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.

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)

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.

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

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

조혈모세포 이식을 받은 소아 환자에서 cyclosporine의 집단 약동학 분석

조소연,강원구,이정,김재연,안숙희,곽혜선 한국임상약학회 2018 한국임상약학회지 Vol.28 No.1

Background: Cyclosporine is an immunosuppressive agent used to treat and prevent graft versus host reaction (GVHR)−a complication associated with stem cell transplantation. This study aimed to develop a population pharmacokinetic model of cyclosporine and investigate factors affecting cyclosporine clearance in pediatric hematopoietic stem cell transplant patients. Methods: A total of 650 cyclosporine concentrations recorded in 65 patients who underwent hematopoietic stem cell transplantation were used. Data including age, sex, weight, height, body surface area (BSA), type of disease, chemotherapy before stem cell transplantation, type of donor, serum creatinine levels, total bilirubin concentration, hematocrit value, and type of concomitant antifungal agents and methylprednisolone used were retrospectively collected. Data related to cyclosporine dosage, administration time, and blood concentration were also collected. All data were analyzed using the non-linear mixed effect model; a twocompartment model with first-order elimination was used. Results: The population pharmacokinetic model of cyclosporine using the NONMEM program was as follows: CL (L/h) = 5.9 × (BSA / 1.2)0.9, V2 (L) = 54.5, Q (L/h) = 3.5, V3 (L) = 1080.0, ka (h-1) = 0.000377. BSA was selected as a covariate of cyclosporine clearance, which increased with an increase in BSA. Conclusion: A population pharmacokinetic model for Korean pediatric hematopoietic stem cell transplant patients was developed, and the important factor affecting cyclosporine clearance was found to be BSA. The model might contribute to the development of the most appropriate dosing regimen for cyclosporine. Further studies on population pharmacokinetics should be carried out, prospectively targeting pediatric patients.

The correlation between cumulative doses of cyclosporine required for remission and IgE level in atopic dermatitis; Single-center, retrospective study

( Dong Seok Shin ),( Young Wook Ko ),( Dong Uk Cheon ),( Won Seon Koh ),( Jeong Eun Kim ),( Joo Yeon Ko ),( Young Suck Ro ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.2

Background: The efficacy of cyclosporine in the treatment of atopic dermatitis has been well documented. However, there are no data covering therapeutic doses of cyclosporine according to serum IgE level in atopic dermatitis. Objectives: The purpose of this study was to elucidate the correlation between cumulative doses of cyclosporine required for remission and IgE level in atopic dermatitis. Methods: We performed a retrospective analysis of 75 patients with atopic dermatitis who had been treated with cyclosporine in our clinic. We conducted univariate analysis between IgE level and cumulative doses of cyclosporine required for remission. Multivariate analysis was additionally done in order to sort out the confounding factors. Results: The cumulative doses of cyclosporine required for remission tended to increase as serum IgE level got higher and this relationship was statistically significant. In a multivariate analysis, serum IgE and EASI (Eczema Area and Severity Index) score were statistically related and both factors were appear to be positively related to cumulative doses of cyclosporine. Conclusion: We found that the positive relationship between cumulative doses of cyclosporine required for remission and IgE level in atopic dermatitis. Our results indicated that high level of initial serum IgE could be regarded as a poor prognostic factor at the beginning of cyclosporine therapy.

Effect of Cyclosporine on Circulating Interleukin-10 and Interleukin-12 in Pateints with Severe, Refractory Rheumatoid Arthritis

Kim, Jeong-Sun,Kim, Wan-Uk,Cho, Mi-La,Youn, Jee-Hee,Lee, Suk-Kyeong,Chae, Eun-Young,Min, Jun-Ki,Hong, Yeon-Sik,Lee, Sang-Heon,Park, Sung-Hwan,Cho, Chul-Soo,Kim, Ho-Youn 가톨릭대학교 2000 Bulletin of The Catholic Research Institutes of Me Vol.28 No.-

Background : To investigate the effect of cyclosporine on interleukin-10 (IL-10) and interleukin-12 (IL-12) in patients with rheumatoid arthrtis (RA) Methods : A 10-week randomized, double blind, placebo-control study of cyclosporine RA who had residual inflammation and isability despite partial reponses to prior maximal tolerated dose of methotrexate (<15 mg/week) and low dose prednisone (<10 mg/day). The clinical and laboratory variables, and circulating leves IL-10 and IL-12 measered by enzymelinked immunosorbent method, were compared between patients (cyclosporine group) treated with cycloporine plus methotreaxte and those (placebo group) treated with placebo plus methotrexate at the entry and 16 weeks of the study. Results : On the 16 weeks into the clinical trial, the cyclosporine group (n=17), compared with the placebo group (n=17), had higher degree of decreases in tender joints, patients global assessment, patients self assessed disability, C-reactive protein as well as having more patients with over 20% improvement. The comparison of the circulating IL-10 and IL-12 at the entry and 16 weeks of the study showed significant decreases of IL-12(median-313 versrs -14 pg/ml, p=0.002) and a significant increase of IL-10 (median 55 versus-12 pg/ml, p <0.001) in the cyclosporine group compared with the placebo group. The degree of IL-10 increases strongly correlated with the degree of IL-12 decreases in the cyclosporine group (r=0.572, p=0.016). Among the cyclosporine group, the improved patients (n 10), compared to the non-improved patients (n=7), had higher rate of increase in the circulating IL-10 (median 172.0 versus 85.2%, p=0.01). The rate of increase of IL-10 strongly correlated with the rate of improvement of joint scores (r=0.718, p=0.001) after administration of cyclosporine. Conclusion : Our results suggest that the therapeuic effect of cyclosporine is achieved by correcting Th1/Th2 imbalance (a shift Th1 type to Th2 type), which may be in the pathogenesis of RA, and circulating IL-10 is useful to assess the clinical improvements in patients with RA after administration of cyclosporine. (Korean Journal of BRM 9(1):19-30, 1999)

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

N/A 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.