• Proceedings of the PSK Conference
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• 2003.10b
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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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• v.17 no.10
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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.

• Korean Journal of Clinical Pharmacy
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• v.30 no.3
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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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• v.54 no.1
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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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• v.49 no.6
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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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• v.18 no.1
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• pp.18-23
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• 2014

Purpose: The pharmacokinetics of tacrolimus, one of the most widely used immunosuppressive drugs, are known to vary by sex, age, and ethnicity during pediatric transplantation. This study assessed the pharmacokinetic characteristics and associated factors of tacrolimus in Korean children receiving a kidney transplant. Methods: We retrospectively reviewed the pharmacokinetic data (therapeutic dose, trough level, clearance, and half-life) of 9 children who were given tacrolimus as one of their initial immunosuppressive drugs after kidney transplantation. In addition, we compared the findings to data from 10 adult kidney transplant recipients. Results: The mean age of our pediatric patients was 13.9 years, and the maleto- female ratio was 4:5. The mean dose of tacrolimus was $0.19{\pm}0.14$ mg/kg/day. The mean dose of tacrolimus for males was $0.23{\pm}0.12$ mg/kg/day, which was significantly higher than the dose for females ($0.16{\pm}0.14$ mg/kg/day). The trough level was not significantly different between both groups. The clearance rate of tacrolimus for males was also significantly higher than females. Although the dosage of tacrolimus for patients over the age of 12 years was lower ($0.18{\pm}0.13$ vs. $0.21{\pm}0.16$ mg/kg/day) and the trough level was higher ($8.2{\pm}4.5$ vs. $7.2{\pm}4.2$ mg/mL) than that for patients under the age of 12 years, there was no significant difference between them. However, there were significant differences between children and adults in dose, clearance, and half-life of tacrolimus. Conclusion: Out study suggests that the pharmacokinetics of tacrolimus tends to vary with sex and age. Therefore, large-scale prospective studies are required to verify the proper therapeutic dosage of tacrolimus in Korean children.

• Journal of Veterinary Clinics
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• v.31 no.2
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• pp.95-101
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• 2014

Five dogs were used to determine whether 0.1% tacrolimus ointment application for one day would inhibit IgE-mediated late-phase reactions (LPRs). It was consisted of three periods: one period without therapeutic administration (control) and two periods of treatment with either the tacrolimus ointment or vehicle. Induction of IgE-mediated LPRs was induced by intradermal injections of 0.05 ml (0.14 mg/ml) of solution of goat anti-canine IgE polyclonal antibodies. Each section for mast cells (MCs) and eosinophils (EPs) was stained with acidified toluidine blue, and Luna's stain, respectively. Assessment of anti-inflammatory effect of tacrolimus ointment composed of cell counts of MC and EP from lesions of induced LPR. In normal canine biopsies, the number of dermal MCs and EPs were $12.3{\pm}1.4cells/mm^2$ and $3.1{\pm}1.3cells/mm^2$, respectively. MC counts dramatically decreased at time dependent manner after anti-IgE administration. However, the number of MCs on 6 hours after challenge was significantly less decreased in the groups treated with the tacrolimus, as compared with control and vehicle group. The number of EPs on 24 hours after challenge was significantly lower in the group treated with the tacrolimus than in the control and vehicle groups. In conclusion, this study revealed that 0.1% tacrolimus ointment in dogs may exert a potent anti-inflammatory effect on inhibition of MC degranulation and also secondary prevention of EP infiltration during LPR.

• Korean Journal of Clinical Pharmacy
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• v.30 no.1
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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.

• Korean Journal of Clinical Pharmacy
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• v.9 no.2
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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.

• Korean Journal of Clinical Pharmacy
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• v.31 no.1
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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.