• Childhood Kidney Diseases
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• v.20 no.2
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• pp.45-49
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• 2016

Purpose: This study was performed to evaluate the effects of cyclosporine-A (CsA) on linear growth in pediatric patients with steroid-dependent (SDNS) or resistant nephrotic syndrome (SRNS). Methods: Thirty-five pediatric patients with SDNS or SRNS undergoing glucocorticoid (GC) and/or CsA treatment were retrospectively reviewed. Seventeen patients were treated with GC alone and 18 were treated with GC and CsA. The cumulative doses of GC and CsA were quantified (mg/kg/day). Linear growth during the follow-up period was defined as the difference in Z-score between the initial and final height according to the follow-up period (${\Delta}$ height Z score/year). The associations between linear growth and clinical parameters were analyzed. Results: The linear growth of patients in the two groups was not significantly different (P=0.262). The ${\Delta}$ height Z score/year did not show a significant correlation with the cumulative doses of CsA, but was negatively correlated with the cumulative dose of GC and positively correlated with the Z score for height at the time of diagnosis. Conclusion: In children with SDNS or SRNS undergoing GC therapy, added CsA treatment may not have harmful effects on linear growth.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.27 no.5
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• pp.438-445
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• 2005

Cyclosporine A(CsA) is a powerful immunossuppresive agent used to prevent graft rejection of organ and treat autoimmune disease. One of the major side effects associated with CsA treatment is the development of gingival overgrowth. The purpose of this study was to evaluate the expression and association of the several growth factors in gingival overgrowth induced CsA using by immunohistochemical technique. Normal tissues as control were obtained from healthy normal gingivae and overgrowth gingival tissues as experiments were obtained from the patients taken the CsA. The expressions of the MMP-1, TIMP-1, TGF$\beta$-1, p21, p53, PCNA were evaluated by immunohistochemical technique. The more overgrowth was detected at the epithelial and connective tissue area in experimental group. The MMP-1, TGF$\beta$-1, p21, p53, PCNA expressions were significantly increased in experimental group. The TIMP-1 expressions was not significantly increased in experimental group. We could conclude that the gingival overgrowth induced CsA was related with the collagen matabolism in connective tissue and also the production of the growth factor from epithelial tissue.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.34 no.4
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• pp.405-411
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• 2008

Purpose : Cyclosporine A (CsA) is a versatile immunosuppresive agent used to prevent graft rejection syndrome and treat autoimmune disease. One of the major side effects associated with CsA is the abnormal gingival hyperplasia. The purpose of this study was to investigate the relationship between the mRNA expression of the MMP-1, TIMP-1, and $TGF-{\beta}_1$ and the concentration of CsA in cultured human gingival keratinocytes. Materials & Methods : Gingival keratocytes were obtained from gingival tissues of 4 healthy donors. The cultured gingival keratocytes were incubated with increasing concentrations of CsA (0-2000 ng/ml) for 24 hours and the expression of MMP-1, TIMP-1, and $TGF-{\beta}_1$ were determined by reverse transcription-polymerase chain reaction (RT-PCR). Results : The expressions of MMP-1 and $TGF-{\beta}_1$ were not significantly different according to the concentrations of CsA. The expression of TIMP-1 was significantly increased at the CsA concentration of 500 ng/ml. Conclusion : We concluded that the gingival hyperplasia induced by CsA was more related with TIMP-1 than MMP-1 or $TGF-{\beta}_1$ on gingival collagen metabolism in patients treated with CsA.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.1
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• pp.166-173
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• 2009

Cyclosporine(CsA) is an immunosupressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It has been studied in transplants of skin, heart, kidney, liver, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Both kidney and liver dysfunction are prominent side effects of CsA. The present study was designed to determine the possible protective effect of salidroside(Sal) isolated from the BuOH extract of Acer termentosum Max against oxidative damage in CsA-treated(50 mg/kg, ip) nephrotoxicity rats. Results showed oral administration of methanol and butanol extact of Acer termentosum Max(200 mg/kg, po) significantly reduced activities of marker enzymes(BUN, Creatinine) and LDH activity in serum to CsA induced experimental kidney injured rats. And significantly decrcease of protein amount level in urine and activities of free radical formation enzyme were significantly improved by the treatment of Sal. And significantly decrcease of MDA level in kidney and activities of calalase, glutathione peroxidation and SOD were significantly improved by the treatment of Sal(20 mg/kg, po). But glutathione concentration and glutathione S-transferase actitity was not affected. Results of this study revealed that Sal could afford a significant protection in the alleviation of CsA-induced nephrotoxicity injury.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.6
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• pp.353-361
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• 2005

The interaction of cyclosporine A (CsA), an immunosuppressant, with rat brain Kv1.5 (Kv1.5) channels, which were stably expressed in Chinese hamster ovary cells, was investigated using the whole-cell patch-clamp technique. CsA reversibly blocked Kv1.5 currents at +50 mV in a reversible concentrationdependent manner with an apparent $IC_{50}$ of 1.0μM. Other calcineurin inhibitors (cypermethrin, autoinhibitory peptide) had no effect on Kv1.5 and did not prevent the inhibitory effect of CsA. Fast application of CsA led to a rapid and reversible block of Kv1.5, and the onset time constants of the CsA-induced block were decreased in a concentration-dependent manner. The CsA-induced block of Kv1.5 channels was voltage-dependent, with a steep increase over the voltage range of channel opening. However, the block exhibited voltage independence over the voltage range in which channels were fully activated. The rate constants for association and dissociation of CsA were $7.0{\mu}M{-1}s^{-1}$ and $8.1s^{-1}$, respectively. CsA slowed the deactivation time course, resulting in a tail crossover phenomenon. Block of Kv1.5 by CsA was use-dependent. CsA also blocked Kv1.3 currents at +50 mV in a reversible concentration-dependent manner with an apparent $IC_{50}$ of $1.1{\mu}M$. The same effects of CsA on Kv1.3 were also observed in excised inside-out patches when applied to the internal surface of the membrane. The present results suggest that CsA acts directly on Kv1.5 currents as an open-channel blocker, independently of the effects of CsA on calcineurin activity.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.5
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• pp.353-359
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• 2010

Introduction: This study examined the effect of cyclosporine A (CsA) on the allogenic cranial bone graft in the mice. Materials and Methods: Twenty eight 12-week-old male ICR mice weighing 40 g were used. The experimental group was injected subcutaneously with CsA (10 mg/kg/day) diluted in Caster oil for 7 days prior to the graft until sacrifice. The control group was injected with the same solution without CsA. Two full-thickness bone defects with a diameter of 3 mm were made with a trephine bur in the parietal bone lateral to the sagittal suture. A calvarial defect of a mouse was grafted with allogenic calvarial bone disc from another mouse. The experimental and control groups were injected with CsA and the solution without CsA in the same manner before surgery, respectively. The mice were sacrificed at 1 week, 2 weeks and 4 weeks after the bone graft, respectively. Results: In the experimental group, fibrous connective tissues and small amounts of inflammatory cells were observed. At 2 weeks after the allograft in the experimental group, new bone formation in fibrous collagenous tissue and around the allogenic bone was noted. At 4 weeks after the allograft, new bone formation was active along and at the periphery of the mature allogenic bone. The proliferation of blood vessels increased in bone marrow. In the control group, fibrous tissues and inflammatory cells were observed around the allogenic bone and existing bone at 1 week. At 2 weeks after the allograft, the proliferation of blood vessels accompanied by inflammatory cells were scattered in the fibrous connective tissues. New bone formation around the allogenic and existing bone could be observed. At 4 weeks after the allograft, inflammatory cells were severely infiltrated around the allogenic bone. Osteoclasts were scattered along the allogenic bone and induced bone resorption. Conclusion: These results suggest that the daily administration of CsA (10 mg/kg/day) induces efficient immunosuppression without serious complications, and this protocol might be useful for the experimental model of allogenic bone grafts.

• YAKHAK HOEJI
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• v.39 no.5
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• pp.487-494
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• 1995

Solid lipid microspheres (SLMs) were prepared using various lipids and solidifying agents, in order to enhance the gastrointestinal absorption of Cyclosporine A (Cs A) which is a practically water-insoluble drug with low systemic bioavailability. Egg lecithin and HCO-60 (polyoxyethylated 60 mol, hydrogenated castor oil) were used as lipids. Stearic acid and stearyl alcohol were used as solidifying agents. Emulsion concentrates containing Cs A were prepared by mixing the melted lipid and solidifying agent with water, employing bile salts as a cosurfactant. SLMs were obtained by dispersing the warm emulsion concentrate in cold distilled water under mechanical stirring, followed by freeze drying. Physical characteristics of each SLM were investigated by particle size analysis, optical microscopy and scanning electron microscopy. Mean particle size of SLMs was in the range of 30 to 40.mu.m. The SLMs were in good appearance with spherical shape before freeze drying, but were deformed partially after freeze drying. Drug loading efficiencies of SLMs were observed as high as 80 to 90% in average. The systemic bioavailability of Cs A from different SLM formula was investigated in rats following oral administration. Cs A in whole blood was extracted and assayed by HPLC. SLMs revealed the higher bioavailabilities than the standard formula based on the marketed product. SLMs might have several advantages over standard formula for enhanced gastrointestinal absorption, controlled release properties, high loading capacity of the water-insoluble drug, and feasibility of solid dosage forms with better stability in storage.

• 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.

• International Journal of Oral Biology
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• v.37 no.4
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• pp.153-159
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• 2012

The effects of the an immunosuppressive drug cyclosporine A (CsA), on the salivary gland are largely unknown, even though clinical trials for the stimulation of salivation using CsA have been attempted. Cyclophilin A (CypA) is known to be a binding protein for CsA. CypA has cell proliferation and tissue matrix change activities. In our present study, the presence of CypA in the gland and effects of CsA on CypA expression were investigated by immunohistochemistry, immunoblotting and RT-PCR analyses. CypA was immunohistochemically detected in various kinds of ducts in the submandibular glands of Sprague Dawley rats. The CypA mRNA level was highest at postnatal day 1 and gradually decreased in a time-dependent manner up to adulthood. The expression of CypA increased after a 10 day subcutaneous administration of CsA in postnatal day 1 rats. Surgical sections of the chorda-lingual nerve with impaired salivation showed no changes in CypA expression. A cell proliferation assay using PCNA anti-serum showed increased cell division following CsA treatment. These results suggest that CsA and CypA may act on ductal cells to regulate saliva composition rather than salivation levels.

• Childhood Kidney Diseases
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• v.3 no.2
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• pp.130-144
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• 1999

Purpose : Long-term use of Cyclosporine(CsA) reduce renal blood flow by afferent arteriolar vasoconstriction and lead to chronic pathologic changes of CsA nephrotoxicity - 1) interstitial nephritis(IN); tubular atrophy (TA) and/or interstitial fibrosis(IF),2) arteriolopathy(AP). The Object of this study is to estimate the incidence of chronic pathologic CsA nephrotoxicity by duration of treatment and type of renal disease, relationship between histologic and clinical nephrotoxicity, and optimal duration of CsA therapy. Methods : 102 children with steroid resistant or dependent nephrotic syndrome confirmed by renal biopsy and treated with CsA from 1986 to 1997 were enrolled in this study(58 MCNS, 10 FSGS, 10 MGN, 15 $Henoch-Sch\"{o}nlein$ purpura nephritis with nephrotic syndrome (HSPN) and 9 IgA nephropathy with nephrotic syndrome(IgAN)). CsA was administered for 1yr, 1.5yr, 2yr in 24, 12, 22 MCNS patients and 2, 2, 6 FSGS patients respectively, 1yr, 2yr in MGN and 1yr in HSPN and IgAN. Sequential biopsies were done in all 102 patients after CsA treatment for evaluation of pathologic nephrotoxicity. Results : Complete remission rate was 92.2% (100% in MCNS and MGN, 80% in FSGS, 86.6% in HSPN and 55.5% in IgAN). Incidence of relapse during 6months after CsA treatment was significantly decreased compaed with relapsing spisodes during 6months before CsA treatment in MCNS(P<0.0001) and FSGS(P<0.0001). According to pathologic changes, 71 patients(69.6%) showed no pathological change, 24 patients(23.5%) showed IN and 7 patients(6.8%) showed AP. IN was 16.6%, 33.3%, 27.2% in 1, 1.5, 2 year of CsA treatment group in MCNS. AP was 0%, 16.6%, 9% in 1, 1.5, 2 year of CsA treatment group in MCNS. 14 out of 58 MCNS(24.1%) showed IN and 4 out of 58 MCNS(6.8%) showed AP. Incidence of pathologic change was significantly lower in CsA therapy of <1yr than >1yr(P=0.03). There were no significant difference of incidence of pathologic change in original renal disease, age and sex. Conclusion : Duration of CsA treatment was significant risk factor for nephrotoxicity and optimal duration seemed to be 1 year. Pathologic change due to nephrotoxicity did not correlate with deterioration of renal function and only detectable by renal biopsy.