Administration Of Cyclosporine Research Articles

Periodontal Microbiological Status Influences the Occurrence of Cyclosporine-A and Tacrolimus-Induced Gingival Overgrowth

Immune suppressed renal transplant patients are more prone to developing oral tissue alterations due to medications associated with a pleiotropic set of side effects involving the oral cavity. Drug-induced gingival overgrowth (DIGO) is the most commonly encountered side effect resulting from administration of calcineurin inhibitors such as cyclosporine-A (CsA), the standard first-line treatment for graft rejection prevention in transplant patients. Pathogenesis of gingival overgrowth (GO) is determined by the interrelation between medications and a pre-existing inflammatory periodontal condition, the main modifiable risk factor. Severity of gingival hyperplasia clinical manifestation is also related to calcium channel blocker association, frequently provided in addition to pharmacological therapy of transplant recipients. Specifically, nifedipine-induced enlargements have a higher prevalence rate compared to amlodipine-induced enlargements; 47.8% and 3.3% respectively. Available epidemiological data show a gender difference in prevalence, whereby males are generally more frequently affected than females. The impact of GO on the well-being of an individual is significant, often leading to complications related to masticatory function and phonation, a side effect that may necessitate switching to the tacrolimus drug that, under a similar regimen, is associated with a low incidence of gingival lesion. Early detection and management of GO is imperative to allow patients to continue life-prolonging therapy with minimal morbidity. The purpose of this study was threefold: firstly, to determine the prevalence and incidence of GO under the administration of CsA and Tacrolimus; secondly, to assess the correlation between periodontal status before and after periodontal therapy and medications on progression or recurrence of DIGO; and finally, to analyse the effect of immunosuppressant in association to the channel blocker agents on the onset and progression of gingival enlargement. We compared seventy-two renal transplant patients, including 33 patients who were receiving CsA, of which 25% were also receiving nifedipine and 9.72% also receiving amlodipine, and 39 patients who were receiving tacrolimus, of which 37.5% were also receiving nifedipine and 5.55% also receiving amlodipine, aged between 35 and 60 years. Medical and pharmacological data were recorded for all patients. Clinical periodontal examination, in order to establish the inflammatory status and degree of gingival enlargement, was performed at baseline (T0), 3 months (T1), 6 months (T2), and 9 months (T3). All patients were subjected to periodontal treatment. Statistically significant correlation between the reduction of the mean value of periodontal indices and degree of gingival hyperplasia at the three times was revealed. The prevalence of GO in patients taking cyclosporine was higher (33.3%) in comparison with those taking tacrolimus (14.7%). In accordance with previous studies, this trial highlighted the clinical significance of the pathological substrate on stimulating drug-induced gingival lesion, confirming the key role of periodontal inflammation in pathogenesis of gingival enlargement, but did not confirm the additional effect of calcium-channel blocker drugs in inducing gingival enlargement.

Cyclosporin A protects trophoblasts from H2O2-induced oxidative injury via FAK-Src pathway

Oxidative stress is associated with functional disorder of trophoblast cells. Our previous studies have demonstrated that cyclosporin A (CsA) promotes the activity of normal human trophoblast cells. We further investigated the role and mechanism of CsA on oxidative stress in trophoblast cells. JEG-3 cells were co-cultured with H2O2 and CsA. Cell viability and morphology were measured by MTT assay and inverted microscope. Reactive oxygen species (ROS) was analyzed by fluorescence microscopy. Cell mitochondrial membrane potential (MMP) was determined by flow cytometric analysis. Malondialdehyde (MDA) production, superoxide dismutase (SOD) and catalase (CAT) activities were examined using colorimetric assays. The expression and phosphorylation of FAK and Src kinase proteins were examined by western blotting. CsA increased JEG-3 cell viability and reduced the morphologic injury induced by H2O2 treatment. CsA decreased ROS and MDA production, increased SOD and CAT activities, and restored the MMP of H2O2 treated JEG-3 cells. CsA administration suppressed H2O2-induced reduction of FAK and Src phosphorylation. Blocking the activation of FAK or Src attenuated the protective effect of CsA on JEG-3 cells in H2O2-induced oxidative injury. CsA protects JEG-3 cells from H2O2-induced oxidative injury, and the FAK/Src signaling pathway plays an important role in this process.

Cyclosporine a-loaded UniORV®: Pharmacokinetic and safety characterization.

This study aimed to improve pharmacokinetic behavior and reduce safety concern of cyclosporine A (CsA) by UniORV® approach, a new platform for solid dispersion formulation. CsA-loaded UniORV® (UO/CsA) was prepared, and its physicochemical properties were evaluated in terms of droplet size distribution and dissolution. The pharmacokinetic behavior and nephrotoxic potential of orally-dosed CsA samples (10 mg-CsA/kg) were assessed in rats. After re-dispersion of UO/CsA in water, fine droplets were observed, and the mean diameter of droplets was calculated to be 45 nm. The UniORV® approach markedly improved the dissolution behavior compared with amorphous CsA in water. After oral administration of amorphous CsA, Neoral®, and UO/CsA in rats, UO/CsA exhibited a 32% lower maximum concentration and 5.1 h longer mean residence time than those of Neoral®. The oral absorption of CsA formulations was higher compared with amorphous CsA; in particular, the oral bioavailability of UO/CsA was 71-fold higher than that of amorphous CsA. Neoral® elicited nephrotoxicity with plasma creatinine level of 1.29 mg/dL; however, Neoral®-induced nephrotoxicity was attenuated in UO/CsA, as evidenced by a 15% lower plasma creatinine level of UO/CsA than that of Neoral®. From these findings, UO/CsA might be a promising dosage form with improved biopharmaceutical properties of CsA.

ステロイド抵抗性を示し，放射線治療とシクロスポリン内服療法が奏効した木村病の 1 例

ステロイド抵抗性を示し，放射線治療とシクロスポリン内服療法が奏効した木村病の 1 例

Intra-Arrest Administration of Cyclosporine and Methylprednisolone Does Not Reduce Postarrest Myocardial Dysfunction.

Objective To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC). Methods Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs. Results Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms. Conclusions Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.

Conversion From Cyclosporine to Once-Daily Tacrolimus on 50:1 mg Basis: A Short-Term Pilot Study.

In addition to graft dysfunction, renal transplant recipients on cyclosporine may be switched to tacrolimus to reduce its drug-related secondary clinical effects and undesirable cosmetic side effects. However, the dose level of once-daily tacrolimus for these patients has yet to be established. The objective of this prospective study was to confirm the safety of converting stable renal transplant recipients on cyclosporine to once-daily tacrolimus at a 50:1 mg ratio. Our study enrolled 17 patients receiving cyclosporine who were observed for 3 months. Graft biopsies did not reveal any acute rejection, and the conversion ratio to once-daily tacrolimus was 50:1 mg. Dose adjustments were made to achieve a target tacrolimus trough concentration of 3 to 5 ng/mL at 2 weeks, and graft biopsies were taken after the 3-month observation period. Dose adjustment was required in 7 recipients (41.2%) within 3 months of conversion. None of the recipients had acute cellular rejection or C4d deposition, and the mean estimated glomerular filtration rate of 38.7 ± 11.0 mL/min/1.73 m2 at baseline was significantly improved to 42.0 ± 10.0 mL/min/1.73 m2 at month 3. Although recipients of renal transplant can be forced to discontinue cyclosporine administration due to undesirable adverse effects, our study showed that a once-daily dose of tacrolimus may be safe when administered at a conversion ratio of 50:1.

Pretransplant assessment of cyclosporine level as a predictor of cyclosporine dose requirements after kidney transplantation

Introduction and aimsPretransplant administration of cyclosporine (CsA) may reduce post-transplant maintenance dose and consequently CsA inhibitor nephrotoxicity and helps in achieving the desired target C2 levels earlier. The optimum dose or timing of administration of CsA induction dose is still debatable.Patients and methodsWe compared three different protocols for pretransplant administration of CsA aiming to reach a target C2 therapeutic level of greater than 800 ng/ml on the third day post-transplant. Sixty kidney transplant recipients from Cairo University hospitals were divided into: group 1 (n=20) who received a single CsA induction dose of 2 mg/kg 12 h pretransplant; group 2 (n=20) who received four CsA consecutive doses of 4 mg/kg 48 h pre-transplant; and group 3 (n=20) who received four CsA consecutive doses of 2 mg/kg 48 h pretransplant.ResultsThe desired therapeutic level in the earlier post-transplantation period was achieved in 65% in group 1, 100% in groups 2 and 3). In group 2 a lower dose was needed to maintain C2 within the therapeutic range during the first year post-transplantation (P<0.01). Furthermore, a lower number of cases were complicated by CsA nephrotoxicity in group 2 in comparison to groups 1 and 3 (25, 0, 5% in group 1, 2, 3, respectively, P<0.039). A higher longer dose of CsA pretransplant associated with early withdrawal of CsA had a better effect on graft function than lower or shorter induction doses with late withdrawal as evidenced by lower serum creatinine levels all through the follow-up period in group 2 compared with group 3.ConclusionForty-eight-hour pretransplant induction with CsA at a dose of 4 mg/kg with early dose reduction post-transplant was associated with lower CsA maintenance and a better 1-year graft function.

Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis.

Inflammatory bowel disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function and inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesized that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to zonula occludens-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.NEW & NOTEWORTHY Inflammatory bowel disease is the result of decreased intestinal epithelial barrier function leading to exposure of the mucosal immune system to luminal antigens causing inflammation, which in turn further decreases epithelial barrier function. We demonstrate for the first time that strengthening the epithelial barrier with a hydroxylase inhibitor in combination with the administration of the immunosuppressive cyclosporine provides additive therapeutic advantage in a murine model of colitis.

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug-Drug Interaction and Associated Biomarker Levels in Healthy Volunteers.

Understanding transporter‐mediated drug–drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)‐I, and CP‐III as clinical biomarkers for evaluating organic anion‐transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1‐Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP‐I, and CP‐III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax) was similar among the four biomarkers (1.8–2.5‐fold, paired t‐test P value < 0.05) in individuals who were homozygotes or heterozygotes of the major allele, c.521T. However, the fold change in AUC and Cmax for HDA and TDA was significantly abolished in the subjects who were c.521‐CC, whereas the respective fold change in AUC and Cmax for pravastatin and CP‐I and CP‐III were slightly weaker in individuals who were c.521‐CC compared with c.521‐TT/TC genotypes. In addition, this study provides the first evidence that SLCO1B1 c.521T>C genotype is significantly associated with CP‐I but not CP‐III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.

Calcineurin Inhibition Impairs the Function of Neuronal Potassium‐Chloride Cotransporter 2

Calcineurin inhibitors (CnI) such as Cyclosporin A (CsA) are instrumental for immunosuppression after organ transplantation but may cause serious neurologic side effects, including seizures.Neuronal excitability depends on intact Cl− homeostasis. Generation of hyperpolarizing synaptic responses to GABA and glycine requires a Cl− gradient across the cell membrane with a low [Cl−]i, mainly established by K+‐Cl− cotransporter 2 (KCC2) and to a lesser extent Na+‐K+‐Clcotransporter 1 (NKCC1); both are cation‐coupled chloride cotransporters (CCCs). Calcineurin has been implicated in the regulation of CCCs, whereas impaired CCC function is a well‐known condition in human pharmacoresistant epilepsy. Therefore, we hypothesized that CsA affects KCC2 or NKCC1 functions, thus causing neuronal hyperexcitability.In ex vivo intracellular recordings with sharp microelectrodes, Wistar rat pyramidal neurons in neocortical slices responded to CsA (5 μM for 1h) with a less negative GABAA reversal potential (+7.2 mV) and prolonged Cl− extrusion time after iontophoretic Cl− loading (+3.9 s). 2‐photon fluorescence lifetime imaging in presence of Cl− sensitive dye MQAE showed an increased [Cl−]i in layer V neurons (+6.9 mM), suggesting reduced KCC2 activity. Co‐immunoprecipitation studies in rodent brain tissue suggested interactions of calcineurin Aβ (CnAβ) with KCC2 and NKCC1.In vivo, CsA administration to rats (5–25 mg/kg i.p.) enhanced levels of inhibitory tyrosine KCC2 phosphorylation at short term (4h; +172%) and reduced levels of activating S940‐KCC2 phosphorylation in the long term (14d; −61%). Reduced phospho‐S940‐KCC2 levels were observed in further models of calcineurin inhibition such as genetic CnAβ‐deficiency in mice (−78%) or CsA treatment of zebrafish larvae (10 μM in water: −54% after 24h). In contrast, NKCC1 and its activating kinase SPAK were stimulated upon calcineurin inhibition in rodents. Similar data were obtained in Drosophila melanogaster.Our results provide evidence that CnI attenuate KCC2 function but may stimulate NKCC1 leading to elevated [Cl−]i. These effects may increase neuronal excitability and contribute to CnI neurological adverse effects. The benefits of KCC2 activators or SPAK inhibitors for enhancing chloride extrusion in patients experiencing CnI neurotoxicity deserve further characterization.Support or Funding InformationThis study was supported by Deutsche Forschergemeinschaft.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabolic dependence of cyclosporineA on cell proliferation of human non‑small cell lung cancer A549 cells and its implication in post‑transplant malignancy.

CyclosporineA (CsA), a widely used immunosuppressant to prevent organ transplant rejection, is associated with an increased cancer risk following transplantation, particularly in the lung. However, the underlying mechanisms remain unclear. In the present study, using human non‑small cell lung cancer A549 cells, it was determined that CsA (0.1 or 1µM) promoted cell proliferation with glucose alone as the energy source. CsA treatment increased the phosphorylation of protein kinaseB (Akt) and consequently the expression of CyclinD1. Inhibiting Akt signaling with the phosphatidylinositol 3‑kinase inhibitor wortmannin prevented this effect. Mechanistically, CsA treatment increased reactive oxygen species (ROS) generation, and the intracellular ROS scavenger N‑acetyl‑cysteine (NAC) attenuated CsA‑induced cell proliferation as well as the activation of Akt/CyclinD1 signaling. However, notably, it was demonstrated that CsA treatment decreased cell proliferation and Akt phosphorylation under normal lipid loading. Further investigation indicated that palmitic acid induced excessive generation of ROS, while CsA treatment further stimulated this ROS production. Scavenging intracellular ROS with NAC attenuated the CsA‑mediated inhibition of cell proliferation. Collectively, the results indicated a pleiotropic effect of CsA in the regulation of A549cell proliferation under different metabolic conditions. This indicated that CsA administration may contribute to increased post‑transplant cancer risk in organ recipients.

Cyclosporine Administration and Graft Versus Host Disease: Continuous Intravenous Infusion vs. Intravenous Bolus Dosing

Introduction Continuous infusion (CIVI) cyclosporine (CSA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). Trough concentrations are an accepted surrogate for monitoring therapy, however total exposure may be dependent on peak concentrations not obtained when given via CIVI. Therefore, maintaining the same trough goals for both routes of administration may lead to decreased CSA exposure and subsequent increased rates of graft versus host disease (GVHD). The purpose of this study was to evaluate the incidence of acute GVHD and overall survival among patients receiving CIVI vs. TDI CSA. Methods We performed a retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017 that received > 48 hours of CSA. All patients initially received CSA via TDI per institutional standard and targeted whole blood trough concentrations of 200-400 ng/mL via HPLC. Any change to CIVI was made at the discretion of the treating physician. All patients were changed to oral CSA when able. Patients were grouped according to administration method; those that received cyclosporine via CIVI for > 48 hours at any time during initial transplant admission were classified as CIVI and those that received CSA exclusively as TDI were classified as TDI. Results 308 patients met inclusion criteria (CIVI 42, TDI 266). Donor type, GVHD prophylaxis, underlying diagnosis, and conditioning intensity were similar between groups. The majority of subjects received HLA-matched sibling or cord blood allografts. There were an equal proportion of myeloablative and reduced intensity conditioning regimens, and nearly all GVHD prophylaxis therapy consisted of cyclosporine combined with either mycophenolate or methotrexate. Forty two patients received CSA via CIVI for > 48 hours for a median of 9 days (range, 3-32 days). The average time of change from TDI to CIVI was 3 days after transplant. The TDI group received only TDI for a median 17 days (range 4-62 days) prior to conversion to oral CSA. CSA concentrations at day -1 and weeks 1, 2, and 3 were similar between the groups (Figure 1). We found no difference between the rates of grade II-IV acute (45% vs 53%, p = 0.59) or chronic (17% vs 30%, p = 0.20) GVHD or overall survival (57% vs 67%, p = 0.10) between groups. Subgroup analysis of patients that received myeloablative conditioning did not reveal significant differences in GVHD or overall survival. Conclusion In contrast to previous studies, we did not observe an association of CIVI CSA administration with acute GVHD. Among patients intolerant of bolus CSA infusions, a brief transition to CIVI CSA appears to be a safe and acceptable route of administration without increased risk of GVHD or adverse effects on overall survival.

Starting Cyclosporine on Day Zero and Mycophenolate on Day + 1 in Unmanipulated Peripheral Blood Haplo Transplant with Cyclophosphamide Post-Transplantation Is Feasible, Abrogate the Severity of Cytokine Release Syndrome and Achieves a Very Low Rate of aGVHD

Introduction The use of unmanipulated peripheral blood from haploidentical donors (UPB Haplo) with post transplantation cyclophosphamide (PT-Cy) is often associated with a higher incidence and severity of cytokine release syndrome (CRS) and aGVHD when it is compared with bone marrow source (BM haplo). Recently it has been published (1) a modification of PT-Cy protocol moving the day of administration of cyclosporine (CsA) and mycophenolate (MMF) from day +5 to zero and + 1 and using BM haplo with encouraging results. With the aim to reduce the incidence of CRS and aGVHD we did the same but keeping UPB haplo as a cellular source. Methods and patients The conditioning used was fludarabine 150 mg/m2, melphalan 100-120 mg/m2, and TBI 200-400 cGy or the same but with busulfan 4 mg/kg instead of melphalan, the CsA began on day zero and continuous until d+180, MMF was administered from d+ 1 to d+ 60 and PT-Cy 50 mg/kg on days +3 and +4 (fig 1). After a signed informed consent, 22 patients were transplanted; median age was 31 y (range 18-64), the diagnoseswere: acute lymphoid leukemia 11, acute myeloid leukemia 7, two had lymphoma, 1 myelodysplasia, and another, chronic myeloid leukemia. 50 % were in first remission, 36% in second, and 14% in third or with active disease. Results All of the donors shared 4 out of 8 alleles with the recipient; their median age was 27 y (range 10-52) in 77% of the cases was a sibling, in 18% a child and in 5% a parent, 4 males received cells from female donors. A median of 7.2 × 10(6)/kg (range 3.9-12) of CD34 and 3 × 10(8)/kg of CD3 were infused. The engraftment rate of 21 patients alive at day +30 was 100%, the median time to achieve 500 neutrophil and self-sustained platelets was 15 and 16 days respectively (range 13-22 and 15-29), one patient with mix chimerism had secondary graft failure. The only manifestation of CRS was fever in 8 out of 22 (36%), range of temperature 38.2 to 39 ¼ C, median duration of 2.5 days. With a median follow-up for surviving patients of 9.5 months (range 3- 18) the incidence of aGVHD (GII-IV) was 5 %. Regarding cGVHD, the follow-up is still short, but only 2 out of 17 evaluable cases had extensive disease. Event was defined as death for any cause or relapse; 3 patients died due to an infection and 2 relapsed, the event-free survival at day 100 was 90% and at one year (Kaplan-Meier) 71.8% (fig 2). Conclusion In this series of 22 patients, the administration of CsA on day zero and MMF on day + 1 in the UPB haplo transplant with PT-Cy was feasible and it decreased the severity and incidence of CRS and of aGVHD, even achieving a rate similar to that which has been reported using BMT haplo. The follow-up is still short to draw conclusions regarding the incidence of cGVHD and relapses, but they also seem encouraging. This strategy deserves further assessment with a bigger number of patients and longer follow-up.

Once-Daily Low-Dose Cyclosporine A Treatment with Angiotensin Blockade for Long-Term Remission of Nephropathy in Frasier Syndrome

Cyclosporine A is known to be effective in some genetic podocyte injury. However, the efficacy of cyclosporine A depends on the degree of histopathological findings, and the relationship between long-term use and renal prognosis remains unknown. Frasier syndrome is a rare genetic disorder caused by intronic mutations in WT1, and is characterized by progressive glomerulopathy, a 46,XY disorder of sex development, and an increased risk of gonadoblastoma. We report here a 16-year-old phenotypically female patient with Frasier syndrome. A renal biopsy at the age of seven years showed segmentally effaced podocyte foot processes with no evidence of glomerulosclerosis. Steroid-resistant proteinuria progressed to the nephrotic range at the age of 10 years, which responded to once-daily administration of cyclosporine A with low two-hour post-dose cyclosporine A (C2) levels; she then achieved stable partial remission in combination with renin-angiotensin system (RAS) blockade. At the age of 12 years, examinations for delayed puberty confirmed the diagnosis of Frasier syndrome. The second renal biopsy showed widespread foot process effacement and a minor lesion of segmental glomerulosclerosis without findings suggestive of cyclosporine A nephropathy. She maintained partial remission and normal renal function with the continuation of once-daily low-dose cyclosporine A. The C2 levels required for the remission were between 212 and 520 ng/ml. Cyclosporine A dosages sufficient for maintaining the C2 levels were 1.1-1.2 mg/kg per day. In conclusion, the long-lasting treatment of once-daily low-dose cyclosporine A with RAS inhibition was effective for induction and maintenance of partial remission in Frasier syndrome.

Neuroprotective Efficiency of Cyclosporine After Traumatic Brain Injury in Rats.

To evaluate the possible neuroprotective effects of systemic administration of cyclosporine (Cyclosporin A) after traumatic brain injury in rats. The modified Feeney method was used as the trauma model in male Sprague Dawley rats. After the trauma, 20 mg/kg of cyclosporine was administered to the one group of the rats (n=12) intraperitoneally. Twenty-four hours after injury, the subjects were sacrificed, and brain samples were removed. The level of brain edema was evaluated through the wet-dry weight method, the lipid peroxidation ratio, and histological examination by transmission electron microscopy. The level of brain edema and lipid peroxidation ratio significantly decreased in the rats that received cyclosporine. Ultrastructural neurodestruction was graded, and a comparison of the scores between the experimental groups revealed significant neuroprotective effects of cyclosporine. The results demonstrated that systemic administration of cyclosporine produces a statistically significant decrease in both the level of brain edema and lipid peroxidation ratio when compared with "no treatment". Cyclosporine, which is regularly used as an immunosuppressant agent, is also known to prevent opening of the mitochondrial permeability transition pore by unbinding mitochondrial matrix cyclophilin. Regulation of transition pore for mitochondrial permeability by cyclosporine implies that mitochondrial dysfunction following traumatic brain injury is an important event in the progressive loss of neuronal tissue.

Effective treatment with once-daily administration of cyclosporine A of a boy with steroid-resistant severe atopic dermatitis

Effective treatment with once-daily administration of cyclosporine A of a boy with steroid-resistant severe atopic dermatitis

Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice.

Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss-of-function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII-induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII-induced CH. Surprisingly, cardiac-specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII-induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac-specific calcineurin deletion. These results show that AngII induces a direct, calcineurin-dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.

Neuropsychiatric complications after living donor liver transplantation: a prospective case series in an Egyptian center

Introduction and aimNeuropsychiatric complications that develop after living donor liver transplantation (LT) are frequently encountered, though not adequately estimated among Egyptian recipients. We aimed to estimate the frequency of neuropsychiatric manifestations and neurocognitive functional changes after living donor LT.Patients and methodsA prospective observational cohort study was conducted to evaluate 30 adult patients with end-stage liver disease preoperatively in a single Egyptian Transplant Center from November 2012 till January 2014. Relevant preoperative, intraoperative, and postoperative data were recorded and recollected and at 3 and 6 months of follow-up. The assessment included neurologic evaluation, Child–Turcotte–Pugh score, model of end-stage liver disease score, clinical hepatic encephalopathy staging scale, West Haven criteria, and International Society for Hepatic Encephalopathy and Nitrogen Metabolism score for semiquantitative assessment of encephalopathy.ResultsHepatitis C virus was the main etiology for liver disease in 27 (90%) patients. Overt hepatic encephalopathy was seen in 26.6%, whereas covert hepatic encephalopathy occurred in 43.3%. Postoperatively, 76.7% of the patients demonstrated neuropsychiatric manifestations, with 50% of them showing mainly early major events, namely, encephalopathy. Late minor manifestation rates were 50%. Early cyclosporine administration and cold ischemia time longer than 40 min were significant predictors of occurrence of early neurologic events postoperatively (P=0.031 and 0.025, respectively). Both risk factors were associated with earlier and higher rates of neurologic complications.ConclusionPatients of living donor LT are at increased risk of developing early postoperative major neurologic sequelae, which become of less clinical significance later on. The patients’ cognitive functions improve with time after transplant.

Down-regulation of miR-200b-targeting Slug axis by cyclosporine A in human gingival fibroblasts

Cyclosporine A (CsA) has been used as an immunosuppressive agent with a side effect of gingival overgrowth. It has been known that CsA-induced epithelial-mesenchymal transition (EMT) in gingiva, but the molecular mechanism has not been fully unveiled. The purpose of the study is to investigate functional roles of microRNAs in gingival overgrowth. The effect of CsA on the expression of microRNA-200b (miR-200b) in normal human gingival fibroblasts (HGFs) was determined using qRT-PCR. Luciferase reporter assay and Western blot were utilized to examine the relationship between miR-200b and EMT inducer Slug. Cell proliferation was assessed by MTT assay. CsA was found to downregulate the miR-200b transcript in HGFs in a dose-dependent manner. Luciferase reporter assay confirmed that Slug was a direct target of miR-200b, and the CsA-induced cell proliferation and Slug upregulation were inhibited by overexpression of miR-200b. Additionally, the silence of Slug reversed the increased proliferation of HGFs by miR-200b inhibitor. Repression of miR-200b after CsA administration led to an increase in Slug expression. Our results suggested that miR-200b was an upstream effector of the CsA-induced EMT and may act as a therapeutic target for CsA-induced gingival overgrowth.

Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats

Caffeic acid (CAA) and chlorogenic acid (CHA) are important members of hydroxycinnamic acid with natural antioxidant and cardio-protective properties. The present study aimed to determine the effect of CAA and CHA on systolic blood pressure, heart rates (HR) as well as on the activity of the angiotensin-1-converting enzyme (ACE), acetylcholinesterase (AChE), butrylcholinesterase (BChE) and arginase in cyclosporine-induced hypertensive rats. Experimental rats were distributed into 7 groups (n = 6): normotensive control rats; hypertensive rats (induced rats) as well as hypertensive- treated groups with captopril (10 mg/kg/day), CAA (10 and 15 mg/kg/day) and CHA (10 and 15 mg/kg/day), respectively. The experiment lasted for 7 days and the systolic blood pressure (SBP) and heart rates were recorded using tail-cuff method. Oral administration of captopril, caffeic acid and chlorogenic acid normalized hypertensive effect caused by cyclosporine administration. CAA and CHA significantly (P < 0.05) reduced SBP and HR, activity of ACE, AChE, BChE and arginase in the treated hypertensive rats compared with cyclosporine induced-hypertensive rats. Likewise, CAA and CHA improved nitric oxide (NO) bioavailability, increased catalase activity and reduced glutathione content while malondialdehyde (MDA) level was reduced compared with cyclosporine hypertensive rats. Findings from this study shows that CAA and CHA exhibited blood pressure lowering properties and reduced activities of key enzymes linked to the pathogenesis of hypertension in cyclosporine-induced rats. These might be some of the possible mechanisms of action by which their cardio-protective properties are exhibited.