• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.136.2-136.2
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• 2003

Previously, we showed that cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC class I-restricted presentation of exogenous antigen in dendritic cells (DCs). We further characterized the effects of cyclosporin A and tacrolimus on the uptake, processing and cross-presentation of a model antigen, ovalbumin (OVA), in DCs. Treatment of DCs with cyclosporin A or tacrolimus did not inhibit phagocytic activity of DCs. Instead, treatment of DCs with cyclosporin A or tacrolimus inhibited the expression of $H-2K^b$/ molecules complexed with the OVA peptied, SIINFEKL, specifically. (omitted)

• Journal of Microbiology and Biotechnology
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• 제17권10호
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• pp.1638-1644
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• 2007

The effect of carbon sources on tacrolimus production by a mutant strain of Streptomyces clavuligerus CKD 1119, an isolate from soil, was examined. Among the carbohydrates and oils tested in this work, a mixed carbon source of soluble starch and com oil was the best. An analysis of the culture kinetics also showed that, in contrast to the carbohydrates, the com oil was consumed later in the antibiotic production phase, implying that the oil substrate was the principal carbon source for the biosynthesis of tacrolimus, and this was directly proven by experiments using $^{14}C$-glucose and $^{14}C$-oleate substrates. Furthermore, com oil induced the formation of lipase by the mutant strain, whereas the addition of glucose significantly repressed lipase activity. The lipase activity exhibited by the FK-506-overproducing mutants was also observed to be directly proportional to their tacrolimus yield, indicating that a high lipase activity is itself a crucial factor for tacrolimus production. A feasibility study with a 200-1 pilot-scale fermentor and the best strain (Tc-XII-15322) identified in this work revealed a high volumetric and specific productivity of about 495 mg/l and 0.34 mg/mg dry mycelium, respectively.

• 한국임상약학회지
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• 제30권3호
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• pp.149-160
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• 2020

Background: Basiliximab is used as an alternative to tacrolimus in patients with decreased renal function. However, studies on basiliximab as a maintenance immunosuppressant, particularly in patients with lung transplantation, are limited. Therefore, here, we investigated the efficacy and safety of basiliximab in patients with lung transplantation. Methods: Adult patients with acute kidney injury (AKI) who received lung transplantation at a single general hospital between July 1, 2014 and June 30, 2018, were selected and classified in tacrolimus and basiliximab groups. Both groups received a triple-drug regimen (tacrolimus, mycophenolate mofetil, and steroids). However, tacrolimus was discontinued in the basiliximab group when AKI occurred, and two or more repeat basiliximab doses were administered within 3 months after transplantation. The electronic medical records were analyzed retrospectively. Results: Of the 85 patients who met the selection criteria, 61 and 24 were assigned to the tacrolimus and basiliximab groups, respectively. Significant improvement in renal function was observed in the basiliximab group (p <0.001). However, there were no differences in acute and chronic rejection rates in both the groups. No difference was observed in the incidence rate of complications between the groups, except for chronic kidney disease, which showed higher incidence in the basiliximab group (25.0% vs. 4.9%; p =0.013). Conclusions: We suggest the use of basiliximab as an immunosuppressant alternative to tacrolimus in patients with acute renal failure after lung transplantation. Basiliximab demonstrated effectiveness as an immunosuppressant and improved renal function. Therefore, basiliximab can be used in patients with decreased renal function.

• Clinical and Experimental Pediatrics
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• 제54권1호
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• pp.40-44
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• 2011

We present a case of tacrolimus-induced encephalopathy after successful kidney transplantation. An 11-year-old girl presented with sudden onset of neurologic symptoms, hypertension, and psychiatric symptoms, with normal kidney function, after kidney transplantation. The symptoms improved after cessation of tacrolimus. Magnetic resonance imaging (MRI) showed acute infarction of the middle cerebral artery (MCA) territory in the right frontal lobe. Three days later, she had normal mental function and maintained normal blood pressure with left hemiparesis. Follow-up MRI was performed on D19, showing new infarct lesions at both cerebral hemispheres. Ten days later, MRI showed further improvement, but brain single photon emission computed tomography (SPECT) showed mild reduction of uptake in both the anterior cingulate gyrus and the left thalamus. One month after onset of symptoms, angiography showed complete resolution of stenosis. However, presenting as a mild fine motor disability of both hands and mild dysarthria, what had been atrophy at both centrum semiovale at 4 months now showed progression to encephalomalacia. There are two points of interest in this case. First, encephalopathy occurred after administration of tacrolimus and improved after discontinuation of the drug. Second, the development of right-side hemiplegia could not be explained by conventional MRI; but through diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) of white matter tract, visualization was possible.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제49권6호
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• pp.311-323
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• 2023

Immunosuppressants are vital in organ transplantation including facial transplantation (FT) but are associated with persistent side effects. This review article was prepared to compare the two most used immunosuppressants, cyclosporine and tacrolimus, in terms of mechanism of action, efficacy, and safety and to assess recent trials to mitigate their side effects. PubMed and Google Scholar queries were conducted using combinations of the following search terms: "transplantation immunosuppressant," "cyclosporine," "tacrolimus," "calcineurin inhibitor (CNI)," "efficacy," "safety," "induction therapy," "maintenance therapy," and "conversion therapy." Both immunosuppressants inhibit calcineurin and effectively down-regulate cytokines. Tacrolimus may be more advantageous since it lowers the likelihood of acute rejection, has the ability to reverse allograft rejection following cyclosporine treatment, and has the potential to reinnervate nerves. Meanwhile, graft survival rates seem to be comparable for the CNIs. To avoid nephrotoxicity, various immunosuppressants other than CNIs have been studied. Despite averting nephrotoxicity, these medications show increases in acute rejection or other types of adverse effects compared to CNIs. FT has been a topic of interest for oral and maxillofacial surgeons, and the postoperative usage of immunosuppressants is crucial for the long-term prognosis of FT. As contemporary transplantation regimens incorporate novel medications along with CNIs, further research is required.

• Childhood Kidney Diseases
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• 제18권1호
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• pp.18-23
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• 2014

목적: 소아 신장 이식 환자에서 흔히 사용되는 면역 억제제 타크롤리무스는 성별, 연령별, 인종별로 다양한 약동학적 특성이 있음이 알려져 있다. 본 연구는 우리나라 소아신장 이식 환자가 가지는 타크롤리무스의 약동학적 특징을 파악하고 관련되는 인자를 알아보기 위해 시행되었다. 방법: 경북대병원 소아청소년과에서 신장 이식을 시행받고 초기 면역 억제치료로 타크롤리무스가 사용된 환자 9명을 대상으로, 사용된 약 용량과 혈중 최저 농도 등을 후향적으로 조사하였고 이들의 약동학적 특성을 성인 대조군과 비교하였다. 결과: 남아의 평균 약 용량은 여아에 비해 유의하게 높았으나 혈중 최저 농도는 두 군 간에 유의한 차이가 없었고 청소율 또한 남아에서 유의하게 높았다. 12세 이상의 평균 약 용량은 12세 미만에 비해 낮았고 혈중 최저 농도는 높은 경향을 보였으나 유의한 차이는 없었다. 성인은 12세 이상, 미만 모두의 경우 보다 유의하게 약 용량이 적었으나 혈중 최저 농도에서는 유의한 차이가 없었다. 또한, 청소율와 반감기에서도 모두 유의한 차이를 보였다. 결론: 소아 신장 이식에서 사용되는 타크롤리무스는 나이가 어릴수록, 남아의 경우에 좀 더 많은 용량을 투여해야 할 가능성이 있음을 확인할 수 있었다. 우리나라 소아 신장 이식 환자에서 타크롤리무스의 적절한 치료용량을 확인하기 위해서는 이상의 관련인자에 대한 추가적인 전향적인 연구가 필요하다고 사료 된다.

• 한국임상수의학회지
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• 제31권2호
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• pp.95-101
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• 2014

Goat-anti-canine IgE polyclonal antibody로 유발한 개 피부염에 대한 0.1% FK-506 연고의 항염효과를 평가하였다. 임상적으로 건강한 성견 5두를 사용하여 실험군은 대조군, 위약적용군, FK-506 적용군으로 구분하였다. 항염효과는 팽진의 크기, 피부생검 검사를 통한 비만세포와 호산구수를 측정하여 평가하였으며 비만세포는 Toluidine blue, 호산구는 Luna 염색법을 사용하였다. 염증유발 15분 후의 팽진의 크기는 FK-506 적용군에서 유의성 있게 감소하였다 (p < 0.01). 6, 12, 24 시간 후 염증유발부위에 대한 피부생검을 각각 실시하였다. 정상피부의 비만세포는 $12.32{\pm}3.27cells/mm^2$ 이었으며 12시간 후에 FK-506 적용군은 $5.79{\pm}0.86cells/mm^2$으로 대조군의 $1.89{\pm}0.49cells/mm^2$, 위약군의 $1.74{\pm}0.50$ 에 비해 유의하게 증가하였다(p < 0.01). 정상피부의 호산구는 $2.73{\pm}2.24cells/mm^2$ 이었다. 대조군, 위약 적용군, FK-506 적용군의 호산구 수는 12 및 24 시간 후 FK-506 적용군에서 대조군과 위약 적용군에 비해 유의하게 증가하였다(p < 0.01). 따라서 FK-506 연고는 급성염증과 아토피증상과 유사한 후기염증에서 항염효과 있는 것으로 사료된다.

• 한국임상약학회지
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• 제30권1호
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• pp.36-43
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• 2020

Background: Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used in post-transplantation maintenance therapy. The drug has a narrow therapeutic range and requires periodic therapeutic drug monitoring. Although many studies have reported the effects of intrapatient variability of tacrolimus on survival, rejection, and complications in renal transplant recipients, very few studies have reported these effects in liver transplant recipients. The purpose of this study was to evaluate the effect of intrapatient variability of tacrolimus on clinical outcomes after liver transplantation. Methods: Intrapatient variability was calculated using individual, averaged tacrolimus concentrations. Patients were divided into two groups according to their median variability value: high-variability and low-variability groups. The rate of deviation from the therapeutic range, incidence of acute rejection, post-transplant diabetes, incidence of infection, and estimated glomerular filtration rate (eGFR) after transplantation were compared between the groups. Results: Of the total patients (n=82), the high-variability group (n=41) exhibited significantly greater deviation from the therapeutic range (65.92% vs. 56.84%; p<0.001). There was no significant difference in acute rejection or post-transplantation diabetes incidence or eGFR; however, the number of infection in the first 6 months was significantly lower in the low-variability group (0.4 vs. 0.9 times; p=0.039). Multiple linear regression analysis showed that the number of infection significantly increased as intrapatient variability increased (p=0.015). Conclusion: High intrapatient variability in tacrolimus concentrations was strongly associated with an increased frequency of deviation from the suggested therapeutic range and an increased number of infection.

• 한국임상약학회지
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• 제9권2호
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• pp.81-87
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• 1999

췌장이식의 성공률은 지난 10년 동안 상당히 상승되었다. International Pancreas Transplant Registry에 따르면 1995년 이래 미국에서만 매년 1,000건 이상의 췌장이식이 실시되고 있다. 장기이식후 나타나는 급성 거부반응은 이식 후 6개월 이내에 가장 높은 빈도수로 나타난다. 췌장이식환자에서는 신장을 이식한 것보다 두배나 높은 거부반응을 나타나며 이로 인한 입원율의 증가 항림프제(antilyinphocyte) 사용과 감염의 증가로 이환율이 높다. 더구나 Cyclosporine (CsA)을 기초로 한 면역억제제요법의 사용은 높은 급성 거부반응률(acute graft rejection)을 초래하여 이식한 장기의 조직손실이 문제가 되고 있다. 새로운 면역억제제인 Tacrolimus (FK506)의 사용은 이식환자에서의 거부반응을 감소시켜 생존율을 증가시키는 것으로 알려져 있다. Tacrolimus는 neutral macrolide로 cyclic peptide인 CsA과는 화학 구조는 매우 다르나 비슷한 면역억제 효과를 보인다. 하지만 Tacrolimus의 사용시 신경독성, 신독성, 특히 고혈당증의 발생률이 높아 일부 이식센터에서는 장기 이식 후에 사용하기를 꺼리기도 한다. 하지만 여러 연구논문에서 간과 신장 이식 후 급성 거부반응 예방에 Tacrolimus는 CsA에 비해 이점이 있는 결과를 발표하였다. 결과적으로, 현재 췌장이식 후 Tacrolimus를 기초로 한 면역억제의 효과에 대한 연구가 활발히 진행중이다. 따라서 본 연구에서는 1994-1996년 사이에 Tacrolimus 또는 CsA를 기초로 한 면역억제요법을 투여 받은 췌장이식환자 101명을 후향적으로 조사하여 Tacrolimus (n=54)와 CsA(n=57)의 급성 거부반응 예방 효과와 신부전 발생률을 비교하였다. 모든 환자는 항림프구 약물, Azathioprine, Prednisone을 이식 후 면역억제제로 투여 받았다 기준선으로부터 $20\%$ 이상의 혈청 creatinine의 상승이 있는 환자에서는 급성 신부전으로 정의하였고 신장생검법으로 거부반응을 진단하였다 Matched-pair analysis에 따르면 췌장이식환자의 6개월 생존율은 CsA군에서 $97\%$, Tacrolimus군에서 $96\%$로 별다른 차이가 없었으며 (p=0.57), 6개월간의 이식한 췌장의 보존율은 CsA군에서는 $88\%, Tacrolimus에서 $91\%$. 유의한 차이는 없었다(p=0.29). 췌장이식 후 6개월 동안 Tacrolimus의 사용은 생검으로 증명되는(biopsy-proven) 급성 거부반응의 발생빈도는 CsA보다 유의하게 낮았을 뿐만 아니라 (p<0.05) 거부반응 증상의 심각도 또한 감소시켰다 (p=0.03). 급성거부반응 발생빈도의 감소로 Tacrolimus군에서 antilymphocyte 치료가 유의하게 줄어들었다(p=0.01). CsA군에서 Tacrolimus보다 신부전의 발생률이 높았으나 통계학적 차이는 없었다. 췌장이식후의 최적의 면역억제요법의 결정하기 위해서는 향후 Tacrolimus와 CsA을 비교하는 전향적 무작위 연구가 필요하다.

• 한국임상약학회지
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• 제31권1호
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• pp.44-52
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• 2021

Background: Post-transplant immunosuppression with calcineurin inhibitors (CNIs) is associated with kidney function impairment while mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, can be used for its renal-sparing effects. In this study, we compared the efficacy and safety of everolimus with low dose tacrolimus (EVR+Low TAC) and conventional dose tacrolimus (TAC) in liver transplantation recipients. Methods: Medical records of recipients who received liver transplantation at Seoul National University Bundang Hospital from January 1st 2009 to December 31st 2018 were retrospectively reviewed. Cohort entry date was defined as the day everolimus was initiated and tacrolimus dosage was reduced. All patients were followed up for 1 year. Indicator of efficacy was the incidence of rejection and safety was evaluated by incidence of drug adverse events including renal function. Results: Among 118 patients, there were 40 patients (33.9%) in EVR+Low TAC group. Incidence of rejection, including both biopsy proven acute rejection and clinical rejection, was similar in two groups [7.5% (n=3) vs. 6.4% (n=5), p=1.000]. Renal dysfunction was less frequent in EVR+Low TAC [17.5% (n=7) vs. 35.9% (n=28), p=0.038]. However, incidence rates of dyslipidemia, oral ulcer were more frequent in EVR+Low TAC [45.0% (n=18) vs. 21.8% (n=17), p=0.009; 15.0% (n=6) vs. 1.3% (n=1), p=0.006]. Conclusions: In terms of prevention of rejection, EVR+Low TAC was as effective as TAC and had renal-sparing effect but was associated with increased risk of dyslipidemia and oral ulcer. This study demonstrates that EVR+Low TAC could be an alternative to liver transplant recipients with nephrotoxicity after administration of conventional dose tacrolimus.