• Journal of Chest Surgery
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• 제27권1호
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• pp.15-23
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• 1994

This study examined the effects of cyclosporin A [CsA] and methylprednisolone[MP] on the viability of the devascularized trachea after heterotopic transplantation. Fourty-two tracheal segments were harvested from 21 donor Wistar rats. Those tracheal segments were heterotopically implanted into the abdomen of recipient rats after wrapping in omentum. Heterotopical implantation was performed in six groups of rats:Group I was Wistar syngeneic controls, and five groups of Sprague Dawley recipients, receiving no immunosuppression[Group II], CsA alone[Group III, V], and CsA in combination with MP[Group IV, VI]. After 14 days, the tracheal segments were histologically evaluated.Epithelial thickness and the degree of epithelial regeneration were significantly different between group I and group II, III, VI, VI [p< 0.05]. There were significant differences in the epithelial thickness between group II, III, IV and group V, VI. In the degree of epithelial regeneration, there were significant differences in group II, group III-IV, and group V-VI. Without immunosuppression there was virtually no epithelium, whereas low-dose immunosuppression yielded intermediated viability, and with high dose CsA and MP we observed improved tracheal viability. Our results suggest that optimal combination of CsA and MP may improve the viability in heterotopic tracheal allografts.

• Biomolecules & Therapeutics
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• 제6권2호
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• pp.130-138
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• 1998

In this study, the effect of verapamil (VER) on cyclosporin A (CsA)-induced nephrotoxicity was investigated in uninephrectomized rats. Male Wistar rats were administered CsA (50 mg/kg/day, p.o.) or VER (0.5 mg/kg/day, i.p.) with CsA (50 mg/kg/day, p.o.) for 20 days. The urinary N-acetyl-$\beta$-D-glucosaminidase (NAG) activity along with BUN, serum creatinine, creatinine clearance (CLcr), body weight, and 24 hr-urine output were measured and histopathologic changes of kidney were evaluated by light and electron microscopy. The results obtained from this study can be summarized as follows: While NAG activity, BUN and serum creatinine was progressively increased and CLcr significantly decreased in CsA group, VER almost signifi-cantly (p<0.05) suppressed and normalized CsA-induced changes in VER+CSA group. While urine output increased until 12th days and thereafter progressively decreased in CsA group, it gradually increased in control and VER+CSA group. While body weight progressively made a gain in control and VER+CSA groups, it significantly (p<0.05) lost in CsA group. On light microscopy, the glomerular hyperemia and proximal convoluted tubular (PCT) dilatation, focal tubular cell vacuolation and necrosis were clearly evident in CsA group, but, were not seen in other groups. Ultrastructural studies revealed thickened glomerular endothelium and basal lamina of capillary, irregular shaped pedicels of podocytes, indistinct slit pores and narrowed bowman's space. The large oval vacuoles with dense debris and phagosome were distributed in apical zone and deformed microvilli and mitochondria were seen in the PCT cell of CsA group. But, glomeruli and PCT cell were relatively preserved in normal apperance in other groups. In conclusion, it is suggested that verapamil has a protective effect on cyclosporine-induced nephrotoxicity in uninephrectomized rats.

• Archives of Pharmacal Research
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• 제27권6호
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• pp.662-669
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• 2004

The highly water-soluble monomethoxypoly(ethyleneglycol) (mPEG) prod rugs of cyciosporin A(CsA) were synthesized. These prod rugs were prepared by initially preparing intermediate in the form of carbonate at the 3'-positions of CsA with chloromethyl chloroformate, in the pres-ence of a base to provide a 3'-carbonated CsA intermediate. Reaction of the CsA intermediate with mPEG derivative in the presence of a base provides the desired water-soluble prod rugs. As a model, we chose molecular weight 5 kDa mPEG in the reaction with CsA to give water soluble prodrugs. To prove that the prod rug is decomposed in the body to produce CsA, the enzymatic hydrolysis test was conducted using human liver homogenate at $37^{\circ}C$. The prodrug was decomposed in human liver homogenate to produce the active material, CsA, and the hydrolysis half-life ($t_{1/2}$) of the prodrug, KI-306 was 2.2 minutes at $37^{\circ}C$. However, a demon-stration of non-enzymatic conversion in pH 7.4 phosphate buffer was provided by the fact that the half-life ($t_{1/2}$) is 21 hours at 37$^{\circ}C$. The hydrolysis test in rat whole blood was also conducted. The hydrolysis was seen with half-life ($t_{1/2}$) of about 9.9, 65.0, 14.2, 3.4, 2.1 9.5, and 1.6 minutes for KI-306, 309, 312, 313, 315, 316, and 317, respectively. This is the ideal for CsA prodrug. The pharmacokinetic study of the prodrug, KI-306, in comparison to the commer-cial product (Sandimmune Neoral Solution) was also carried out after single oral dose. Each rat received 7 mg／kg of CsA equivalent dose. Especially, the prodrug KI-306 exhibits higher AUC and $C_{max}$ than the conventional Neoral. The AUC and $C_{max}$ were increased nearly 1.5 fold. The kinetic value was also seen with $T_{max}$ of about 1.43 and 2.44 hours for KI-306 and Neoral, respectively.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.202.3-203
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• 2003

Calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (FK506), have been studied extensively regarding their effects on T lymphocytes, but their effects on dendritic cells (DC) are relatively unknown. DC can really capture Ag from dead and dying cells for presentation to MHC class I-restricted CTL. The main targets for the immunosuppressive calcinerin inhibitors, FK506 and CsA. have been considered to be activated T cells, but not antigen presenting cells (APCs). (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.203.1-203.1
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• 2003

Calcineurin inhibitors, cyclosporine A (CsA)and tacrolimus (FK506), have been studied extensively regarding their effects on T lymphocytes, but their effects on dendritic cells (DC) are relatively unknown. DC can really capture Ag from dead and dying cells for presentation to MHC class I-restricted CTL. The main targets for the immunosuppressive calcinerin inhibitors, FK506 and CsA, have been considered to be activated T cells, but not antigen presenting cells (APCs). (omitted)

• International Journal of Oral Biology
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• 제40권3호
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• pp.127-133
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• 2015

The salivary gland undergoes complex process of growth and differentiation of the branching morphogenesis of ductal system during the prenatal and early postnatal periods which are regulated by various elements in the extracellular matrix. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a cell adhesion molecule. In the present study, localization and expression of EMMPRIN in development and effects of chorda-lingual denervation and cyclosporine A (CsA) treatment on the EMMPRIN expression were investigated. Immunohistochemistry, RT-PCR and Western blot were used to determine expression level. Immunohistochemistry revealed that EMMPRIN was localized specifically in the cytoplasm of ductal cells, not acini of the submandibular gland all the postnatal periods. At prenatal day 18, when the formation of ducts was not definite, no immunoreactivity was observed. Both Western blot and RT-PCR analyses revealed that EMMPRIN expression was maintained up to postnatal day 7, decreased after postnatal day 10. The EMMPRIN expression was upregulated by the surgical denervation of the chorda-lingual nerve in the gland as well as by the CsA treatment. The present study suggests that EMMPRIN is a crucial molecule for maintaining physiological functions of the salivary gland.

• 치위생과학회지
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• 제15권4호
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• pp.488-494
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• 2015

치주인대세포의 효과적인 조절은 성공적인 치주 조직 재생에 중요한 역할을 한다. NFATc1의 활성화가 골모세포에서 분화를 자극하지만, 치주인대세포가 골모세포로 분화하는 과정에서 NFATc1의 역할은 아직 보고되지 않았다. 본 연구는 hPDLCs가 골모세포로 분화하는 동안 NFATc1의 mRNA의 발현과 단백질 발현이 유도됨을 처음으로 확인하였다. CsA에 의한 NFATc1의 억제는 세포증식을 감소시켰다. 게다가, CsA를 처리한 결과, 분화표지자, ALP activity 및 광화결정형성을 감소시켰다. 이러한 연구 결과는 NFATc1이 치주 재생을 위한 골모세포 분화에 중요한 조절자 역할을 할 수 있을 것으로 생각된다.

• 동의생리병리학회지
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• 제28권5호
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• pp.499-505
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• 2014

Immunosuppressors cyclosporine A(CsA) and tacrolimus(FK506), the primary cellular target of which is calcineurin/nuclear factor of activated T cells(NFAT) signalling pathways, decrease beta-cell insulin content and mRNA expression. The posttransplantation diabetes mellitus(PTDM) is a frequent complication in immunosuppressive therapy. The present study was to examine the effect of a crude water extracts of medicinal herbs such as Sanguisorba officinalis(SOE) on the immunosuppressive activity with lymphocyte and insulin secretion in insulinoma cell lines with RIN-5mF. It was found that SOE treatment had effect of immunosuppressor on lymphocytes and also significantly increased insulin secretion in RIN-5mF compared to other agents. we might suggest a mechanism on insulin secretion by HNF4a. Taken together, the present study suggested that SOE might serve as immunosuppressive drug in PTDM.

• Journal of Chest Surgery
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• 제39권10호
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• pp.739-748
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• 2006

토끼의 25분간의 척수허혈 모델에서 cyclosporin A의 신경보호효과를 신경병리학적 연관성과 면역조직화학적분석을 통하여 알아보고자 하였다. 대상 및 방법: 몸무게가 3.0 kg 전후의 뉴질랜드산 토끼를 이용하였고 복부 대동맥을 25분간 차단하였다. 32마리의 토끼를 무작위로 4군으로 나누어 대조군인 12군(n=8)과 17군(n=8)은 복부 대동맥 차단만 시행한 후 12군은 2일째, 17군은 7일째 희생시켜 신경학적 평가와 조직학적 검사를 시행하였다. 실험군인 Cs2군(n=8)과 Cs7군(n=8)은 복부 대동맥을 차단 후 재관류 15분 후에 cyclosporin A (25 mg/kg)를 정맥 주입한 후 Cs2군은 2일째, Cs7군은 7일째 희생시켜 신경학적 평가와 조직학적 검사를 시행하였다. 결과: 모든 토끼가 술 후 생존하였으며 술 후 2일째 신경학적 평가에 있어서는 군들 간 차이가 얼었으나 술 후 7일째 시행한 평가에서 복부대동맥 허혈 후 cyclosporin A를 투여한 Cs7군의 Tarlov score가 평균 $2.75{\pm}0.89$로 투여하지 않은 17군의 $1.25{\pm}1.39$에 비해 의미 있게 높아 신경학적 평가상 덜 손상을 받았음을 알 수 있었다(p<0.05). 또한 대조군 17군에서는 신경학적 평가가 2일째보다 7일째 악화하는 경향이었으나 통계학적으로 의미 있는 차이는 없었고 실험군 Cs7군에 있어서는 신경학적 평가가 2일째 $1.87{\pm}0.83$에 비해 7일째 $2.75{\pm}0.89$로 의미 있게 호전되었다(p<0.05). 모든 군을 조직학적으로 손상의 정도에 따라 등급을 매겼으며 신경학적 평가와의 상관관계를 분석하였는데 상관계수 -0.44로 조직학적 손상정도와 신경학적 평가사이에 유의한 관계가 있었다(p=0.009). 병리조직학적 등급을 4군 간 비교하였을 때 2일째 희생시킨 대조군과 실험군 사이에는 유의한 차이가 없었으나 7일째 희생시킨 17군은 조직학적 등급이 $2.13{\pm}1.36$이었으나 Cs7군은 $1.0{\pm}0.53$으로 두 군 간 유의한 차이가 있어 병리학적으로도 cyclosporin A를 투여한 실험군 Cs7군이 대조군 17군에 비해 덜 손상을 받았음을 알 수 있었다(p=0.039). 12군과 Cs2군에서 TUNEL 염색에 양성반응을 보이는 신경세포의 수는 12군이 $17.5{\pm}22.6$개였고 Cs2군이 $12.5{\pm}11.1$개로 통계학적으로 유의한 차이가 없었다. Heat shock protein-70 (HSP70)과 neuronal nitric oxide synthase (nNOS)에 대한 면역조직화학검사에서 실험군 Cs2군의 신경세포가 대조군 12군에 비해 HSP70과 nNOS의 과발현을 보였으며, 이는 통계학적으로 유의한 차이를 보였다(p<0.05). nNOS와 HSP70의 발현은 강한 연관성을 보였고(상관계수 0.91, p=0.000), nNOS를 발현하는 세포가 동시에 HSP70도 발현함을 확인할 수 있었다. 결론: 우리는 cyclosporin A가 토끼의 25분간의 척수허혈에 대해 척수보호 효과가 있었으며 이는 HSP70의 과발현과 연관이 있으리라 생각한다.

• 한국임상약학회지
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• 제20권1호
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• pp.9-16
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• 2010

Purpose: 본 연구는 한국인 성인 조혈모세포이식환자를 대상으로 경구용 사이클로스포린의 집단약동학 분석을 통하여 사이클로스포린의 약동학적 파라미터에 영향을 미치는 요인 분석을 실시하고자 하였다. Methods: 2000년 12월부터 2006년 8월까지 서울대학교병원에서 동종조혈모세포이식을 받고 면역억제제로 사이클로스포린을 복용한 성인 백혈병환자를 대상으로 후향적으로 자료를 수집하였다. 사이클로스포린의 약동학에 영향을 미치는 인자로는 연령, 성별, 이식 후 날짜, 신기능, 공여자와의 관계, 질병의 종류, 혈중 빌리루빈 농도, 사이클로스포린의 대사를 유도하는 프레드니솔론의 투여량, 헤마토크리트, 사이클로스포린의 대사를 저해하는 약물의 병용여부 등을 검토하였다. 분석은 NONMEM$^{(R)}$ VI 프로그램을 이용하였으며, 변수를 추가하지 않은 기본 모형을 만든 후에 단계적인 요인의 추가와 제거를 통해 최종모형을 제작하였다. Results: 최종 상관 모형은 다음과 같다; CL/F (L/h) = $85.6{\times}e^{(0.646\;{\times}\;HCT/28.9\;+\;0.0464\;{\times}\;Gender)}$. 사이클로스포린의 겉보기 클리어런스는 환자의 성별이 남자일 때 또는 헤마토크릿이 감소할수록 증가하였다. 그 외 파라미터는 다음과 같이 계산되었다; $K_{\alpha}=0.0787\;(h^{-1})$; Q=57.1(L/kg/h); $V_{d-central\;compartment}$=1,100 (L); $V_{d-peripheral\;compartment}$ = 213,000(L). 개체간 편차는 40% 미만이었으며, 개체내 편차를 포함하는 잔차는 24.02%였다. Conclusions: 사이클로스포린의 약동학적 특징과 그 클리어런스에 영향을 끼칠 수 있는 임상적 요인을 이해하는 것은 환자 개개인의 용량과 용법의 결정 및 이상반응 발생의 예방에 유용할 수 있다. 한국인 조혈모세포이식환자에서 사이클로스포린의 약동학에 영향을 미치는 최종 파라미터를 구한 본 연구의 결과는 조혈모세포이식을 받은 한국인 성인환자에서 사이클로스포린의 모니터링 및 용량조절에 유용할 것으로 전망된다.