Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established...Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.展开更多
AIM:To explore the inhibitory effect of a sustained cyclosporin A (CsA) delivery microsphere (CsA-MS) on posterior capsular opacification (PCO) in rabbit eyes after cataract extraction. ·METHODS:Twenty New Zealan...AIM:To explore the inhibitory effect of a sustained cyclosporin A (CsA) delivery microsphere (CsA-MS) on posterior capsular opacification (PCO) in rabbit eyes after cataract extraction. ·METHODS:Twenty New Zealand white rabbits accepted cataract extraction plus intraocular lens implantation and their left eyes were intraoperatively injected CsA-MS prepared using polymer polylactioglycolic acid (PLGA) as a carrier and their right eyes were injected with empty MS. The changes in cornea, anterior chamber reaction, intraocular pressure, PCO and CsA concentration in aqueous humor were examined postoperatively and all the eyes were enucleated 3 months after surgery for histopathological and morphological examination with light microscopy and electron microscopy. · RESULTS:Conjunctival hyperemia, corneal edema, intraocular pressure and anterior chamber response of experimental and control eyes were similar, while PCO in CsA MS injected eyes was greatly improved compared with that in control eyes. Posterior capsules in CsA-MS injected eyes were smooth and lens epithelial cells (LEC) did not proliferate significantly (P >0.05), while LEC in posterior capsule of control eyes had different degrees of proliferation and cortical regeneration. LEC in CsA-MS injected eyes were not functionally active and underwent apoptosis, whereas LEC in control eyes were functionally active (F-test, P =0.025). In addition, the cornealultrastructure showed no differences between CsA-MS and MS injected eyes. CONCLUSION:CsA-MS has high bioavailability in rabbit eyes and could inhibit postoperative PCO occurrence and development during the study period, suggesting that CsA-MS may be a promising, effective and safe administration route to prevent PCO in clinic.展开更多
AIM:To determine the effect of topical 0.05%cyclosporine A(CsA) on corneal endothelium in patients with dry eye disease.·METHODS:Observational,prospective,case series study.Fifty-five eyes of 29 consecutive patie...AIM:To determine the effect of topical 0.05%cyclosporine A(CsA) on corneal endothelium in patients with dry eye disease.·METHODS:Observational,prospective,case series study.Fifty-five eyes of 29 consecutive patients(9 males and 20 females;median age:66.8 years,interquartile range:61-73.2 years) with moderate-severe dry eye disease were evaluated.All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day.The followup period was 12 months.Before treatment and at 3 and12 months post-treatment central corneal specular microscopy was performed.The endothelial cell density(ECD),coefficient of variation of cell size(CoV),and percentage of hexagonal cells(Hex %) were analyzed.·RESULTS:The median ECDs pre-treatment and at 3and 12 months post-treatment were 2 352.5/mm2(interquartile range,2 178-2548.5),2 364/mm2(interquartile range,2 174.25-2 657.5),and 2 366 cells/mm2(inter-quartile range,2 174.75-2 539.75),respectively(P =0.927,one way ANOVA).The median CoVs pre-treatment and at3 and 12 months post-treatment were 34.5(interquartile range,30-37),35(interquartile range,30-38),and 34(interquartile range,30.75-38.25),respectively(P =0.7193,one way ANOVA).The median Hex % values pre-treatment and at 3 and 12 months post-treatment were53(interquartile range,47-58),54(interquartile range,45.75-59),and 50.5(interquartile range,45.75-58),respectively(P =0.824,one way ANOVA).·CONCLUSION:Treatment of patients with dry eyedisease for 12 months with topical 0.05% CsA does not seem to cause substantial changes on corneal endothelium.展开更多
AIM: To investigate the efficacy of combined topical 0.05% cyclosporine A(CsA; Restasis~?, Allergan pharmaceuticals, USA) and 0.1% sodium hyaluronate treatment in dry eyes with meibomian gland dysfunction(MGD).METHODS...AIM: To investigate the efficacy of combined topical 0.05% cyclosporine A(CsA; Restasis~?, Allergan pharmaceuticals, USA) and 0.1% sodium hyaluronate treatment in dry eyes with meibomian gland dysfunction(MGD).METHODS: In a retrospective analysis, 53 patients(106 eyes) with MGD were enrolled and performed lid warm massage for 10 min daily and be instilled preservative free sodium hyaluronate 0.1% eye drops 4 times daily. Patients were divided into subjects treated with topical 0.05% CsA and preservative free sodium hyaluronate vehicle(experimental group, n=74 eyes) and subjects treated with the preservative free sodium hyaluronate vehicle(control group, n=32 eyes). They were evaluated at baseline and 1, 2, and 3 mo for subjective symptoms and objective signs including tear film break-up time(t BUT), Schirmer test, corneal staining(CS) score, lid margin telangiectasia(LMT), meibomian gland secretion(MGS), and conjunctival injection(CI).RESULTS: In the short-term treatment, the experimental group showed a statistically significant improvement in the ocular surface disease index(OSDI; P<0.001), tBUT(P=0.004), Schirmer test score(P=0.008) and LMT(P=0.021) by repeated measure ANOVA. Additionally, mean changes from baseline in OSDI(P<0.001), tBUT(P=0.001), Schirmer test score(P=0.029), CS score(P=0.047), LMT(P=0.002), CI(P=0.030) were improved better in the experimental group than in the control group at 3 mo. However, there was no significant difference between the two groups in MGS(P=0.67).CONCLUSION: In dry eyes with MGD, 0.05% CsA improves the tear film stability as well as subjective ocular discomfort, and is effective in controlling lid margin inflammation.展开更多
AIM: To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS: One hundred and ten patients with rosacea were s...AIM: To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS: One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline.RESULTS: Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes(P <0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs(P =0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group(P <0.05).CONCLUSION: Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.展开更多
BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infect...BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infection following transplantation is regarded as a major factor affecting the long-term survival of transplant recipients especially in Chi- na. Cyclosporine A (CsA), which is routinely used to pre- vent the allograft rejection, is reported to have the inhibito- ry activity on hepatitis B virus (HBV) replication in vitro. In this paper, we review the inhibitory effect and its possi- ble mechanisms of CsA on HBV replication in vitro. DATA RESOURCES: An English-language literature search was conducted using MEDLINE (1990-2004) on cyclospo- rine A, hepatitis B virus, mitochondria, calcium and other related reports and review articles. RESULTS: Hepatitis B x protein (HBx) is essential to HBV replication. The cytosolic calcium signaling mediated by mitochondria and the Src kinase pathway were involved during HBx activation of HBV replication. CsA inhibits the HBV replication in vitro by its binding to mitochondrial cy- clophilin D, then blocking the mitochondria-mediated cy- tosolic calcium signaling. The derivates of CsA also have the HBV replication inhibitory effect in vitro. CONCLUSIONS; By interacting with mitochondria, pre- venting the release of intramitochondrial calcium, and then blocking the cytosolic calcium signaling, CsA inhibits the HBV replication in vitro. The derivates of CsA also have this activity.展开更多
AIM: To observe the effect of topical 0.05% cyclosporine A(CsA) on the ocular surface and tear protein lacritin in a botulinum B-induced dry eye rat model. METHODS: A total of 36 female SD rats were randomly divided i...AIM: To observe the effect of topical 0.05% cyclosporine A(CsA) on the ocular surface and tear protein lacritin in a botulinum B-induced dry eye rat model. METHODS: A total of 36 female SD rats were randomly divided into 3 groups, botulinum B was injected into the right lacrimal gland of all rats. Group A and group B were treated with 0.05% CsA and 0.1% sodium hyaluronate, respectively, 3 times daily. The control group was not treated. Basal tear flow, corneal epithelial defects, and lacritin levels were measured. RESULTS: Tear secretion in all rats was reduced on day 3 and was even lower on day 7 postoperation(P<0.05). Tear secretion in group A increased by day 14 and was at the preoperative level on day 42. Tear secretion in group B and control rats was lower on days 14 and 42 compared with preoperative level(P<0.05). Corneal fluorescein staining in group A was higher on day 3, peaked on day 7, and then decreased gradually from day 7 until day 14, returning to normal by day 42 post-procedure. However, in group B, corneal fluorescein staining had improved, but was not fully recovered by day 42. Corneal fluorescein staining was more intense than before the operation and then in the control group at all time points. Tear protein lacritin levels reached the lowest levels on day 7 in all groups. In group A, tear protein lacritin levels began to increase on day 14 and were normal on day 42. In group B, tear protein lacritin levels began to increase on day 14, but had not completely recovered on day 42. In the control group, tear protein lacritin levels remained low post-procedure. CONCLUSION: CsA 0.05% prompts tear protein lacritin expression in a rat model of dry eye and improves the signs and symptoms of dry eye disease.展开更多
AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diag...AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion.All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy.Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL.Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score,with a reduction of ≥ 5 considered to indicate a response.Among responders,we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine.Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex,age,disease duration,clinical activity index score,C-reactive protein level,hemoglobin level,disease extent,endoscopic findings,and clinical course.RESULTS: Cyclosporine was not discontinued due to side effects in any patient.Nineteen(65.5%) of 29 patients were considered responders.A statistically significant(P = 0.004) inverseas sociation wa s observed between an endoscopic finding of "mucosal bleeding" and responsive cases.Fifteen(9 males,6 females) of these 19 patients were followed for 5 years or more,of whom 9(60%) exhibited long-termefficacy of cyclosporine.Of the 10 non-responders,9(90%) underwent surgery within 6 mo of cyclosporine therapy.None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex,age,duration of disease,clinical activity index score,C-reactive protein level,hemoglobin level,extent of disease,endoscopic findings,or clinical course.In contrast,a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy(P = 0.0014).CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.展开更多
Dear Sir,Iam Yonca A.Akova,MD-from the Department of Ophthalmology,Bayindir Kavaklidere Hospital,Turkey.I wrote this letter to evaluate the efficacy of 0.05%topical cyclosporine A(CsA)eye drops(Restasis Allergan,Irvin...Dear Sir,Iam Yonca A.Akova,MD-from the Department of Ophthalmology,Bayindir Kavaklidere Hospital,Turkey.I wrote this letter to evaluate the efficacy of 0.05%topical cyclosporine A(CsA)eye drops(Restasis Allergan,Irvine,USA)in symptomatic patients with recurrent subepithelial infiltrates(SEIs)due to adenoviral keratoconjunctivitis following steroid eye drops tapering or discontinuation.展开更多
<Abstrat>The proliferation of mesangial cells on cyclosporin (CsA) test mediumwas studied by MTT assay and TNF-Q in cultured supernatant was examined byusing ELISA. The results showed that cyclosporin A signific...<Abstrat>The proliferation of mesangial cells on cyclosporin (CsA) test mediumwas studied by MTT assay and TNF-Q in cultured supernatant was examined byusing ELISA. The results showed that cyclosporin A significantly inhibited theproliferation of mesangial cells at the concentration between 0. 25 - 15 μg/ml(IC50 1μg/ml). This action appeared to be dose-dependent. Release of TNF-αfrom mesangial cells stimulated by LPS was also dose-dependently suppressed. Itis suggested that cyclosporin A play an important role in antiproliferation mecha-nism of mesangial cells in vitro.展开更多
AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observatio...AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.展开更多
AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral cons...AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG(donor) and DA(recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later(C_2). The blood levels of Cs A(Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay(EMIT) on Cobas Mira. Statistical analyses of interactions were done by an acceleratedfailure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and Cs A in the prolongation of cardiac allograft survival for dose ranges of Cs A by castanospermine of(0 to 2) mg/kg by(0 to 200) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and(0 to 3) mg/kg by(0 to 100) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of Cs A. On the contrary, cessation of castanospermine in the presence of Cs A at 2 mg/kg significantly increased the Cs A level(P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between castanospermine and Cs A in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of Cs A provides an explanation.展开更多
AIM To compare the impact of tacrolimus(FK) and cyclosporine(CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors(CN...AIM To compare the impact of tacrolimus(FK) and cyclosporine(CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors(CNIs).METHODS Retrospective review of 1835 patients who received a kidney transplant(KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group(P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejectionrates [odds ratio(OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival(OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.展开更多
AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS...AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS After staphylococcal enterotoxin B(SEB ) mixed with D--galactosamine (D-GaiN )were injected intraperitoneally into Balb/c miceand those previously treated with cyclosporin A,blood samples were collected and livers wereisolated at 2, 6, 12 and 24 h. Patterns othepatocellular death were studiedmorphologically and biochemically, circulatingcytokines (TNF-a, IFN--y ) and mice mortalitywithin 24h was assessed.RESU’LTS The SEB could induce the typicalapoptotic changes of hepatocytes, the D-GaiNcould induce hepatocytes apoptosis anddegeneration at the same time, and the micehaving received the SEB + D-GaiN injectionsdeveloped apoptosis at 2 and 6 h, but after 12 hhepatocytes were characterized by severein jury, whereas all the examinations in thecyclosporin A treated mice were normal.CONCLUSION Hepatic cell apoptosis might berelated to necrosis, and massive hepatocyteapoptosis is likely the initiating step of acutehepatic necrosis in mice. The effects induced bySEB and D--GaiN on hepatocytes might bemediated by T cells, and could be prevented bycyclosporin A.展开更多
AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease(VOD) in non-adult patients undergoing hematopoietic stem cell transplantation(HSCT) during cyclosporine therapy.METHODS: A tot...AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease(VOD) in non-adult patients undergoing hematopoietic stem cell transplantation(HSCT) during cyclosporine therapy.METHODS: A total of 123 patients taking cyclosporinewere evaluated using an electronic medical system at the Seoul National University Children's Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions(ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease(a GVHD) and VOD. Although the incidences of a GVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level(BILmax) of ≥ 1.4 mg/d L correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/d L, suggestive of more sensitive VOD indication in this age group.展开更多
Cyclosporine (CsA) has revolutionized transplant medicine and is currently one of the most important immunosuppressive agents for a wide range of organ transplantations and of autoimmune and inflammatory diseases, suc...Cyclosporine (CsA) has revolutionized transplant medicine and is currently one of the most important immunosuppressive agents for a wide range of organ transplantations and of autoimmune and inflammatory diseases, such as rheumatoid arthritis, uveitis, psoriasis, and atopic dermatitis. Renal impairment represents the main limitation to CsA long-term continuous therapy. However, it has been shown that nephrotoxicity is associated with longer treatment duration, larger cumulative doses and higher daily dose of CsA. With low dose regimens (<5 mg/kg/day), stable serum creatinine levels have been observed up to 15-20 years after kidney transplantation. Intermittent therapy may offer a good therapeutic strategy to limit long-term renal dysfunction, given the fact that renal structural changes are dose- and time-dependent. The best predictor of permanent renal damage is a persistent increase in serum creatinine level one month after treatment withdrawal. In patients with autoimmune diseases, the percentage increase in serum creatinine above baseline value during CsA therapy has been shown to predict CsA-induced nephropathy. Before CsA therapy initiation, patients should undergo a thorough baseline evaluation including laboratory assessments, in particular electrolytes, serum creatinine, and urea levels. Furthermore, patients should be evaluated for factors that might increase the risk of nephrotoxicity, such as obesity, older age, hypertension, concomitant use of nephrotoxic drugs, and pre-existing renal conditions. In the present paper, CsA-induced nephropathy will be reviewed in terms of pathophysiology, pathologic and clinical findings, and strategies for prevention and management.展开更多
基金financially supported by Key Science and Technology Project of Haikou City,with grant number 2011-0142
文摘Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.
基金National Natural Science Foundation of China (No. 81070721)Fundamental Research Funds for the Central Universities
文摘AIM:To explore the inhibitory effect of a sustained cyclosporin A (CsA) delivery microsphere (CsA-MS) on posterior capsular opacification (PCO) in rabbit eyes after cataract extraction. ·METHODS:Twenty New Zealand white rabbits accepted cataract extraction plus intraocular lens implantation and their left eyes were intraoperatively injected CsA-MS prepared using polymer polylactioglycolic acid (PLGA) as a carrier and their right eyes were injected with empty MS. The changes in cornea, anterior chamber reaction, intraocular pressure, PCO and CsA concentration in aqueous humor were examined postoperatively and all the eyes were enucleated 3 months after surgery for histopathological and morphological examination with light microscopy and electron microscopy. · RESULTS:Conjunctival hyperemia, corneal edema, intraocular pressure and anterior chamber response of experimental and control eyes were similar, while PCO in CsA MS injected eyes was greatly improved compared with that in control eyes. Posterior capsules in CsA-MS injected eyes were smooth and lens epithelial cells (LEC) did not proliferate significantly (P >0.05), while LEC in posterior capsule of control eyes had different degrees of proliferation and cortical regeneration. LEC in CsA-MS injected eyes were not functionally active and underwent apoptosis, whereas LEC in control eyes were functionally active (F-test, P =0.025). In addition, the cornealultrastructure showed no differences between CsA-MS and MS injected eyes. CONCLUSION:CsA-MS has high bioavailability in rabbit eyes and could inhibit postoperative PCO occurrence and development during the study period, suggesting that CsA-MS may be a promising, effective and safe administration route to prevent PCO in clinic.
文摘AIM:To determine the effect of topical 0.05%cyclosporine A(CsA) on corneal endothelium in patients with dry eye disease.·METHODS:Observational,prospective,case series study.Fifty-five eyes of 29 consecutive patients(9 males and 20 females;median age:66.8 years,interquartile range:61-73.2 years) with moderate-severe dry eye disease were evaluated.All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day.The followup period was 12 months.Before treatment and at 3 and12 months post-treatment central corneal specular microscopy was performed.The endothelial cell density(ECD),coefficient of variation of cell size(CoV),and percentage of hexagonal cells(Hex %) were analyzed.·RESULTS:The median ECDs pre-treatment and at 3and 12 months post-treatment were 2 352.5/mm2(interquartile range,2 178-2548.5),2 364/mm2(interquartile range,2 174.25-2 657.5),and 2 366 cells/mm2(inter-quartile range,2 174.75-2 539.75),respectively(P =0.927,one way ANOVA).The median CoVs pre-treatment and at3 and 12 months post-treatment were 34.5(interquartile range,30-37),35(interquartile range,30-38),and 34(interquartile range,30.75-38.25),respectively(P =0.7193,one way ANOVA).The median Hex % values pre-treatment and at 3 and 12 months post-treatment were53(interquartile range,47-58),54(interquartile range,45.75-59),and 50.5(interquartile range,45.75-58),respectively(P =0.824,one way ANOVA).·CONCLUSION:Treatment of patients with dry eyedisease for 12 months with topical 0.05% CsA does not seem to cause substantial changes on corneal endothelium.
基金Supported by a grant from University Research Park Project of Busan National University funded by Busan Institute of S&T Evaluation and Planning(No.201726550002)
文摘AIM: To investigate the efficacy of combined topical 0.05% cyclosporine A(CsA; Restasis~?, Allergan pharmaceuticals, USA) and 0.1% sodium hyaluronate treatment in dry eyes with meibomian gland dysfunction(MGD).METHODS: In a retrospective analysis, 53 patients(106 eyes) with MGD were enrolled and performed lid warm massage for 10 min daily and be instilled preservative free sodium hyaluronate 0.1% eye drops 4 times daily. Patients were divided into subjects treated with topical 0.05% CsA and preservative free sodium hyaluronate vehicle(experimental group, n=74 eyes) and subjects treated with the preservative free sodium hyaluronate vehicle(control group, n=32 eyes). They were evaluated at baseline and 1, 2, and 3 mo for subjective symptoms and objective signs including tear film break-up time(t BUT), Schirmer test, corneal staining(CS) score, lid margin telangiectasia(LMT), meibomian gland secretion(MGS), and conjunctival injection(CI).RESULTS: In the short-term treatment, the experimental group showed a statistically significant improvement in the ocular surface disease index(OSDI; P<0.001), tBUT(P=0.004), Schirmer test score(P=0.008) and LMT(P=0.021) by repeated measure ANOVA. Additionally, mean changes from baseline in OSDI(P<0.001), tBUT(P=0.001), Schirmer test score(P=0.029), CS score(P=0.047), LMT(P=0.002), CI(P=0.030) were improved better in the experimental group than in the control group at 3 mo. However, there was no significant difference between the two groups in MGS(P=0.67).CONCLUSION: In dry eyes with MGD, 0.05% CsA improves the tear film stability as well as subjective ocular discomfort, and is effective in controlling lid margin inflammation.
文摘AIM: To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS: One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline.RESULTS: Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes(P <0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs(P =0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group(P <0.05).CONCLUSION: Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.
基金This study was supported by a grant from the National Key Basic ResearchProgram of China (No. 2003CB515501).
文摘BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infection following transplantation is regarded as a major factor affecting the long-term survival of transplant recipients especially in Chi- na. Cyclosporine A (CsA), which is routinely used to pre- vent the allograft rejection, is reported to have the inhibito- ry activity on hepatitis B virus (HBV) replication in vitro. In this paper, we review the inhibitory effect and its possi- ble mechanisms of CsA on HBV replication in vitro. DATA RESOURCES: An English-language literature search was conducted using MEDLINE (1990-2004) on cyclospo- rine A, hepatitis B virus, mitochondria, calcium and other related reports and review articles. RESULTS: Hepatitis B x protein (HBx) is essential to HBV replication. The cytosolic calcium signaling mediated by mitochondria and the Src kinase pathway were involved during HBx activation of HBV replication. CsA inhibits the HBV replication in vitro by its binding to mitochondrial cy- clophilin D, then blocking the mitochondria-mediated cy- tosolic calcium signaling. The derivates of CsA also have the HBV replication inhibitory effect in vitro. CONCLUSIONS; By interacting with mitochondria, pre- venting the release of intramitochondrial calcium, and then blocking the cytosolic calcium signaling, CsA inhibits the HBV replication in vitro. The derivates of CsA also have this activity.
基金Supported by Natural Science Foundation of Shaanxi Province(No.S2010JC376)Xi’an Science and Technology Program Funding Project [No.SF1022(1)]
文摘AIM: To observe the effect of topical 0.05% cyclosporine A(CsA) on the ocular surface and tear protein lacritin in a botulinum B-induced dry eye rat model. METHODS: A total of 36 female SD rats were randomly divided into 3 groups, botulinum B was injected into the right lacrimal gland of all rats. Group A and group B were treated with 0.05% CsA and 0.1% sodium hyaluronate, respectively, 3 times daily. The control group was not treated. Basal tear flow, corneal epithelial defects, and lacritin levels were measured. RESULTS: Tear secretion in all rats was reduced on day 3 and was even lower on day 7 postoperation(P<0.05). Tear secretion in group A increased by day 14 and was at the preoperative level on day 42. Tear secretion in group B and control rats was lower on days 14 and 42 compared with preoperative level(P<0.05). Corneal fluorescein staining in group A was higher on day 3, peaked on day 7, and then decreased gradually from day 7 until day 14, returning to normal by day 42 post-procedure. However, in group B, corneal fluorescein staining had improved, but was not fully recovered by day 42. Corneal fluorescein staining was more intense than before the operation and then in the control group at all time points. Tear protein lacritin levels reached the lowest levels on day 7 in all groups. In group A, tear protein lacritin levels began to increase on day 14 and were normal on day 42. In group B, tear protein lacritin levels began to increase on day 14, but had not completely recovered on day 42. In the control group, tear protein lacritin levels remained low post-procedure. CONCLUSION: CsA 0.05% prompts tear protein lacritin expression in a rat model of dry eye and improves the signs and symptoms of dry eye disease.
文摘AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion.All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy.Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL.Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score,with a reduction of ≥ 5 considered to indicate a response.Among responders,we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine.Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex,age,disease duration,clinical activity index score,C-reactive protein level,hemoglobin level,disease extent,endoscopic findings,and clinical course.RESULTS: Cyclosporine was not discontinued due to side effects in any patient.Nineteen(65.5%) of 29 patients were considered responders.A statistically significant(P = 0.004) inverseas sociation wa s observed between an endoscopic finding of "mucosal bleeding" and responsive cases.Fifteen(9 males,6 females) of these 19 patients were followed for 5 years or more,of whom 9(60%) exhibited long-termefficacy of cyclosporine.Of the 10 non-responders,9(90%) underwent surgery within 6 mo of cyclosporine therapy.None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex,age,duration of disease,clinical activity index score,C-reactive protein level,hemoglobin level,extent of disease,endoscopic findings,or clinical course.In contrast,a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy(P = 0.0014).CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.
文摘Dear Sir,Iam Yonca A.Akova,MD-from the Department of Ophthalmology,Bayindir Kavaklidere Hospital,Turkey.I wrote this letter to evaluate the efficacy of 0.05%topical cyclosporine A(CsA)eye drops(Restasis Allergan,Irvine,USA)in symptomatic patients with recurrent subepithelial infiltrates(SEIs)due to adenoviral keratoconjunctivitis following steroid eye drops tapering or discontinuation.
文摘<Abstrat>The proliferation of mesangial cells on cyclosporin (CsA) test mediumwas studied by MTT assay and TNF-Q in cultured supernatant was examined byusing ELISA. The results showed that cyclosporin A significantly inhibited theproliferation of mesangial cells at the concentration between 0. 25 - 15 μg/ml(IC50 1μg/ml). This action appeared to be dose-dependent. Release of TNF-αfrom mesangial cells stimulated by LPS was also dose-dependently suppressed. Itis suggested that cyclosporin A play an important role in antiproliferation mecha-nism of mesangial cells in vitro.
文摘AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.
基金Supported by Kiriwina Investments Limited of Australia
文摘AIM: To investigate the interaction between castanospermine and cyclosporin A(Cs A) and to provide an explanation for it.METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG(donor) and DA(recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later(C_2). The blood levels of Cs A(Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay(EMIT) on Cobas Mira. Statistical analyses of interactions were done by an acceleratedfailure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and Cs A in the prolongation of cardiac allograft survival for dose ranges of Cs A by castanospermine of(0 to 2) mg/kg by(0 to 200) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and(0 to 3) mg/kg by(0 to 100) mg/kg(HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of Cs A. On the contrary, cessation of castanospermine in the presence of Cs A at 2 mg/kg significantly increased the Cs A level(P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between castanospermine and Cs A in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of Cs A provides an explanation.
文摘AIM To compare the impact of tacrolimus(FK) and cyclosporine(CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors(CNIs).METHODS Retrospective review of 1835 patients who received a kidney transplant(KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group(P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejectionrates [odds ratio(OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival(OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.
文摘AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS After staphylococcal enterotoxin B(SEB ) mixed with D--galactosamine (D-GaiN )were injected intraperitoneally into Balb/c miceand those previously treated with cyclosporin A,blood samples were collected and livers wereisolated at 2, 6, 12 and 24 h. Patterns othepatocellular death were studiedmorphologically and biochemically, circulatingcytokines (TNF-a, IFN--y ) and mice mortalitywithin 24h was assessed.RESU’LTS The SEB could induce the typicalapoptotic changes of hepatocytes, the D-GaiNcould induce hepatocytes apoptosis anddegeneration at the same time, and the micehaving received the SEB + D-GaiN injectionsdeveloped apoptosis at 2 and 6 h, but after 12 hhepatocytes were characterized by severein jury, whereas all the examinations in thecyclosporin A treated mice were normal.CONCLUSION Hepatic cell apoptosis might berelated to necrosis, and massive hepatocyteapoptosis is likely the initiating step of acutehepatic necrosis in mice. The effects induced bySEB and D--GaiN on hepatocytes might bemediated by T cells, and could be prevented bycyclosporin A.
基金Supported by The Education and Research Encouragement Fund of Seoul National University Hospital
文摘AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease(VOD) in non-adult patients undergoing hematopoietic stem cell transplantation(HSCT) during cyclosporine therapy.METHODS: A total of 123 patients taking cyclosporinewere evaluated using an electronic medical system at the Seoul National University Children's Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions(ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease(a GVHD) and VOD. Although the incidences of a GVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level(BILmax) of ≥ 1.4 mg/d L correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/d L, suggestive of more sensitive VOD indication in this age group.
文摘Cyclosporine (CsA) has revolutionized transplant medicine and is currently one of the most important immunosuppressive agents for a wide range of organ transplantations and of autoimmune and inflammatory diseases, such as rheumatoid arthritis, uveitis, psoriasis, and atopic dermatitis. Renal impairment represents the main limitation to CsA long-term continuous therapy. However, it has been shown that nephrotoxicity is associated with longer treatment duration, larger cumulative doses and higher daily dose of CsA. With low dose regimens (<5 mg/kg/day), stable serum creatinine levels have been observed up to 15-20 years after kidney transplantation. Intermittent therapy may offer a good therapeutic strategy to limit long-term renal dysfunction, given the fact that renal structural changes are dose- and time-dependent. The best predictor of permanent renal damage is a persistent increase in serum creatinine level one month after treatment withdrawal. In patients with autoimmune diseases, the percentage increase in serum creatinine above baseline value during CsA therapy has been shown to predict CsA-induced nephropathy. Before CsA therapy initiation, patients should undergo a thorough baseline evaluation including laboratory assessments, in particular electrolytes, serum creatinine, and urea levels. Furthermore, patients should be evaluated for factors that might increase the risk of nephrotoxicity, such as obesity, older age, hypertension, concomitant use of nephrotoxic drugs, and pre-existing renal conditions. In the present paper, CsA-induced nephropathy will be reviewed in terms of pathophysiology, pathologic and clinical findings, and strategies for prevention and management.
