사이클로스포린 신독성의 병리기전

김용진 대한신장학회 1993 대한신장학회잡지 Vol.12 No.부록7

비만 환자의 조혈모세포이식 후 체중 적용 기준에 따른 Cyclosporine 초기 농도 비교

권지은,박애령,김순주,나현오 한국병원약사회 2014 病院藥師會誌 Vol.31 No.6

Cyclosporine is the most common immunosuppressant agent against graft-versus-hostdisease (GVHD) in patients with hematopoietic stem cell transplantation (HSCT). The therapeuticrange of cyclosporine is narrow, and there is significant inter-individual and intra-individual variabilityin the pharmacokinetics of the drug. Therefore, therapeutic drug monitoring of cyclosporine isessential to optimize immunosuppressant therapy. In Seoul St. Mary’s hospital, the dose ofcyclosporine is based on the actual body weight. Cyclosporine 5 mg/kg/day is given the day beforeHSCT by 24hrs intravenous infusion. The dose is then changed to 3 mg/kg/day after HSCT. We conductedtherapeutic drug monitoring for the optimal therapeutic range of cyclosporine. The concentrationof cyclosporine is often higher for obese patients than the initial therapeutic range of200~300 ng/ml. As a result, obese patients have a greater risk of cyclosporine side effects than nonobese patients. We evaluated the effects of cyclosporine at an initial dose based on ideal body weightin obese patients. We retrospectively collected the data from obese patients (actual body weight > 120% ideal bodyweight) who received cyclosporine therapy after HSCT, at the Catholic BMT (blood and marrowtransplantation) center from April 2009 to September 2011. Pharmacokinetic parameters were calculatedfrom data collected from monitored patient profiles and actual blood concentration ofcyclosporine. We subsequently calculated the concentration of cyclosporine, according to the dosebased on ideal body weight. Out of 32 patients who received cyclosporine therapy after HSCT, 1 patient who receivedcyclosporine based on actual body weight reached the therapeutic range (3.1%). However, 7 patientswho received cyclosporine based on ideal body weight reached the therapeutic range (21.9%). Theresults showed a significant difference (p=0.014). The median gap between the actual blood concentrationand the upper limit of therapeutic range was 164.1 (-25.3~440.0) ng/ml in patients whoreceived cyclosporine based on actual body weight. The median gap between the calculated bloodconcentration and the upper limit of therapeutic range was 67.7 (-74.0~239.0) ng/ml in patients whoreceived cyclosporine based on ideal body weight. The blood concentration of cyclosporine based onideal body weight was indicative of a more efficient approach to a therapeutic range of cyclosporine. In conclusion, this study suggested that the administration of cyclosporine based on ideal bodyweight might lead to optimal blood concentration and a reduction in cyclosporine side effects. Thecurrent observation needs to be confirmed by prospective investigation in order to determine appropriatecyclosporine therapy in obese patients.

Cyclosporin에 의해 나타는 뇌 조직의 전기적 변화

최병준(Byung Joon Choi),이미희(Mi Hee Lee) 대한소아신경학회 2001 대한소아신경학회지 Vol.9 No.2

목 적 : Cyclosporin은 면역 억제제로서, 임상에서 사용시 종종 중추 신경계 합병증 증세가 나타난다. Cyclosporin에 의한 신경계 합병증이 발생하는 것은 확실하지만 현재까지 정확한 기전은 알려져 있지 않다. Cyclosporin의 신경계 영향이 cyclosporin단독 효과인지 혹은 다른 여러 가지 임상증상과 관련되어 나타나는 것인지 불확실하다. 임상에서는 칼슘이 저하되어있을 때 사용하면 중추 신경계 합병증이 나타날 가능성이 많은 것으로 나타나 있다. 따라서, 칼슘 저하상태가 cyclosporin의 중추 신경계에 대한 영향을 알기 위해 동물 실험을 통하여 알아보았다. 방 법 : 연령 14-21일 사이의 Sprague-Dawley쥐를 대상으로 뇌 조직을 가능한 빨리 얻었다. 이를 깨끗이 씻고 차가운 산소 함유 인공 뇌척수액-NaCl 120 mM; KCl 3.3 mM; NaH2PO4 1.23 mM; MgSO4 0.9 mM; NaHCO3 25 mM; CaCl2 2 mM; Dextrose 10 mM, pH 7.3-7.4, 삼투압 315-325 mOsm/㎏ -에 넣고 수분을 포함하고 있는 가스(95% O2, 5% CO2)를 공급한 상태로 30-45초 놓아 두었다. 뇌 조직을 꺼내어 여과 종이에 놓고 절단하였다. 왼쪽 뇌는 깨끗하고 차가운 산소 함유 인공 뇌척수액에 놓고, 오른쪽은 조직 절단기 (Mc Ilwain)에 넣은 후 처음 3개 조직 절편은 버리고 그 이후의 3-8개의 조직을 650 ㎛ 두께로 해마에서 얻었다. 이 절편을 저 칼슘 인공 뇌척수액 및 cyclosporin 함유 뇌척수액에서, 각각 경련 활동 변화를 관찰하였다. 결 과: 칼슘 농도에 따른 변화는, 인공 뇌척수액 내 칼슘 농도가 1.3 mM인 경우부터 경련 간기에 활동파가 보엿는데 1.3 mM인 경우 경련 간기 활동은 18.8%에서 보였고, 칼슘 농도가 0.8 mM인 경우 간질 간기 활동은 41.7%에서 보였으며, 칼슘 농도가 0 mM인 경우 경련 활동은 60%에서 보이고 경련 간기 활동이 모두 나타났다. Cyclosporin 3 ㎛ 처치 뇌 조직에서 경련 간기 활동파를 관찰할 수 있다. 경련 간기 활동파의 평균 시간과 수는 116.4±44.4 초, 63.6±35.8 이었다. 경련 간기 활동파의 시간과 수는 대조군과 비교하여 큰 차이는 없었다. 경련 간기 활동파가 나타날 때까지 잠복 시간은 166.2±29.8 초였다. 결 론: 본 연구 결과 뇌척수액의 칼슘 농도가 1.3 ㎛ 농도에서부터 cyclosporin이 경련 활동을 증가시키는 것을 알 수 있었다. 따라서, cyclosporin은 환자의 여러 가지 임상 상태에 따라 중추 신경계 독성을 나타낼 수 있고, 특히 칼슘이 저하된 환자 상태에서 cyclosporin 사용은 피하여야 하며, 피치 못해 사용하여야 할 경우에는 중추 신경계의 합병증에 대한 자세한 관찰이 동반되어야 한다고 생각한다. Purpose : Cyclosporin is used in children with immune-mediated diseases, chronic disease, organ transplantation, or malignancy. These diseases often require a higher dose of cyclosporin, and cyclosporin displayed neurotoxicity of the central nervous system (CNS) neurotoxicity. Especially, cyclosporin-induced seizures often represent a physical threat to patients. And, the adverse effects of cyclosporin on CNS are considered. Methods : The study was done with Sprague-Dawley rats(14-21 days), weighting from 28.7 g to 49.2 g. The animal were kept in-groups with mother rat in cages, and had free access to food and tap water. The temperature of the animal room is room temperature. Hippocampal slices were taken. Hippocampal slices were exposed to cyclosporin dissolved by 0.1% DMSO(Dimethyl sulfoxide). Then, we began to record electrical activity of slices every 10 minutes in low calcium environment. We observed the frequency and duration of electrical activity. Results : The mean duration and frequency of cyclosporin 3M-treated ictal activity was 35.51.4 seconds and 133.017.9. These results were significantly different compared to the control group. The mean duration and frequency in cyclosporin 3M-treated interictal activity was 116.444.4 seconds, 63.635.8. There were no significant differences in the duration and frequency of onset in cyclosporin 3M-treated interictal activity compared with control showing interictal activity. The mean duration of latency time of onset in cyclosporin 3M-treated interictal activity was 166.229.8 seconds(n=9), and there was a significant difference in the latency of onset time in cyclosporin 3M-treated interictal activity compared with control showing interictal activity. Conclusion : Although cyclosporin neurotoxicity is well recognized, and the exact mechanism of cyclosporin neurotoxicity is still unclear, cyclosporin neurotoxicity is present under hypocalcemia. And, our results suggest that careful usage of cyclosporin in clinical conditions with hypocalcemia is required to avoid cyclosporin neurotoxicity.

High Sensitivity C-reactive Protein을 이용하여 분석한 전신 염증과 단기간 저용량 Cyclosporine의 건선 치료효과의 상관관계

정택조 ( Taek Jo Jeong ),신민경 ( Min Kyung Shin ),김낙인 ( Nack In Kim ) 대한피부과학회 2010 대한피부과학회지 Vol.48 No.3

Background: Cyclosporine is an immunosuppressant that acts on T-cells and cytokines. Although the efficacy of systemic cyclosporine in the treatment of psoriasis has been established, the relationship between response to cyclosporine and systemic inflammation using the high sensitivity C-reactive protein (hs-CRP) immunoassay is still unclear. Objective: The aim of this study is to investigate whether systemic inflammation with clinical and laboratory findings indicate a response after 8 weeks of oral 3 mg/kg cyclosporine therapy in patients with psoriasis. Methods: Thirty-five patients with psoriasis were treated with oral cyclosporine for 8 weeks. The clinical response to oral cyclosporine was determined using the PASI score. The correlation between hs-CRP and the treatment response to cyclosporine was analyzed. Also, descriptive characteristics of psoriatic patients with psoriatic arthritis, metabolic syndrome, and high BMI (BMI≥25) were investigated. Results: Hs-CRP levels and PASI scores were significantly reduced after 8 weeks of oral cyclosporine treatment. Eight patients showed excellent response, fifteen a good response, and twelve a moderate response. The baseline hs-CRP levels in excellent and good response groups (1.35±0.59 mg/L and 1.32±0.86 mg/L, respectively) to oral cyclosporine were significantly higher than the moderate response group (0.51±0.20 mg/L, p=0.004). Psoriatic patients with psoriatic arthritis, metabolic syndrome, and high BMI demonstrated higher levels of baseline hs-CRP. Patients with psoriatic arthritis and metabolic syndrome showed greater response to cyclosporine treatment. Conclusion: Patients with greater inflammatory burden, as demonstrated by elevated baseline hs-CRP, have better treatment responses to cyclosporine compared to patients with lesser inflammation. (Korean J Dermatol 2010; 48(3):171~178)

국산 Microemulsion Cyclosporine(사이폴-엔)을 사용한 신장이식 74예의 조기성적

구본일,윤영철,이홍섭 인제대학교 1999 仁濟醫學 Vol.20 No.1S

cyclosporine의 면역학적 특징이 발견된 이래로, 현재 Cyc10sporine은 모든 종류의 동종이식 수술의 가장 중요한 면역억제제로 자리잡았다. 1995년에는 convention cyclosporine에 비하여 더욱 안정적으로 흡수와 분포를 보이는 microemulsion cyclosporine인 SANDIMUM MEORAL이 개발되었고, 현재 널리 사용되도 있다. 최근 국내에서도 기존의 miceroemulsion cyclosporine과 생물역동학적으로 같은 CIPOL-N 이 개발되었다. 본 연구는 신장 이식 환자에서 CIPOL-N 의 면역억제 효능을 알아보고자 하였다. 1997년 6월부터 1998년 8월까지 인제대학교 서울백병원에서 신장이식술을 받은 74예를 대상으로 하여 microemulsion cyclosporine의 투여 용량, 혈액 레벨, 이식편 실패율, 생존을 등을 분석하였다. 환자의 연령은 16세부터 67세까지의 분포를 보였으며(평균 42.67±12.00세). 성별은 남자 52예(70.3%), 여자 22예(29.7%)였다. 술 후 1, 3, 5, 7, 9, 12, 15개월의 체중 kg당 평균 cyclosporine의 평균 투여 용량(mg)은 4.69±1.09. 4.15±1.17. 3.92±0.65, 3.80±0.78, 3.05±0.91, 2.24±0.00 였고, 평균 혈액 레벨(ng/ml)은 386.73±157.04, 328.60 ±98.70, 283.85 ±71.66, 302.13±65.02, 373.16±73.12, 243.00±0.00였다. 18예(24.3%)에서 급성 거부반응을 보였고. 이 중 11예(l1/18, 61.6%)는 methyl prednisolone 다량 투여 요법으로 회복되어 이 후 CIPO-N 을 주면역억제제로 사용하였다. 나머지 7예(7/18, 38.83%)는 methyl prednisolone 다량 투여 요법에 반응하지 않았고, 이 중 4예는 anti-lymphocyte globulin(ALG)으로 회복되었고, ALG에 완전하게 반응하지 않은 2예는 Tacrolimus(FK506, Prograf)로 회복되었다. 전체적인 이식편 생존율은 94.6%(70/74)였고, 환자 생존율은 97.3%(72/74)였다. 조기 신장 이식 술 후 기간 동안, 국산 microemulsion cyclosporine인 CIPOL-N은 SANDIMUM NEORAL 과 비교하여 급성 거부반응, 이식편 생존율, 환자 생존율에 있어서 유사하다는 결론을 얻었다. Background: Since the discovery of its immunologic properties and its approval for clinical use, cyclosporine has become the central component of most immunosuppressive regimen in all types of allografts. Since 1995, a microemulsion formulation of the drug, named SANDIMUM NEORAL has been available and widespread for to its more stable absorption and distribution compared to conventional cyclosporine. Recently, a new microemulsion capsule of cyclosporin, namely CIPOL-N (Chong Kun Dang, Korea) was developed and its bioaequivalance was confirmed as same as SANDIMUM NEORAL. This present study was conducted to clarify the immunosuppressive efficacy of CIPOL -N in clinical erea. Material and Method: From June 1997 to August 1998, a total of 74 renal transplant patients from Seoul Paik Hospital entered in this study. We analyzed cyclosporin dosage, cyclosporin blood level, graft failure, and survival rate. Result: The subjects were of ages 16 to 67 years(mean 42.67±12.00 year) and number of male patients were 52(70.3%), female 22(29.3%). The mean dose of cyclosporin(mg/kg) were 4.69±1.09, 4.15±1.17, 3.92±0.65, 3.80±0.78, 3.05±0.91, 2.24±0.00, and the mean cyclosporin blood trough level(ng/ml) were 386.73±157.04, 328.60±98.70, 283.85±71.66, 302.13±65.02, 373.16±73.12, 243.00±0.00 at postoperative 1, 3, 5, 7, 9, 12, and 15 months. Eighteen cases(24.3% ) were reported to have acute rejection episode. Eleven acute rejection cases(11/18, 61.6%) were treated with methyl prednisolone pulse therapy and were continued immunosuppression with CIPOL-N .. Seven acute rejection cases(7/18, 38.83%) were steroid-resistant and Six of them were treated with antilymphocyte globulin and 4 of 6 were rescued and last 2 were rescued with Prograf conversion for weak response to ALG Over all graft survival was 94.6% (70/74), and the patient survival was 97.3% (72/74). Conclusion: CIpol-N in renal transplants showed nearly same effect compared to SANDIMUM NEORAL in frequency of acute rejection episodes, graft survival, and patient survival in early posttransplant period.

국산 Microemulsion Cyclosporine(사이폴-엔)을 사요한 신장이식 74예의 조기성적

구본일,윤영철,이홍섭 인제대학교 1999 仁濟醫學 Vol.20 No.1

조혈모세포 이식환자에서 항생제 투여에 의한 cyclosporine의 혈중농도변화

송헌정,유옥리,최유리,방준석,나현오 한국임상약학회 2011 한국임상약학회지 Vol.21 No.4

조혈모세포이식술(또는 HSCT)을 받은 환자에게는 이식관련 부작용의 예방 또는 치료를 위해 면역억제 약물이 투여되는데, 그 중 하나인 cyclosporine은 therapeutic index가 작고 다양한 요인에 의해 혈중농도가 변화되므로 사용시에는 세심한 관찰과 조절이 필요하다. 특히 HSCT 환자에서 발생하는 호중구 감소성 발열(또는 NPF)의 치료목적으로 투여하는 항생제에 의하여 cyclosporine의 혈중농도가 변화될 수 있고, 또 임상적 경과에 따라 항생제 처방이 중도에 변경되는 경우도 빈번하지만, 실제로 항생제 처방의 중간변경에 의한 cyclosporine의 혈중농도 변화양상을 연구한 결과는 많지 않다. 이에, 과거 2년 동안 한 상급종합병원에서 HSCT후 cyclosporine을 투여 받았던 환자 중에서 통상적인 NPF 치료용 항생제인 ciprofloxacin을 투여하다가 치료성과를 높이기 위하여 cefepime으로 대체 투여했던 환자들의 의무기록을 후향적으로 분석하였다. 1차 선택약인 ciprofloxacin에서 항생제를 변경했을 때 cyclosporine의 혈중농도가 유의성 있게 증가했는데, 이는 ciprofloxacin 보다 cefepime이 간에서 cyclosporine을 분해시키는 효소생성을 억제시켰기 때문일 것으로 예측되며, HSCT 환자에서 NPF 치료용 항생제를 ciprofloxacin에서 cefepime으로 변경 시에는 병용중인 cyclosporine 유지용량을 약 13% 감량하는 것이 cyclosporine의 효과는 유지하면서 부작용의 발생위험을 감소시키는 데 유용한 방안이 될 것으로 사료된다.

Enhancement of Cyclosporine-Induced Oxidative Damage of Kidney Mitochondria by Iron

Yoon-Young Jang,Eun-Sook Han,Chung-Soo Lee,Young-Ki Kim,Jin-Ho Song,Yong-Kyoo Shin 대한생리학회-대한약리학회 1999 The Korean Journal of Physiology & Pharmacology Vol.3 No.6

<P> The present study investigated the stimulatory effects of iron (or ascorbate) on cyclosporine-induced kidney mitochondrial damage. Damaging effect of 50 μM cyclosporine plus 20 μM Fe<SUP>2⁢</SUP> on mitochondrial lipids and proteins of rat kidney and hyaluronic acid was greater than the summation of oxidizing action of each compound alone, except sulfhydryl oxidation. Cyclosporine and 100 μM ascorbate showed an enhanced damaging effect on lipids but not on proteins. The peroxidative action of cyclosporine on lipids was enhanced with increasing concentrations of Fe<SUP>2⁢</SUP>. Ferric ion (20 μM) also interacted with cyclosporine to stimulate lipid peroxidation. Damaging action of cyclosporine on mitochondrial lipids was enhanced by ascorbate (100 μM and 1 mM). Iron chelators, DTPA and EDTA, attenuated carbonyl formation induced by cyclosporine plus ascorbate. Cyclosporine (100 μM) and 50 μM Fe<SUP>2⁢</SUP> (or 100 μM ascorbate) synergistically stimulated degradation of 2-α deoxyribose. Cyclosporine (1 to 100 μM) reduced ferric ion in a dose dependent manner, which is much less than ascorbate action. Addition of Fe<SUP>2⁢</SUP> caused a change in absorbance spectrum of cyclosporine in 230∼350 nm of wavelengths. The results show that cyclosporine plus iron (or ascorbate) exerts an enhanced damaging effect on kidney mitochondria. Iron and ascorbate appear to promote the nephrotoxicity induced by cyclosporine.

성인 미세변화형 신증후군의 치료에서 Cyclosporine 의 효과

조성수(Seong Soo Cho),이준호(Jun Ho Lee),이수형(Soo Hyeong Lee),박성배(Sung Bae Park),김현철(Hyun Chul Kim) 대한내과학회 1994 대한내과학회지 Vol.46 No.3

We studied the effects of cyclosporine in 18, steroid dependent or relapsing patients with adult minimal change nephrotic syndrome. The 5 mg/kg/day of cyclosporine was given two divided oral doses with or without prednisolone and mean duration of cyclosporine administration was 7.1 months. Cyclosporine induced complete remission in 13 patients, partial remission in 2 patients and failed in 3 patients, namely overall response rate was 83.3%. There was no correlation between the previous response to steroid therapy and efficacy of cyclosporine. Urinary excretion of protein decreased significantly at 1 months of treatment (p<0.05). There was no significant changes in blood pressure and blood chemistry including BUN, creatinine, potassium, magnesium and uric acid during cyclosporine treatment. Tolerance to the treatment was excellent. Minor side effect such as tremor, hypertrichosis, hypertension and GI trouble were reported in small number of patients, but these were not serious enough to interrupt the study. Relapse occurred in seven out of 8 patient (87.5%) within a mean duration of 4.3±4.0 weeks after withdrawal of cyclosporine. In conclusion, cyclosporine may be a good alternative to steroid in the treatment of minimal change nephrotic syndrome, particulary in steroid dependent and frequent relapser. However prolonged administration of cyclosporine is needed to achieve continued remission because of high incidence of relaspses on withdrawal of cyclosporine.

만성 광선 피부염에서 Cyclosporine 치료의 효과 및 의의

조흔정,한승경,신항계,박윤기,이광훈 ( Heun Jung Cho,Seung Kyung Hann,Hang Kye Shin,Yoon Kee Park,Kwang Hoon Lee ) 대한피부과학회 1997 大韓皮膚科學會誌 Vol.35 No.3

Background: Chronic actinic dermatitis comprises a spectrum of chronic photosensitivity disorders. Treatment includes avoidance of UV light, application of broad-spectrum topical sunscreens, PUVA therapy, corticosteroid, azathioprine and cyclosporine. Objective : Our purpose was to determine the efficacy of cyclosporine in the treatment of chronic actinic dermatitis. Methods : Six patients with chronic actinic dermatitis refractory to conventional treatment were treated with cyclosporine 100-200mg a day for four to eighteen weeks. Results . In all six patients improvement of the skin lesions and itching were dramatic, but in three of them hyperterision developed during the cyclosporine treatment. After stopping the cyclosporine therapy, their blood pressures normalized within two to five weeks. Other side effects of cyclosporine were not found. Although the skin lesions of all of the six patients were aggravated more or less after stopping the cyclosporine therapy, we could maintain their improved states with topical corticosteroids and oral antihistamines. Conclusion 1. Cyclosporine is a good alternative in treating chronic actinic dermatitis patients who are suffering from severe symptoms refractory to conventional therapy. 2. Hypertension is the frequent side effect of cyclosporine. (Kor J Dermatol 1997;36(3): 458-464)