsequent marked improvement of disease activity whereas her disease had been refractory to these medications. Conclusions: These results underscore the feasibility and potential efficacy of intensive immunosuppression followed by autologous HSCT for treatment of refractory rheumatoid arthritis. The durability of remission remains to be clarified.
β-Cyclodextrin Piroxicam의 약역동학적 연구와 골관절염 환자에서의 치료효과
이상헌 ( Sang Heon Lee ),민도준 ( Do Jun Min ),박성환 ( Sung Hwan Park ),조철수 ( Chul Soo Cho ),박동준 ( Dong Jun Park ),김호연 ( Ho Youn Kim ) 대한류마티스학회 1994 대한류마티스학회지 Vol.1 No.2
연구배경: 소염진통제는 골관절염환자의 통증을 완화시키고 염증을 감소시키는데 대표적인 약제이다. 이런 약제들을 장기간 복용할 경우 위장관에 심각한 부작용이 일어날 수 있다. piroxicam은 널리 사용되고 있는 소염진통제이다. 이 약제를 β-cyclodextrin으로 분자 포접하여 개발한 β-cyclodextrin-piroxicam(Brexin(R))의 약역동학적인 조사와 골관절염 환자에서의 소염진통효과 및 위장관에 대한 내성을 알아보기 위하여 본 연구를 시행 하였다. 방법: 1993년 7월부터 가톨릭의대부속 강남성모병원 류마티스 크리닉을 내원한 환자중 슬관절의 골관절염 환자 30명에서 β-cycloextrin-piroxicam 1일 20mg씩 약 8주간 투여후 임상적 효과 및 부작용을 조사하였다. 그리고 4명의 건강성인에서 이 약제의 약역동학을 조사하기 위해 투여직전, 투여후 15분, 30분, 60분, 2시간, 3시간, 24시간에 각각의 혈장내 농도를 HPLC로 측정하여 이를 piroxicam과 비교하였다. 결과: 약물을 투여받은 환자들중 90%에서 임상적 호전을 보였으며, 휴식시 동통, 운동시 동통, 압통 및 부종의 의미있는 감소를 나타내었다. 부작용은 위장관 부작용이 3예로 가장 많았으며 이중 1예에서는 약물을 중단하였으나, 그외 특이한 부작용은 발견되지 않았다. 약역동학적 조사에서는 기존의 piroxicam제제에 비해 흡수가 빠르게 나타났고 24시간 동안 지속적으로 높은 혈중 농도를 보였다. 결론: β-cyclodextrin-piroxicam은 골관절염 및 여러 류마티스 질환을 가진 환자에서 특히 위장관 부작용이 우려되는 경우 유용한 치료 약제로 생각된다. Objectives: To evaluate the efficacy, safety and pharmacokinetics of β-cyclodextrin-piroxicam in patients with osteoarthritis of knee. Methods: Thirty patients with osteoarthritis (28 women, 2 men) were enrolled in the study. β-cyclodextrin-piroxicam 20mg was administered orally, once daily for 8 weeks. The indices of efficacy (evaluation of the pain, joint swelling, tenderness and functional limitation) were evaluated at 0, 2, 4, 8 weeks. Piroxicam plasma concentrations were determined by HPLC over 24 hours in 4 healthy volunteers, and were compared with those of reference formulation. Results: There were statistically significant improvement in the indices of efficacy between entry and end of the study. The majority of side effects were related to the gastrointestinal tract, but the symptoms were mild except 1 drop-out case. According to pharmacokinetic study, the bioavailability and absorption rate of piroxicam were improved in β-cyclodextrin-piroxicam group. Peak plasma piroxicam concentrations were higher in β-cyclodextrin-piroxicam group than were in reference group. Conclusions: β-cyclodextrin-piroxicam is efficacious and well tolerated in patients with osteoarthritis. Because of its rapid absorption, good bioavailability and fewer gastrointestinal disturbance, it seems to be a useful drug for long-term management of osteoarthritis.