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Sample records for cyclosporine

  1. Cyclosporine Ophthalmic

    MedlinePlus

    Ophthalmic cyclosporine is used to increase tear production in people with dry eye disease. Cyclosporine is in a class of medications called immunomodulators. It works by decreasing swelling in the eye ...

  2. Cyclosporine nephrotoxicity.

    PubMed

    Grinyó, J M; Cruzado, J M

    2004-03-01

    The polypeptide immunosuppressant cyclosporine is a prodrug that binds an intracellular immunophilin. The complex cyclosporine-cyclophilin binds and inhibits the phosphatase activity of calcineurin interfering with the dephosphorilation of members of the nuclear factor of activated T cells, which is involved in the regulation of genes encoding many cytokines. However, calcineurin is not exclusive from T cells; it is also present in many organs, such as the kidney, and their inhibition accounts for both the immunosuppressive and the nephrotoxic effects of cyclosporine. In renal transplantation, it was shown that graft survival improved progressively between 1998 to 1996, mainly due to reduction of acute rejection episodes. There is no doubt that cyclosporine contributed to that success. After 20 years, cyclosporine targets for maintenance immunosuppression have not been defined and the magnitude of chronic cyclosporine nephrotoxicity in renal allografts is not known, in part by the limitations of histologic classification of chronic allograft nephropathy. In the future, the new technology based on DNA microarrays can be a valuable tool to separate chronic drug toxicity from other causes of graft deterioration. On the other hand, in the cyclosporine era, chronic renal failure has emerged as a frequent adverse event after transplantation of nonrenal organs and it is associated with increased risk of death. Although there is not yet enough evidence to support a generalization of calcineurin-free immunosuppression, we should open our minds to the upcoming new concepts on immunosuppression. PMID:15041345

  3. Cyclosporine Ophthalmic

    MedlinePlus

    ... used to increase tear production in people with dry eye disease. Cyclosporine is in a class of medications ... Be sure to mention other eye drops for dry eye disease.if you are using artificial tears, instill ...

  4. Neoral: the new cyclosporine.

    PubMed

    Corbett, J; Ross, K

    1998-02-01

    Neoral is an improved formulation of cyclosporine which, through microemulsion technology, provides a more consistent rate of absorption and exposure. If patients are able to take less Neoral and still maintain the same cyclosporine level, there will also be a cost savings involved. A dose reduction of 30% yields pharmacoeconomic savings. With a more consistent rate of absorption, the risks of nephrotoxicity may be reduced. PMID:9543913

  5. Cyclosporine and tacrolimus.

    PubMed

    Vaden, S L

    1997-08-01

    Cyclosporine and tacrolimus are potent immunosuppressant agents that have been used extensively in humans, primarily for prevention of transplant rejection but also for the treatment of autoimmune disorders. Both agents have similar mechanisms of action and pharmacokinetic profiles. However, the expected toxicity of the agents is dissimilar. Although cyclosporine usage in veterinary medicine is limited, it has been used enough for therapeutic guidelines to be established. Tacrolimus, however, has undergone limited use in veterinary medicine. The drug is too toxic in dogs for its use to be recommended in most clinical situations. This article reviews the mechanism of action, pharmacokinetics, expected drug interactions and toxicities, and clinical usage of cyclosporine and tacrolimus in veterinary medicine. PMID:9283240

  6. Retinoids, methotrexate and cyclosporine.

    PubMed

    Dubertret, Louis

    2009-01-01

    Acitretin alone is efficient (PASI 90: 40%). In responders, it is the best long-term maintenance treatment (up to 29 years of continuous treatment). The main side effect is its teratogenicity in females. It is necessary to begin retinoid treatment at low doses (10 mg/day), increasing the dose step by step, looking for the maximum well-tolerated dose (usually defined as a mild cheilitis). Doses higher than the highest well-tolerated dose are frequently responsible for the Kobner phenomenon. In children, retinoids are very efficient and nearly always well tolerated, but it seems important to never give more than 0.5 mg/kg/day. Methotrexate is the best treatment for severe psoriasis. Given at low doses once a week, it is a safe, cheap, convenient and efficient treatment, if carefully monitored. The main problem is the possible long-term liver toxicity of methotrexate. The risk is very low in patients not at risk (no liver disease). In these cases, liver biopsies are dangerous and useless. In the other cases, the need for liver biopsy is very rare, decided only by the hepatologist, and should be replaced by FibroTest and FibroScan. The old American guidelines should not be followed, and new guidelines are needed. Cyclosporine at low doses is an outstanding emergency treatment. It was first used as the last possible systemic treatment, but long-term continuous treatments are seldom possible due to alterations in kidney functions. A careful follow-up of kidney functions, with measurement of the glomerular filtration rate after each year of cumulative treatment, is necessary. The cyclosporine dose must be calculated according to the theoretical body weight in obese patients to avoid overdosage. Cyclosporine is mainly used now as a short-term treatment that is very efficient for young people, who find this illness particularly difficult. Cyclosporine is not contraindicated during pregnancy. PMID:19710551

  7. [Topical administration of cyclosporin in psoriasis vulgaris].

    PubMed

    Bunse, T; Schulze, H J; Mahrle, G

    1990-06-01

    Two groups of patients with chronic plaque psoriasis were topically treated either with 10% cyclosporin in a jelly base or with 5% cyclosporin in an ointment base under occlusion. We found that cyclosporin penetrates into the lower epidermis and the dermis, when it is applied under occlusion. Obviously, the target cells are neutrophil granulocytes, since they decrease in number under cyclosporin, whereas the other inflammatory cells as well as the epidermal proliferation remain unchanged. In contrast to systemic application of cyclosporin, we did not observe any clinical differences between plaques treated with cyclosporin and those treated with placebo. PMID:2202163

  8. Cyclosporine A-Induced Renal Fibrosis

    PubMed Central

    Slattery, Craig; Campbell, Eric; McMorrow, Tara; Ryan, Michael P.

    2005-01-01

    Cyclosporine A, which has been the foremost immunosuppressive agent since the early 1980’s, significantly improves the success of organ transplantation. However, common complications of cyclosporine A therapy, such as severe renal tubulointerstitial fibrosis, limit the drug’s clinical use. Although the exact mechanisms driving cyclosporine A-induced tubulointerstitial fibrosis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating human proximal tubular cells with cyclosporine A. Morphological changes were observed after cyclosporine A treatment, including cell elongation (with a large degree of detachment), cytoskeletal rearrangement, and junctional disruption. In addition, expression of the myofibroblast-specific marker α-smooth muscle actin was detected in treated cells. These observations are consistent with events described during EMT. Using Affymetrix gene microarrays, we identified 128 genes that were differentially regulated in renal tubular cells after cyclosporine A treatment, including known profibrotic factors, oncogenes, and transcriptional regulators. Cyclosporine A induced a dose-dependent increase in transforming growth factor-β secretion from proximal tubular cells. Subsequent functional studies revealed that protein kinase C-β isoforms play a key role in cyclosporine A-induced effects. These findings provide novel insights into cyclosporine A-induced renal fibrosis and the molecular mechanisms underlying EMT, events that may be relevant in other disease states. PMID:16049326

  9. Production of cyclosporins by Tolypocladium niveum strains.

    PubMed Central

    Isaac, C E; Jones, A; Pickard, M A

    1990-01-01

    Nine strains of Tolypocladium niveum (= inflatum) were compared for their production of cyclosporins. Two of the strains, which were originally from the parental NRRL 8044 strain, were among the lower producers, while seventeen Tolypocladium strains belonging to seven other species produced no detectable cyclosporins. Variable cyclosporin production was observed initially. Once extraction and quantitation methods had been established, spore inoculum density and cultural morphology and carbon and nitrogen sources were found to be among the variables affecting cyclosporin production. Cyclosporin A was identified by cochromatography by using high-performance liquid chromatography, and cyclosporins A, B, and C were identified by gas chromatography-mass spectroscopy; all three compounds exhibited biological activity. They were routinely produced as a mixture in the ratio 7:1:2 in T. niveum UAMH 2472, which was selected on the basis of single-spore isolate total cyclosporin production and was used for most studies. This strain routinely produced total cyclosporin levels of 150 to 200 mg.liter-1 after 12 days of growth on a 2% sorbose-1% vitamin assay Casamino Acids medium. PMID:2327746

  10. Cyclosporine inhibits macrophage-mediated antigen presentation

    SciTech Connect

    Ziegler, H.K.; Palay, D.; Wentworth, P.; Cluff, C.

    1986-03-01

    The influence of cyclosporine on antigen-specific, macrophage-dependent T cell activation was analyzed in vitro. Murine T cell activation by antigens derived from Listeria monocytogenes was monitored by the production of interleukin-2. Pretreatment (2 hrs., 37/sup 0/C) of macrophages with cyclosporine resulted in a population of macrophages with a markedly diminished capacity to support the activation of T lymphocytes. When cyclosporine-pretreated macrophages were added to cultures of antigen and untreated T cells, the dose of cyclosporine which produced 50% inhibition was 1.5 ..mu..g/ml. Appropriate control experiments indicated that cyclosporine was indeed inhibiting at the macrophage level. The addition of interleukin-1 or indomethacin to the cultures did not alter the inhibitory effect of cyclosporine. Under conditions which produced >90% inhibition of antigen presentation, macrophage surface Ia expression was not altered, and the uptake and catabolism of radiolabelled antigen was normal. Thus, cyclosporine inhibits antigen presentation by a mechanism which appears unrelated to changes in Il-1 elaboration, prostaglandin production, Ia expression, or antigen uptake and catabolism.

  11. Derivatives of cyclosporin compatible with antibody-based assays. I. The generation of (/sup 125/I)-labeled cyclosporin

    SciTech Connect

    Mahoney, W.C.; Orf, J.W.

    1985-03-01

    The immunosuppressive drug cyclosporin A, has been successfully iodinated to a specific activity of 300 Ci per gram. /sup 125/I-labeled cyclosporin and (/sup 3/H)cyclosporin are nearly equivalent as tracers in a radioimmunoassay in producing standard lines (suppression by unlabeled cyclosporin) and in assigning values to clinical samples. In addition, the (/sup 125/I)-labeled cyclosporin has greater than twice the sensitivity, and it is stable to long-term storage. Use of a (/sup 125/I)-labeled cyclosporin tracer is more convenient, more reproducible, more precise, and easier than the tritiated-cyclosporin alternative in radioimmunoassay of this compound.

  12. Cyclosporine

    MedlinePlus

    ... modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some ... as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this ...

  13. Cyclosporine

    MedlinePlus

    ... oral solution may be mixed with milk, chocolate milk, or orange juice. You should choose one drink from the appropriate list and always mix your medication with that drink.To take either type of oral solution, follow these steps: Fill a glass (not plastic) cup with the drink you have chosen. Remove ...

  14. [Cyclosporin A--dermatologic indications].

    PubMed

    Mahrle, G; Schulze, H J

    1990-01-01

    The pharmacology, the biological action, as well as the clinical indications for systemic or topical application of cyclosporin A (CSA) is reviewed. Our studies yielded the following results: In chronic stationary psoriasis, systemic treatment with CSA in very low doses (2.5 mg/kg/d, 13 patients, 10 weeks) led to a 75% reduction of the PASI score without any side reactions. After topical application of CSA (40 patients, 1/5/10% gel and ointment), we observed a subclinical effect. CSA permeated into the deeper layers of the skin and accumulated up to a concentration of 3.880 ng/g (80-39.000 ng/g, polyclonal RIA); these quantities correspond with those found after systemic administration. In spite of this, CSA was not measurable in the blood. Topical CSA reduced the neutrophils in psoriatic skin both selectively and significantly, but did not affect the epidermal synthesis of DNA. PMID:2183505

  15. Novel Oxidation of Cyclosporin A: Preparation of Cyclosporin Methyl Vinyl Ketone (Cs-MVK)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cyclosporin A (CsA) was converted into cyclosporin methyl vinyl ketone (Cs-MVK) by either a biocatalytic method utilizing 1-hydroxybenzotriazole-mediated laccase oxidation or by a chemical oxidation using t-butyl hydroperoxide and potassium ­periodate as co-oxidants. Cs-MVK is a novel, versatile sy...

  16. Cyclosporine and Herbal Supplement Interactions

    PubMed Central

    Colombo, D.; Lunardon, L.; Bellia, G.

    2014-01-01

    Cyclosporine (CyA) is a well-known immunosuppressant with a narrow therapeutic window. Its bioavailability is affected by many other traditional drugs and herbal extracts. Cytochrome P-450 isoenzymes CYP3A4 and CYP3A5 and protein P-glycoprotein (P-gp) are involved in CyA bioavailability. Interactions of CyA with herbal extracts are not well known, but, given their increased concomitant use, it is important to know which extracts, many of which are commonly self-prescribed, can affect CyA blood concentrations. Decreased CyA blood concentration has been shown with St John's wort in case reports and, in vivo animal studies, with ginger, liquorice, scutellariae radix, and quercetin. Increased CyA concentration has been reported in patients with grapefruit juice, chamomile, or berberine, and with cannabidiol or resveratrol in animal studies. Effects of Echinacea and Serenoa repens on CyA levels have not been shown consistently, but concomitant use should be avoided. Although findings from animal studies cannot be directly translated into humans, avoiding concomitant use of herbal extracts is prudent until human clinical studies have ruled out any possible interaction. Clinicians should interview their patients carefully about their use of herbal supplements before CyA administration, and those receiving CyA should be warned about possible interactions between herbal preparations and CyA. PMID:24527031

  17. Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients.

    PubMed

    First, M R; Schroeder, T J; Weiskittel, P; Myre, S A; Alexander, J W; Pesce, A J

    1989-11-18

    18 renal transplant recipients receiving cyclosporin, prednisone, and azathioprine were given ketoconazole, a potent inhibitor of the cytochrome P-450 enzyme system. Within a month ketoconazole-induced blockade of cyclosporin metabolism allowed a significant reduction (451 vs 106 mg/day; 77%) of the mean dose of cyclosporin without altering cyclosporin whole blood trough levels, although maximum blood levels were almost halved. This dose reduction was maintained in patients followed up for up to 13 months. Renal and hepatic function were unchanged after the addition of ketoconazole. This drug interaction has the potential to reduce dramatically expenditure on cyclosporin in transplant recipients. PMID:2572912

  18. 21 CFR 524.575 - Cyclosporine ophthalmic ointment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cyclosporine ophthalmic ointment. 524.575 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS § 524.575 Cyclosporine ophthalmic ointment. (a) Specifications. Each gram of ointment contains...

  19. Possible Antipruritic Mechanism of Cyclosporine A in Atopic Dermatitis.

    PubMed

    Ko, Kyi Chan; Tominaga, Mitsutoshi; Kamata, Yayoi; Umehara, Yoshie; Matsuda, Hironori; Takahashi, Nobuaki; Kina, Katsunari; Ogawa, Mayuko; Ogawa, Hideoki; Takamori, Kenji

    2016-06-15

    Cyclosporine A is an immunosuppressive agent that suppresses pruritus and is currently used in the treatment of patients with severe atopic dermatitis. The aim of this study was to elucidate the antipruritic mechanism of cyclosporine A using a mouse model of atopic dermatitis. Intraperitoneal injection of cyclosporine A (5 mg/kg) significantly reduced epidermal nerve density, number of scratching bouts, dermatitis scores, and transepidermal water loss, as well as decreasing the numbers of inflammatory cells in the dermis and decreasing epidermal thickness. Intraperitoneal injection of cyclosporine A dose-dependently inhibited increased itch-related receptor gene expression, such as interleukin-31 receptor A and neurokinin-1 receptor, in the dorsal root ganglion of atopic dermatitis model mice. Thus, the antipruritic efficacy of cyclosporine A may involve reduced epidermal nerve density and expression levels of itch-related receptor genes in the dorsal root ganglion, as well as improvement in acanthosis and reduction in cutaneous inflammatory cell number. PMID:26671728

  20. Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

    PubMed

    First, M R; Schroeder, T J; Alexander, J W; Stephens, G W; Weiskittel, P; Myre, S A; Pesce, A J

    1991-02-01

    Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well

  1. The effect of oral metoclopramide on the absorption of cyclosporine.

    PubMed

    Wadhwa, N K; Schroeder, T J; O'Flaherty, E; Pesce, A J; Myre, S A; First, M R

    1987-02-01

    This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients with stable renal function. The study was conducted on two consecutive days. Ten patients were studied twice and four patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole blood cyclosporine levels were analyzed by high performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/mL nu 388 ng/mL) and mean area under the blood concentration nu time curve (4120 ng X h/mL nu 3370 ng X h/mL), and a significant decrease in mean time to reach maximum concentration: The mean increase in area under the blood concentration versus time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine. PMID:3547879

  2. The effect of oral metoclopramide on the absorption of cyclosporine.

    PubMed

    Wadhwa, N K; Schroeder, T J; O'Flaherty, E; Pesce, A J; Myre, S A; First, M R

    1987-02-01

    This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients. The study was conducted on two consecutive days. Ten patients were studied twice, and 4 patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole-blood cyclosporine levels were analyzed by high-performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/ml versus 388 ng/ml) and mean area under the blood-concentration-versus-time curve (4120 ng X hr/ml versus 3370 ng X hr/ml); and a significant decrease in mean time to reach maximum concentration. The mean increase in area under the blood-concentration-versus-time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine. PMID:3544377

  3. Optimized method for measuring cyclosporin A with /sup 125/I-labeled cyclosporin

    SciTech Connect

    Felder, R.A.; Mifflin, T.E.; Bastani, B.

    1986-07-01

    We evaluated the use of the new iodinated ligand for the in vitro measurement of cyclosporin A by radioimmunoassay (RIA). Substitution of the iodinated cyclosporin (/sup 125/I-CyA) for the corresponding tritium-labeled analog (/sup 3/H-CyA) considerably simplifies and accelerates the currently available RIA, and improves its precision. Analysis of the respective dose-response curves showed that the 50% B0 value was lower for the /sup 125/I-CyA assay than for the /sup 3/H-CyA assay (37 vs 77 micrograms/L). Use of whole-blood specimens minimized interferences from temperature and hematocrit. We conclude that the use of /sup 125/I-CyA in a commercially available RIA for whole-blood specimens is accessible to most laboratories and provides rapid, reproducible data for management of transplant patients.

  4. Radioimmunoassay of salivary cyclosporine with use of /sup 125/I-labeled cyclosporine

    SciTech Connect

    Coates, J.E.; Lam, S.F.; McGaw, W.T.

    1988-08-01

    We prepared /sup 125/I-labeled cyclosporine (/sup 125/I-CS) by modifying the procedure of Mahoney and Orf and characterized it with regards to maximal immunoreactivity (greater than 90%), trichloroacetic acid precipitability (greater than 90%), and stability (90% immunoreactive after five half-lives of /sup 125/I). For a particular preparation of /sup 125/I-CS, we estimated its immunoreaction concentration (50 pmol/L) and the equilibrium constant for its reaction with Sandoz polyclonal antiserum (K = 3.9 X 10(9) L/mol). By substituting /sup 125/I-CS as tracer in the Sandoz radioimmunoassay and by modifying other aspects of the assay, we developed a procedure that is sufficiently sensitive (0.34 micrograms/L) to allow measurement of trough (lowest inter-dose) cyclosporine concentrations in parotid saliva. Of 38 kidney-transplant patients, 35 had measurable concentrations in saliva (mean 8.3, SD 5.2 micrograms/L), and these correlated moderately with paired serum concentrations (r = 0.68, P less than 0.001). We believe that measurement of salivary cyclosporine may offer a simple way of estimating the free fraction of the drug in serum or plasma.

  5. Use of Cyclosporine in Uterine Transplantation

    PubMed Central

    Saso, Srdjan; Logan, Karl; Abdallah, Yazan; Louis, Louay S.; Ghaem-Maghami, Sadaf; Smith, J. Richard; Del Priore, Giuseppe

    2012-01-01

    Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring. PMID:22132302

  6. Cyclosporin metabolism by human gastrointestinal mucosal microsomes.

    PubMed Central

    Webber, I R; Peters, W H; Back, D J

    1992-01-01

    The in vitro metabolism of the immunosuppressant cyclosporin (CsA) by human gastrointestinal mucosal microsomes has been studied. Macroscopically normal intestinal (n = 4) and liver (n = 2) tissue was obtained from kidney transplant donors, and microsomes prepared. Intestinal metabolism was most extensive with duodenal protein (15% conversion to metabolites M1/M17 after 2 h incubation at 37 degrees C; metabolite measurement by h.p.l.c). Western blotting confirmed the presence of P-4503A (enzyme subfamily responsible for CsA metabolism) in duodenum and ileum tissue, but not in colon tissue. The results of this study indicate that the gut wall may play a role in the first-pass metabolism of CsA, and could therefore be a contributory factor to the highly variable oral bioavailability of CsA. PMID:1389941

  7. Cyclosporine alters opiate withdrawal in rodents.

    PubMed

    Dafny, N; Wagle, V G; Drath, D B

    1985-05-01

    Opiates exert numerous effects on all levels of the central nervous system with tolerance, physical dependence and withdrawal being characteristics of this drug class. The degree of dependence is directly correlated to the intensity of withdrawal. Therefore, success in modifying the withdrawal syndrome may shed light on the dynamics of opiate addiction. The present study demonstrates that cyclosporine, a widely used immunosuppressive drug, considerably modified the behavioral signs of a naloxone-induced abstinence syndrome in morphine-addicted rats. In previous experiments, alpha-interferon has shown similar results. The similarity in actions of these two immunomodulator drugs is discussed and we suggest that opiate addiction may involve the immune system. PMID:4039025

  8. Treatment of myelodysplasia with oral cyclosporin.

    PubMed

    Atoyebi, W; Bywater, L; Rawlings, L; Brunskill, S; Littlewood, T J

    2002-08-01

    Recent studies have shown a good response to immunosuppressive treatment with cyclosporin A (CSA) in patients with the myelodysplastic syndrome (MDS). We have treated six transfusion-dependent MDS patients with CSA for a minimum of 3 months. None of these patients showed a significant response, while the drug was withdrawn in 3/6 patients because of intolerable side-effects. Two reasons for the failure of this treatment in our patients can be advanced. Firstly, the hypoplastic variant of MDS predominated in previous studies in contrast to ours. Secondly, the concomitant use of other immunosuppressive agents in previous studies might have enhanced the effect of CSA. We suggest further therapeutic trials of CSA in MDS, selecting patients on the basis of in vitro studies that predict an immunological basis for their disease, to assess its efficacy in prolonging survival. PMID:12181023

  9. Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

    PubMed

    Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon; Chang, Yoon-Seok

    2015-07-01

    Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

  10. Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

    PubMed Central

    Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon

    2015-01-01

    Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

  11. Cyclosporin for treatment of life-threatening alloimmunization.

    PubMed

    Tilly, H; Azagury, M; Bastit, D; Lallemand, A; Piguet, H

    1990-05-01

    We describe a 16-year-old girl with aplastic anemia who, 1 year after initial diagnosis developed a refractory state to platelet transfusions due to alloimmunization and resulting in severe bleeding. Treatment with cyclosporin, initially prescribed as treatment of the bone marrow failure, resulted in prompt decrease in lymphocytotoxic antibodies, which paralleled a marked improvement in platelet recovery. To our knowledge, such a dramatic effect of cyclosporin on alloimmunization has not been previously reported and merits further attention. PMID:2327409

  12. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats.

    PubMed

    Elshama, Said Said; El-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  13. Effects of Nigella sativa and Lepidium sativum on Cyclosporine Pharmacokinetics

    PubMed Central

    Al-Jenoobi, F. I.; Al-Suwayeh, S. A.; Muzaffar, Iqbal; Al-Kharfy, Khalid M.; Korashy, Hesham M.; Al-Mohizea, Abdullah M.; Raish, Mohd

    2013-01-01

    The present study was conducted to investigate the effects of Nigella sativa and Lepidium sativum on the pharmacokinetics of cyclosporine in rabbits. Two groups of animals were treated separately with Nigella sativa (200 mg/kg p.o.) or Lepidium sativum (150 mg/kg p.o.) for eight consecutive days. On the 8th day, cyclosporine (30 mg/kg p.o.) was administered to each group one hour after herbal treatment. Blood samples were withdrawn at different time intervals (0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hrs) from marginal ear vein. Cyclosporine was analyzed using UPLC/MS method. The coadministration of Nigella sativa significantly decreased the Cmax and AUC0−∞ of cyclosporine; the change was observed by 35.5% and 55.9%, respectively (P ≤ 0.05). Lepidium sativum did not produce any significant change in Cmax of cyclosporine, although its absorption was significantly delayed compared with control group. A remarkable change was observed in Tmax and AUC0−t of Lepidium sativum treated group. Our findings suggest that concurrent consumption of Nigella sativa and Lepidium sativum could alter the pharmacokinetics of cyclosporine at various levels. PMID:23957013

  14. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats

    PubMed Central

    Elshama, Said Said; EL-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  15. Tissue distribution, disposition, and metabolism of cyclosporine in rats

    SciTech Connect

    Wagner, O.; Schreier, E.; Heitz, F.; Maurer, G.

    1987-05-01

    Tissue distribution, disposition, and metabolism of /sup 3/H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak /sup 3/H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. /sup 3/H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.

  16. Cyclosporin in cell therapy for cardiac regeneration.

    PubMed

    Jansen Of Lorkeers, S J; Hart, E; Tang, X L; Chamuleau, M E D; Doevendans, P A; Bolli, R; Chamuleau, S A J

    2014-07-01

    Stem cell therapy is a promising strategy in promoting cardiac repair in the setting of ischemic heart disease. Clinical and preclinical studies have shown that cell therapy improves cardiac function. Whether autologous or allogeneic cells should be used, and the need for immunosuppression in non-autologous settings, is a matter of debate. Cyclosporin A (CsA) is frequently used in preclinical trials to reduce cell rejection after non-autologous cell therapy. The direct effect of CsA on the function and survival of stem cells is unclear. Furthermore, the appropriate daily dosage of CsA in animal models has not been established. In this review, we discuss the pros and cons of the use of CsA on an array of stem cells both in vitro and in vivo. Furthermore, we present a small collection of data put forth by our group supporting the efficacy and safety of a specific daily CsA dosage in a pig model. PMID:24831573

  17. Lack of effect of spiramycin on cyclosporin pharmacokinetics.

    PubMed Central

    Vernillet, L; Bertault-Peres, P; Berland, Y; Barradas, J; Durand, A; Olmer, M

    1989-01-01

    1. The influence of spiramycin coadministration on cyclosporin pharmacokinetics was studied in five renal transplant patients. The plasma concentrations of cyclosporin were measured both by non-specific radioimmunoassay (RIA) and high-performance liquid chromatography (h.p.l.c.). 2. The kinetics of cyclosporin were followed before treatment, and after 1 day and then 2 weeks of oral treatment with spiramycin (3 X 10(6) iu, twice daily). The main pharmacokinetic parameters (the area under the plasma drug concentration-time curve, the maximum plasma drug concentration and the time to reach it) obtained both by RIA and h.p.l.c. were not modified by spiramycin cotreatment after 1 day, nor after 2 weeks of spiramycin administration. Therefore, the pharmacokinetics of cyclosporin (parent drug and parent drug plus metabolites) are not influenced by the coadministration of spiramycin macrolide at therapeutic dosage. 3. Spiramycin may be preferable to other macrolide antibiotics known to interact with cyclosporin such as erythromycin or josamycin. PMID:2667601

  18. Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis.

    PubMed

    Kawahara, Takashi; Kashiwagi, Eiji; Li, Yi; Zheng, Yichun; Miyamoto, Yurina; Netto, George J; Ishiguro, Hitoshi; Miyamoto, Hiroshi

    2016-02-01

    The functional role of nuclear factor of activated T-cells (NFAT), while it has been extensively investigated in the immune system, remains uncertain in bladder cancer development. We here aim to assess the effects of cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressants known to specifically inactivate the NFAT pathway in immune cells, on neoplastic transformation of urothelial cells. Immunohistochemistry revealed that the expression levels of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, were elevated in urothelial neoplasms, compared with non-neoplastic urothelial tissues, and in low-grade and high-grade papillary urothelial carcinomas, compared with papillary urothelial neoplasms of low malignant potential. In an immortalized normal urothelial cell line SVHUC, CsA and FK506 reduced NFATc1 expression, NFAT transcriptional activity, and the expression of c-myc, a downstream target of NFATc1 signals. Treatment with CsA or FK506 in the SVHUC cells undergoing neoplastic transformation induced by exposure to a chemical carcinogen 3-methylcholanthrene resulted in strong inhibition in colony formation in vitro as well as tumor formation in NOD-SCID mice. CsA and FK506 were additionally found to up-regulate the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and p27, and down-regulate that of oncogenic genes, such as cyclin D1, cyclin D3, and cyclin E, in SVHUC cells with the carcinogen challenge. Thus, CsA and FK506 likely inhibit urothelial tumorigenesis. These findings offer a potential chemopreventive approach for urothelial tumors using NFAT inhibitors. PMID:25594762

  19. Cyclosporine Amicellar delivery system for dry eyes

    PubMed Central

    Kang, Han; Cha, Kwang-Ho; Cho, Wonkyung; Park, Junsung; Park, Hee Jun; Sun, Bo Kyung; Hyun, Sang-Min; Hwang, Sung-Joo

    2016-01-01

    Background The objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy. Materials and methods CsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining. Results MS-CsA had a smaller particle size (average diameter 14–18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups (P<0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells. Conclusion The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes. PMID:27382280

  20. [Pregnancy following liver transplantation and during immunosuppression with cyclosporine].

    PubMed

    Günter, H H; Mauz, S; Ringe, B; Niesert, S

    1990-05-11

    Orthotopic liver transplantation had been performed in 1983 in a now 40-year-old woman in the terminal stage of posthepatitis liver cirrhosis with recurrent oesophageal bleedings and precoma from complete liver-cell failure. She became pregnant in 1988 while under immunosuppression with cyclosporin (2.1-2.7 mg/kg body-weight) and prednisolone (5 or 7.5 mg daily in rotation). Pregnancy proceeded without complication and there were no side effects from cyclosporin. After premature membrane rupture in the 39th week of pregnancy uterine inertia developed during oxytocin stimulation of contractions, and caesarean section was performed. The female infant was normally developed without any malformations. Liver, kidney and adrenal functions were normal, as was haemopoiesis. But possible late sequelae of cyclosporin treatment in the child cannot as yet be assessed because of the short follow-up. PMID:2338057

  1. [Cyclosporine-induced gingival hyperplasia: report of one case].

    PubMed

    Bahamondes, Carlos; Godoy, Jorge

    2007-03-01

    Gingival enlargement can be an adverse effect of cyclosporine A and nifedipine use. It has a high relapse rate if the drugs are not discontinued. There is a genetic predisposition to the development of this condition and dental biofilm can also play a role. We report a 64 years old male who received a renal allograft and was treated with cyclosporine and nifedipine. He required six surgical interventions for generalized gingival enlargement. After the sixth relapse, the patient was subjected to a periodontal treatment to eliminate the dental biofilm, which decreased the rate of recurrence of gingival enlargement. PMID:17505584

  2. Successful treatment of postoperative pyoderma gangrenosum with cyclosporin.

    PubMed

    Schöfer, H; Baur, S

    2002-03-01

    Postoperative pyoderma gangrenosum (PPG), also known as postoperative progressive gangrene of Cullen, is a rare and rapidly evolving complication of surgical procedures. Since the first description by Cullen in 1924 (Surg Gynecol Obstet 1924; 38: 579-582) various case reports have been published. Even in typical cases PPG is often misdiagnosed and therefore wrongly treated; the unknown aetiology makes treatment difficult. The therapies used for pyoderma gangrenosum include systemic corticosteroids, azathioprine, dapsone, mercaptopurine, sulphasalazine, sulphapyridine, thalidomide, cyclophosphamide, clofazimine, isotretinoin, immunoglobulins and cyclosporin. We report on two patients with PPG following breast surgery who were successfully treated with low-dose cyclosporin (2.5-5 mg/kg per day). PMID:12046819

  3. Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats.

    PubMed

    Yang, C Y; Chao, P D L; Hou, Y C; Tsai, S Y; Wen, K C; Hsiu, S L

    2006-09-01

    Quercetin was reported to modulate CYP isoenzymes and P-glycoprotein (Pgp), a drug efflux transporter. Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs. Ginkgo and onion contain quercetin and its glycosides as St. John's Wort. The coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as St. John's Wort. Therefore, this study aimed to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin in rats. Cyclosporin was administered orally and intravenously to rats with and without an oral dose of ginkgo or onion in crossover designs. Blood samples were collected via cardiopuncture and blood cyclosporin concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. Everted gut sac was used to investigate the effects of ginkgo and onion on the function of intestinal Pgp. Oral coadministration of ginkgo and onion significantly decreased the Cmax of cyclosporin by 62% and 60%, and reduced the AUC0-t by 51% and 68%, respectively, whereas no influence was observed when cyclosporin was given intravenously. This indicates that the interactions between cyclosporin and ginkgo or onion occurred mainly at the absorption site. In conclusion, ginkgo and onion markedly decreased the oral bioavailability of cyclosporin. We suggest that concurrent intake of quercetin-rich herbs or foods with cyclosporin are better avoided in order to ensure the efficacy of cyclosporin. PMID:16762474

  4. Effects of embryonic cyclosporine exposures on brain development and behavior

    PubMed Central

    Clift, Danielle E.; Thorn, Robert J.; Passarelli, Emily A.; Kapoor, Mrinal; LoPiccolo, Mary K.; Richendrfer, Holly A.; Colwill, Ruth M.; Creton, Robbert

    2015-01-01

    Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning, since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate, because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures. PMID:25591474

  5. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  6. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  7. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  8. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  9. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  10. Effects of embryonic cyclosporine exposures on brain development and behavior.

    PubMed

    Clift, Danielle E; Thorn, Robert J; Passarelli, Emily A; Kapoor, Mrinal; LoPiccolo, Mary K; Richendrfer, Holly A; Colwill, Ruth M; Creton, Robbert

    2015-04-01

    Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures. PMID:25591474

  11. Pomelo enhances cyclosporine bioavailability in healthy male Thai volunteers.

    PubMed

    Anlamlert, Wirin; Sermsappasuk, Pakawadee; Yokubol, Dhirayudh; Jones, Sirada

    2015-04-01

    The aim of this study was to investigate the effect of pomelo pulp on the pharmacokinetics of cyclosporine in healthy male Thai volunteers. The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. A single oral dose of 2 × 100 mg cyclosporine was administered with 200 mL of water. Each subject received 250 g of pomelo pulp or 250 mL of water 1 hour before drug administration and once again 10 minutes following drug administration. Blood samples were collected over a 24 hour period. The point estimates (90% confidence intervals) of the test/control ratio using logarithmic transformed data for the area under the curve (AUC) for blood concentration from time 0 to infinity (AUC(0- ∞)) and the observed maximum concentration (C(max)) were 128.8% (120.6-137.6) and 136.1% (126.0-146.8), respectively. These 90% confidence intervals were higher than the accepted bioequivalence range defined by the European Medicines Agency guidelines for narrow therapeutic index drugs (90%-111% for AUC and 80%-125% for C(max)). However, the apparent terminal half-life (t(1/2)) was not significantly different. In conclusion, co-administration of cyclosporine and pomelo pulp increased the relative bioavailability of cyclosporine. PMID:25408261

  12. [Value of protecting mitochondrial functions during treatment with cyclosporin A].

    PubMed

    Simon, N; Albengres, E; Barré, J; Jolliet, P; Urien, S; Settaf, A; Tillement, J P

    1997-01-01

    The use of cyclosporin A is often limited by its nephrotoxicity. This dose-dependent toxicity can occur in all kinds of transplantation and is reversed with drug withdrawal. Cyclosporin A induces a vasoconstriction leading to an increase of renal vascular resistance and a reduction of glomerular filtration. Histochemical studies show mitochondrial alterations and an excess of cytosolic and mitochondrial calcium leading to a decrease of ATP synthesis. Two strategies can be evoked for limiting cyclosporin-A-induced nephrotoxicity. First, the use of drugs counteracting the vasoconstriction has been proposed. Second, drugs acting by restoration of ATP synthesis could also be of interest. For example, calcium channel blockers may be used for limiting the Ca2+ fluxes into cells. Another way to protect ATP synthesis is to inhibit the cyclosporin-A-induced increase of mitochondrial Ca2+ concentrations; Trimetazidine has shown its efficiency in vitro for protecting mitochondria against these modifications of Ca2+ homeostasis and is under clinical evaluation. PMID:9231511

  13. Study of Aplastic Anaemia with Cyclosporine in Resource Poor Setting

    PubMed Central

    Narendra, Anukonda Moti Venkata Raja; Adiraju, Krishna Prasad; Modugu, Nageshwar Rao

    2016-01-01

    Introduction Aplastic Anaemia (AA) is a syndrome characterized by peripheral pancytopenia with hypo-cellular marrow. Acquired idiopathic AA is the most common variety, probably of an autoimmune aetiology. Bone Marrow Transplantation (BMT) is the treatment of choice but cost is the limiting factor. Antithymocyte Globulin and Cyclosporine-A is an alternative to BMT. Cyclosporine alone has been tried as a single agent in resource poor setting. Aim The study was conducted with the aim to observe the treatment response in aplastic anaemia to Cycloserine-A. Materials and Methods Patients who were diagnosed as AA and opted for Cyclosporine with informed consent were included in the study. All the subjects were started on 5mg/kg of Cyclosporine and were followed up for three months to see the treatment response. This study had the approval from IEC. Results Twenty patients were enrolled in the study. Age of the patients ranged from 10 to 65 years. Maximum number (10/20) of patients was in the 2nd decade. Most of the patients presented with mucosal bleeds and breathlessness on exertion; the predominant sign was pallor. Eleven patients had severe AA, eight had non severe and one had very severe anaemia. Out of 20, three patients were lost to follow-up and one patient discontinued therapy due to renal dysfunction; finally sixteen patients’ data was analysed. Out of 16 patients, 9 responded was and 7 did not respond. Complete response was observed in three patients, partial response in six patients. Seven patients had drug toxicity in the form of acute renal failure and gum hypertrophy. Conclusion Cyclosporine seems to be a reasonable therapeutic option with good response rate and minimal side effects. PMID:27504327

  14. Effect of cyclosporine in a murine model of experimental colitis.

    PubMed

    Banić, Marko; Anić, Branimir; Brkić, Tomislav; Ljubicić, Neven; Plesko, Sanja; Dohoczky, Csaba; Erceg, Damir; Petrovecki, Mladen; Stipancić, Igor; Rotkvić, Ivo

    2002-06-01

    The use of immunosuppressive therapy may be associated with significant toxicity. The aim of this study was to investigate the effect of cyclosporine A (CsA) in murine model of experimental colitis. Experimental colitis was induced in NMRI mice using an enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. After inducing colitis, experimental groups of animals were treated with CsA (1, 3, 5, 10, 25, 50 mg/kg/day) intraperitoneally (i.p.) or intracolonically (i.c.), and control groups were treated with phosphate-buffered saline intraperitoneally or intracolonically, respectively. Colonic inflammatory changes were assessed using a histopathologic score of 0-30, and pooled whole blood samples were processed with monoclonal antibodies for cyclosporine concentration. In addition, two groups of animals with experimental colitis were treated intraperitoneally or intracolonically with 3 mg/kg/day of CsA, and the colons were also taken for immunohistochemistry for CD25. CsA diminished the extent of colitis in groups treated with 3, 5, 10, or 25 mg/kg intraperitoneally or intracolonically, and in groups treated with 1 and 50 mg/kg intracolonically (P < 0.05). The effect of intracolonic application of CsA was not related to whole blood cyclosporine concentrations. In addition, the effect of CsA at 3 mg/kg, applied intraperitoneally or intracolonically was, in part, expressed in decreasing the numbers of CD25+ cells within colonic mucosa/submucosa (P < 0.05). In conclusions, the results of this study indicate the possibility of intracolonic application of cyclosporine in order to widen the therapeutic window for effective, but possibly toxic drug, such as cyclosporine. PMID:12064814

  15. Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma.

    PubMed

    Rojnuckarin, Ponlapat; Nakorn, Thanyaphong Na; Assanasen, Thamathorn; Wannakrairot, Pongsak; Intragumtornchai, Tanin

    2007-03-01

    Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of hematologic malignancy characterized by lesions in subcutaneous fat associated with systemic symptoms. The standard treatment of the disease, currently, is not established, but CHOP or CHOP-like regimens are usually given. We report, herein, 4 cases of SPTCL diagnosed by histopathology and immunohistochemistry who were refractory to CHOP and/or ESHAP and/or fludarabine-based regimen, but showed rapid improvement within weeks after oral cyclosporin 4 mg/kg/day. Three sustained complete remission for the durations of 8 - 9 months off-treatments. T-cell receptor gene rearrangement revealed polyclonality in 3 cases and monoclonality in 1 case. Our data suggest the benefit of incorporating cyclosporin into the treatment regimen for SPTCL. PMID:17454599

  16. [A case of nephrotic syndrome achieving remission with cyclosporine monotherapy].

    PubMed

    Nagatoya, Katsuyuki

    2010-01-01

    The case was a female in her early 80's. Due to abdominal bloating and lower limb edema, she visited a nearby doctor, was diagnosed to have nephrotic syndrome, and then was referred to our department. Upon initial consultation, TP of 4.1 g/dl, Alb of 1.7 g/dl, UN of 73 mg/dl, and Cr of 1.43 mg/dl, along with pleural effusion were observed by chest X-ray. A renal biopsy was not performed because permission could not be obtained. Despite the fact that management of the edema was performed using diuretic agents and albumin preparations, a reduced renal function and deterioration of the fluid retention were gradually observed. She originally displayed lower back pain and digestive symptoms and, therefore, cyclosporine monotherapy was initiated in order to address concerns of side effects such as osteoporosis and peptic ulcer due to adrenocortical steroid drugs (hereinafter abbreviated as steroid). Subsequently, hemodialysis was temporarily required but reduced urine protein and an improved renal function were gradually observed and she eventually achieved a complete remission. The possibility of a spontaneous remission of membranous nephropathy, etc. was considered, but a relapse occurred when the amount of cyclosporine was reduced. Thereafter, a complete remission was obtained with an increased dosage. As a result, the effectiveness of cyclosporine was thus confirmed. In treating nephrotic syndrome, steroid therapy is commonly performed and it is common for cyclosporine to be limited to steroid-resistant cases and/or steroid-dependent cases. However, it is believed that monotherapy could also be an option in cases in which the use of steroids is difficult, such as in cases of elderly patients. PMID:21116092

  17. Management of Cyclosporine and Nifedipine-Induced Gingival Hyperplasia

    PubMed Central

    Dilber, Erhan; Aral, Kübra; Sarica, Yagmur; Sivrikoz, Oya Nermin

    2015-01-01

    Gingival enlargements modified by medications are becoming more common because of the increased use of inducing drugs, and may create speech, mastication, tooth eruption, periodontal, and aesthetic problems. We hereby present a case of a 54-year-old man with 12-month history of generalized gingival enlargement in the keratinized gingiva was referred to our clinic. The patient had a history of kidney transplant and was under medication of cyclosporine and nifedipine. After medical consultation, cyclosporine was changed to tacrolimus and nifedipine was changed to captopril. Gingivectomy was performed using a diode laser, and scaling and root planning were performed. At five months postoperative, the gingival enlargements relapsed and diode laser-assisted surgery was repeated. The patient was followed-up on second postoperatively at 18 months and no relapse was seen. Diode laser-assisted gingivectomy was found to be useful for coagulation during surgery and decreased postoperative bleeding. Recurrence risk of cyclosporine and nifedipine-induced gingival overgrowth is high, thus, there is a great need for prolonged care of patients following treatment and prosthetic restoration. PMID:26812935

  18. The Genome of Tolypocladium inflatum: Evolution, Organization, and Expression of the Cyclosporin Biosynthetic Gene Cluster

    PubMed Central

    Bushley, Kathryn E.; Raja, Rajani; Jaiswal, Pankaj; Cumbie, Jason S.; Nonogaki, Mariko; Boyd, Alexander E.; Owensby, C. Alisha; Knaus, Brian J.; Elser, Justin; Miller, Daniel; Di, Yanming; McPhail, Kerry L.; Spatafora, Joseph W.

    2013-01-01

    The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role

  19. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.

    PubMed

    Johnston, Atholl; Belitsky, Philip; Frei, Ulrich; Horvath, John; Hoyer, Peter; Helderman, J Harold; Oellerich, Michael; Pollard, Stephen; Riad, Hany; Rigotti, Paolo; Keown, Paul; Nashan, Björn

    2004-08-01

    Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician. PMID:15205865

  20. Use of cyclosporine and ketoconazole without nephrotoxicity in two heart transplant recipients.

    PubMed

    Schroeder, T J; Melvin, D B; Clardy, C W; Wadhwa, N K; Myre, S A; Reising, J M; Wolf, R K; Collins, J A; Pesce, A J; First, M R

    1987-01-01

    A cyclosporine-ketoconazole drug interaction was first described in 1981. It has been suggested that the two drugs should not be used concomitantly because of the danger of severe nephrotoxicity. Two reported cases indicate that cyclosporine and ketoconazole can be safely coadministered, provided that the dosage of cyclosporine is reduced appropriately. Two patients were initially given 8 mg/kg/day of cyclosporine at the time of heart transplantation, and the dosage was tapered to meet appropriate blood levels (250 to 350 ng/ml by whole blood high-performance liquid chromatography). During ketoconazole therapy (400 mg daily for 4 weeks), patient 1 received 80 to 100 mg/day of cyclosporine, which is equal to approximately 1 mg/kg/day, and patient 2 received between 40 and 80 mg/day of cyclosporine, which is equivalent to 0.4 to 0.8 mg/kg/day. Neither patient exhibited a creatinine value above 1.4 mg/dl while on combined therapy, and there were no problems with allograft rejection. Both patients had inappropriately high cyclosporine blood levels even with this marked reduction in dosage (patient 1, 520 to 1310 ng/ml and patient 2, 320 to 600 ng/ml). Thus it appears that cyclosporine and ketoconazole can be administered together safely, provided that there is an appropriate reduction in the dosage of cyclosporine; this results in the maintenance of adequate immunosuppression without development of nephrotoxicity. PMID:3305834

  1. Importance of endogenous prostaglandins for the toxicity of cyclosporin A to rat endocrine and exocrine pancreas?

    PubMed Central

    Rünzi, M; Peskar, B M; von Schönfeld, J; Müller, M K

    1992-01-01

    Previous work has shown that cyclosporin A is toxic to the endocrine and exocrine pancreas. The aim of this study was to examine whether endogenous eicosanoids play a role in controlling cyclosporin A induced toxicity. Rats were treated for eight days with indomethacin (2 mg/kg, twice daily) in addition to cyclosporin A (5 or 10 mg/kg daily). Effects of drug treatments on exocrine (as assessed by amylase and protein secretion into the pancreatic juice) and endocrine (as assessed by the glucose dependent insulin release) pancreatic functions, and pancreatic formation of prostaglandins and thromboxane were evaluated. Treatment with cyclosporin A in the doses used did not inhibit eicosanoid formation by the pancreatic tissue ex vivo. Indomethacin caused significant inhibition of pancreatic formation of prostaglandin E2, 6k prostaglandin F1 alpha and thromboxane B2. Combined treatment with indomethacin and cyclosporin A (5 or 10 mg/kg) augmented cyclosporin A induced pancreatic toxicity with further impairment of insulin release, amylase secretion, and pancreatic juice protein content, but did not result in more pronounced inhibition of pancreatic eicosanoid formation. The increased toxicity of the combined treatment was, however, associated with raised cyclosporin A whole blood concentrations. The data suggest that the potentiation of pancreatic toxicity of cyclosporin A observed during coadministration of indomethacin is not the result of suppression of endogenous pancreatic eicosanoid biosynthesis, but more likely results from altered cyclosporin A pharmacokinetic which may be caused by an interference of indomethacin with the hepatic cytochrome P-450 dependent monooxygenase involved in cyclosporin A metabolism. The possibility that coadministration of non-steroidal antiinflammatory drugs aggravates toxic effects in cyclosporin A treated patients should be considered. PMID:1280611

  2. Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

    PubMed Central

    Sánchez-Ortega, Isabel; Vázquez, Lourdes; Montes, Carmen; Patiño, Beatriz; Arnan, Montserrat; Bermúdez, Arancha; Yáñez, Lucrecia; Caballero, Teresa

    2012-01-01

    The posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. PMID:23027192

  3. Cyclosporin-erythromycin interaction in renal transplant patients.

    PubMed Central

    Gupta, S K; Bakran, A; Johnson, R W; Rowland, M

    1989-01-01

    1. The interaction between cyclosporin (CyA) and erythromycin was studied in renal transplant patients following oral and intravenous administration of CyA. 2. Blood and plasma CyA concentrations and blood concentrations of metabolite 17 were measured by h.p.l.c. 3. Erythromycin produced almost a two-fold increase in bioavailability, from 36% to 60%; with a small (13%) decrease in clearance of CyA. 4. The metabolite 17 data further support the postulate that erythromycin increases the absorption of CyA rather than inhibits its metabolism, as generally believed. PMID:2655690

  4. Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats.

    PubMed

    Santa, T; Nishihara, K; Horie, S; Kotaki, H; Sawada, Y; Kawabe, K; Iga, T

    1994-07-01

    Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression. PMID:7996392

  5. Effect of cyclosporin on hair-existing area of nude mice.

    PubMed

    Hozumi, Y; Imaizumi, T; Kondo, S

    1994-07-01

    We investigated the effect of cyclosporin, as well as minoxidil, testosterone, estradiol and corticosteroid on the hair growth on the hairy part of nude mice. Aliquots of solutions of cyclosporin and other agents were applied once per every day topically on the tails and the lower backs of 5 week-old BALB/c nude mice, for as long as 6 weeks. Cyclosporin prolonged the hair-existing phase of the hair cycle, but did not change the term of the hair cycle, i.e., the resting phase was not affected. Minoxidil, testosterone and estradiol did not influence the hair growth cycle. Combination of cyclosporin and other agents demonstrated that there was neither additive nor synergistic effect, but a high dose of corticosteroid inhibit the cyclosporin effect, as well as suppressing completely the reappearance of the growing phase. PMID:7999675

  6. L-arginine prevents bone loss and bone collagen breakdown in cyclosporin A-treated rats.

    PubMed

    Fiore, C E; Pennisi, P; Cutuli, V M; Prato, A; Messina, R; Clementi, G

    2000-11-24

    Cyclosporin A is implicated in the pathogenesis of post-transplantation bone disease. Because of recent evidence that cyclosporin A may cause renal and cardiovascular toxicity by inhibiting nitric oxide (NO) activity, and that NO slows bone remodeling and bone loss in animal and human studies, we investigated a possible link between NO production and beneficial effects on bone health in cyclosporin A-treated rats. Thirty-six 10-week-old male rats were assigned to six groups of six animals each, and treated for 4 weeks with: vehicle; cyclosporin A; L-arginine; N(G)-nitro-L-arginine methylester (L-NAME, a general inhibitor of NO synthase activity); a combination of cyclosporin A+L-arginine; and a combination of cyclosporin A+L-NAME. Whole body and regional (spine and pelvis) bone mineral content of rats were measured under basal conditions and at the end of the treatment period by dual-energy X-ray absorptiometry (DXA) scanning. Femur weights and serum concentrations of pyridinoline, a reliable marker of bone resorption, were measured at the end of the study period. Cyclosporin A-, L-NAME-, and cyclosporin A+L-NAME-treated rats had significantly lower bone mineral content and femur weights, and significantly higher pyridinoline levels than did control animals. The administration of L-arginine appeared to prevent bone loss caused by cyclosporin A, suggesting that this amino acid, which can be converted to produce NO, might prove useful in preventing disturbed bone modeling and inhibition of bone growth associated with cyclosporin A therapy. PMID:11090650

  7. Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

    PubMed Central

    Lim, Sun Woo; Doh, Kyoung Chan; Jin, Long; Piao, Shang Guo; Heo, Seong Beom; Zheng, Yu Fen; Bae, Soo Kyung; Chung, Byung Ha; Yang, Chul Woo

    2013-01-01

    Background This study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury. Methods Mice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, β cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2′-deoxyguanosine in serum, tissue sections, and culture media. Results Four weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic β cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic β cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2′-deoxyguanosine in pancreatic β cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine. Conclusions The results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic β cell injury via reducing oxidative stress. PMID:24009697

  8. Investigation of developmental toxicity and teratogenicity of cyclosporine A, tacrolimus and their combinations with prednisolone.

    PubMed

    Unver Dogan, Nadire; Uysal, Ismihan Ilknur; Fazliogullari, Zeliha; Karabulut, Ahmet Kagan; Acar, Hasan

    2016-06-01

    In this study, it was aimed to investigate the toxic and teratogenic effects of cyclosporine A and tacrolimus and their combinations with prednisolone using an in vitro rat embryo culture technique. Cyclosporine A (4-40 μg/ml), tacrolimus (1-20 μg/ml) and combinations of these drugs with prednisolone (20 μg/ml) at different concentrations were tested. Cyclosporine A and its combination with prednisolone were determined to have toxic effects on embryonic growth after 10 μg/ml. When used alone, the lowest dose of tacrolimus had embryotoxic effects on the total morphological score and number of somites. It was determined that cyclosporine A caused hematoma at 4 μg/ml and higher doses, and tacrolimus especially at 20 μg/ml caused an open neural tube beside hematoma. It was observed that cyclosporine A at 40 μg/ml dose initiated apoptotic effects at a very low rate, prednisolone increased this effect, tacrolimus led to excessive apoptosis after 15 μg/ml, and this effect did not change with prednisolone supplement. We are of the opinion that the doses should be determined carefully when cyclosporine A and tacrolimus are required to be administered to pregnant women with prednisolone combination, as prednisolone increases the toxic effects of cyclosporine A, and increases teratogenic effects of tacrolimus. PMID:26993750

  9. Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis.

    PubMed

    Rubin, Michael; Rao, Sanjay N

    2006-02-01

    We assessed the efficacy of topical cyclosporin 0.05% ophthalmic emulsion versus tobramycin 0.3%/dexamethasone 0.1% in patients with posterior blepharitis. Posterior blepharitis improved significantly from the initial study visit with both cyclosporin treatment and tobramycin/dexamethasone. Cyclosporin provided greater improvements in Schirmer's scores (P < 0.001) and tear break-up time (P = 0.018) than tobramycin/dexamethasone after 12 weeks of treatment. Eyelid health also improved in both groups, but the mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin than with tobramycin/dexamethasone (P = 0.015). Moreover, a higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision, burning, and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia. The findings in this prospective study suggest that posterior blepharitis can be more effectively treated with cyclosporin than with tobramycin/dexamethasone. These findings should be further evaluated in large-scale, controlled, clinical trials. PMID:16503775

  10. Prolonged heart xenograft survival using combined total lymphoid irradiation and cyclosporine

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Saad, T.; Bollinger, R.R.

    1986-05-01

    Total lymphoid irradiation and cyclosporine have profound immunosuppressive properties and permit successful heart allotransplantation. Cyclosporine used alone has not permitted consistently successful transplantation between species in all cases. Total lymphoid irradiation has not been applied to xenotransplantation. The efficacy of total lymphoid irradiation alone and in combination with cyclosporine was examined using an animal model of heart xenotransplantation. Heterotopic heart transplants were performed using inbred Syrian hamsters as donors and Lewis rats as recipients. Total lymphoid irradiation was administered preoperatively over 3 weeks for a total dose of 15 gray. Cyclosporine was started on the day of surgery and was given as a daily intramuscular injection of 2.5, 5, or 10 mg/kg/day until rejection was complete. Neither total lymphoid irradiation nor cyclosporine alone markedly prolonged graft survival. However, combined total lymphoid irradiation and cyclosporine, 5 or 10 mg/kg/day, dramatically prolonged graft survival to greater than 100 days in most recipients. There were no treatment-related deaths. In conclusion, combined total lymphoid irradiation and cyclosporine permit successful long-term survival of heart xenotransplants in this hamster-to-rat model.

  11. Pharmacokinetic interaction studies of fenugreek with CYP3A substrates cyclosporine and carbamazepine.

    PubMed

    Al-Jenoobi, Fahad I; Alam, Mohd Aftab; Alkharfy, Khalid M; Al-Suwayeh, Saleh A; Korashy, Hesham M; Al-Mohizea, Abdullah M; Iqbal, Muzaffar; Ahad, Abdul; Raish, Mohammad

    2014-06-01

    The present study investigated the effect of fenugreek seed powder on disposition of CYP3A substrates, cyclosporine and carbamazepine. Rabbits were treated with fenugreek seed powder (300 mg/kg p.o.) for 8 days and on 8th day the single dose of cyclosporine (30 mg/kg, p.o.) and carbamazepine (40 mg/kg, p.o.) were administered to the corresponding group after 1 h of fenugreek administration. Blood samples were drawn at several time points and analyzed by using UPLC-MS (cyclosporine) and HPLC (carbamazepine). Pharmacokinetic parameters were calculated by using PK Solver. The present investigation reveals that there was no statistically significant difference between pre- and post-treated pharmacokinetic parameters such as AUC(o-t), AUC(o-∞), C(max), T(max), T(1/2), K(el), MRT(o-∞) , V(z/F), and Cl/F for cyclosporine and carbamazepine. Two tailed "P" values for all these pharmacokinetic parameters were more than 0.05, indicating insignificant impact of fenugreek treatment on the disposition of cyclosporine and carbamazepine. Further, fenugreek may also not have any significant effect on the functionality of P-glycoprotein as cyclosporine is a substrate to P-glycoprotein. The outcomes of present study suggested that fenugreek may not likely to interfere cyclosporine and carbamazepine pharmacokinetics, when co-administered with these drugs. PMID:24022709

  12. Cyclosporine A stimulated hair growth from mouse vibrissae follicles in an organ culture model

    PubMed Central

    Xu, Wenrong; Fan, Weixin; Yao, Kun

    2012-01-01

    Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy. It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice. In the present study, to explore the mechanisms of cyclosporine A, we investigated the effects of cyclosporine A on hair shaft elongation, hair follicle cell proliferation, apoptosis, and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae. In this model, cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation. In addition, cyclosporine A caused an increase in the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and nerve growth factor (NGF), and inhibited follistatin expression. Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth. The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth. PMID:23554774

  13. Immunotoxic effects of cyclophosphamide and cyclosporine in the dog.

    PubMed

    Legrand, Jean-Jacques; Bouchez, Caroline; Mimouni, Cécile; N'Guyen, Armelle; Bouchard, Johanne; Ameller, Thibault; Descotes, Jacques

    2013-01-01

    Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5 mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM and anti-KLH IgG levels in blood samples taken pre-test, on Days 18 and 23, and pre-test, on Days 23 and 28, respectively. At the end of the treatment period, all animals were submitted to histological examination of lymphoid organs, liver, and kidneys. No signs of marked toxicity were observed. No changes in lymphocyte subsets, but markedly decreased primary anti-KLH IgM and IgG responses, and a slightly-to-markedly increased cortex/medulla ratio in the thymus were observed in cyclosporine-treated dogs. Lower total WBC counts correlating with lower total and B-lymphocyte subset and decreased germinal center development in mesenteric lymph nodes, but no changes in primary anti-KLH IgM and IgG responses were observed in cyclophosphamide-treated dogs. These results demonstrate that widely accepted immunotoxicity endpoints can adequately detect the effects of known immunosuppressive drugs in the dog and support the conclusion that it is a relevant animal species

  14. Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.

    PubMed Central

    Krüger, H U; Schuler, U; Proksch, B; Göbel, M; Ehninger, G

    1990-01-01

    The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination. PMID:2203301

  15. S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

    PubMed

    Albengres, E; Le Louët, H; d'Athis, P; Tillement, J P

    2001-02-01

    S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant. PMID:11468012

  16. Conformational Heterogeneity of Cyclosporin A in Cyclophilin 18 Binding

    PubMed Central

    Lin, Weilin; Quintero, Andres; Zhang, Yixin

    2016-01-01

    The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of kon value (8.34 ± 0.22 x106 M-1s-1) in solution. Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition. PMID:27082870

  17. Partial response to cyclosporine in a patient with Schnitzler's syndrome.

    PubMed

    Carbone, J; Paravisini, A; Sarmiento, E; Rodríguez-Molina, J; Fernández-Cruz, E

    2007-01-01

    Schnitzler's syndrome is an unusual clinical association of chronic urticaria, intermittent fever and monoclonal immunoglobulin M (IgM) gammopathy. The pathogenesis of the urticaria is unclear and treatment is problematic. We describe the case of a 61-year-old woman with a long history of chronic urticaria with severe pruritus, spiking fever and malaise. The IgM-kappa monoclonal component was detected in the patient's serum 4 years after symptom onset. After ineffective treatment with antihistamines and systemic corticosteroids, oral cyclosporine resulted in complete remission of the fever and malaise, which has persisted after an 18-month follow-up. Partial but maintained remission of the urticaria was also observed, allowing corticosteroid doses to be decreased. PMID:17428403

  18. Modern approaches to the ocular delivery of cyclosporine A.

    PubMed

    Agarwal, Priyanka; Rupenthal, Ilva D

    2016-06-01

    Cyclosporine A (CsA) has long been the mainstay treatment for dry eye syndrome (DES), one of the most common disorders of the eye. However, the poor water solubility of CsA renders it difficult to formulate it into topical ocular dosage forms. Restasis® is currently the only US Food and Drug Administration (FDA)-approved CsA formulation, while Ikervis® has recently been launched in Europe, with both commonly associated with severe ocular discomfort. Therefore, several CsA formulations have been investigated with the aim to improve bioavailability while reducing adverse effects associated with the marketed formulations. In this review, we summarize recent advances in ocular CsA delivery that provide safer and more effective alternatives for the management of DES and other ocular inflammatory conditions. PMID:27080149

  19. Posterior encephalopathy subsequent to cyclosporin A presenting as irreversible abulia.

    PubMed

    Nishie, Makoto; Kurahashi, Kozo; Ogawa, Masaya; Yoshida, Yasuji; Midorikawa, Hiroshi

    2003-08-01

    A case of cyclosporin A (Cys A)-induced posterior encephalopathy developed into persistent abulia despite rapid and marked improvement of abnormal T2- and FLAIR MRI hyperintense regions. Diffusion-weighted MRI signal intensity was also high at the onset. This change is atypical in Cys A-induced encephalopathy and was thought to predict poor recovery from the encephalopathy. Persistent abulia was probably due to marked hypoperfusion in the whole cortex including bilateral frontal lobes and basal ganglia as detected by SPECT. Apart from the breakdown of the blood-brain barrier, direct toxicity of Cys A to the brain may play a role in the pathogenesis of chronic, irreversible encephalopathy. PMID:12924507

  20. Treatment of chronic dry eye: focus on cyclosporine

    PubMed Central

    Kymionis, George D; Bouzoukis, Dimitrios I; Diakonis, Vassilios F; Siganos, Charalambos

    2008-01-01

    To review the current treatment of chronic dry eye syndrome, focusing on cyclosporine A (CsA), a systematic literature search was performed using PubMed databases in two steps. The first step was oriented to articles published for dry eye. The second step was focused on the use of CsA in dry eye. A manual literature search was also undertaken based on citations in the published articles. The knowledge on the pathogenesis of dry eye syndrome has changed dramatically during the last few years. Inflammation and the interruption of the inflammatory cascade seem to be the main focus of the ophthalmologic community in the treatment of dry eye, giving the anti-inflammatory therapy a new critical role. The infiltration of T-cells in the conjuctiva tissue and the presence of cytokines and proteasis in the tear fluid were the main reason introducing the use of immunomodulator agents such as corticosteroids, cyclosporine, and doxycicline in order to treat dry eye syndrome. CsA emulsion is approved by the FDA for the treatment of dry eye, while clinical trials of this agent have demonstrated efficacy and safety of CsA. CsA seems to be a promising treatment against dry eye disease. New agents focused on the inflammatory pathogenesis of this syndrome in combination with CsA may be the future in the quest of treating dry eye. More studies are needed to determine the efficacy, safety, timing, and relative cost/effect of CsA. PMID:19668437

  1. Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine.

    PubMed Central

    Hiestand, P C; Mekler, P; Nordmann, R; Grieder, A; Permmongkol, C

    1986-01-01

    Lymphocyte responsiveness in rats was found to depend on serum prolactin levels. Blocking pituitary prolactin release with bromocriptine severely reduces lymphocyte reactivity in vitro (mixed lymphocyte reaction) as well as in vivo (graft-versus-host reaction). In addition, evidence for a prolactin/growth hormone-related mRNA species produced in mitogen- and antigen-stimulated lymphocytes has been obtained. Prolactin was shown to compete in a dose-dependent fashion with the immunosuppressant cyclosporine (cyclosporin A) for a common binding site on the surface of T lymphocytes. Further, stimulation of prolactin secretion reversed the immunosuppression induced by cyclosporine. We conclude that prolactin is involved in the maintenance of T-cell immunocompetence and that the immunosuppressive effects of cyclosporine may be mediated by the displacement of prolactin from binding sites on lymphocytes. Images PMID:2939454

  2. Cyclosporin A-mediated cholestasis in patients with chronic hepatitis after heart transplantation.

    PubMed

    Myara, A; Cadranel, J F; Dorent, R; Lunel, F; Bouvier, E; Gerhardt, M; Bernard, B; Ghoussoub, J J; Cabrol, A; Gandjbakhch, I; Opolon, P; Trivin, F

    1996-03-01

    Viral chronic hepatitis often occurs in heart transplant recipients receiving cyclosporin. This essential immunosuppressive drug may induce cholestasis. We investigated the effect of treatment with cyclosporin on serum conjugated bile acids in patients with chronic hepatitis developing after heart transplantation. Fifty-nine patients were studied: 17 with chronic hepatitis, 15 heart transplant patients with normal alanine aminotransferase activity, and 27 heart transplant patients with chronic hepatitis, the last two groups receiving cyclosporin. Hepatic biochemical tests and total bile acid concentration were determined on fasting blood samples. The individual glyco- and tauroconjugated bile acids were quantified by high-performance liquid chromatography and direct spectrometry. In patients taking cyclosporin the bilirubin concentration and the alkaline phosphatase activity were increased only when hepatitis was present, in association with a slight increase in cholic acid level (5.13 microM vs. 0.68 microM; P < 0.01). Conjugated lithocholate concentration was dramatically higher when hepatitis and immunosuppression with cyclosporin were associated (1.17 microM vs. 0.03 and 0.04 microM; P < 0.01). Chenodeoxycholate was the main circulating bile acid only in the heart transplant patients treated with cyclosporin but without hepatitis. These results suggest that the mechanisms which explain the cyclosporin-associated modifications of the bile acid pool are different according to the presence or absence of hepatitis. The occurrence of hepatitis in patients on cyclosporin led to an increase in serum lithocholate and primary bile acid concentrations. Further studies are required to assess the effect of ursodeoxycholic acid for this cholestasis. PMID:8724029

  3. [Pharmacological modulation of mitochondrial oxidative phosphorylation: inhibition by cyclosporine A, restoration by trimetazidine].

    PubMed

    Tillement, J P; Crevat, A; Testa, B; Le Ridant, A

    1996-01-01

    When applied to a suspension of isolated mitochondria extracted from rat hepatocytes, cyclosporine A decreases ATP synthesis and induces Ca2+ accumulation. Both effects are considered as possible determinants, even partly, of renal toxicity observed with this drug. Trimetazidine antagonizes both effects at concentrations easily reached in man with therapeutic dosages. It is concluded that the association of both drugs may improve the renal tolerance of Cyclosporine A. PMID:9008901

  4. Risks and benefits of low-dosage cyclosporin in rheumatoid arthritis.

    PubMed

    Pasero, G; Ferraccioli, G F; Portioli, I

    1997-05-01

    The effects of cyclosporin on the activity of rheumatoid arthritis have mainly been investigated in patients with active, refractory, long-standing disease. The data obtained in these trials suggest that cyclosporin is not only a symptomatic treatment for rheumatoid arthritis but can also be considered a disease-modifying antirheumatic drug (DMARD), since it seems to be capable of slowing the progression of cartilage and bone damage due to rheumatoid arthritis. The trials conducted so far have led to a better understanding of cyclosporin toxicity and, therefore, to better monitoring of patients in order to avoid it. The reasons for studying the role of cyclosporin in patients with early, active and potentially severe rheumatoid arthritis are the poor prognosis of the disease despite the use of the presently available DMARDs, and the hypothesis that the drug is more efficacious and better tolerated in early rheumatoid arthritis. A new classification of antirheumatic drugs proposes that disease-controlling antirheumatic therapies decrease inflammatory synovitis and prevent structural joint damage or significantly reduce its rate of progression. However, few existing drugs meet these criteria. The 12-month results of a disease-controlling antirheumatic therapy clinical trial with a blinded radiological end-point, named GRISAR (Gruppo Reumatologi Italiani Studio Artrite Reumatoide) comparing cyclosporin with conventional DMARDs in patients with early rheumatoid arthritis provide strong evidence that cyclosporin offers better control of ongoing joint damage than do conventional DMARDs. PMID:18031101

  5. The NMR structure of cyclosporin A bound to cyclophilin in aqueous solution

    SciTech Connect

    Weber, C.; Wilder, G.; von Freyberg, B.; Braun, W.; Wuethrich, K. ); Traber, R.; Widmer, H. )

    1991-07-02

    Cyclosporin A bound to the presumed receptor protein cyclophilin was studied in aqueous solution at pH 6.0 by nuclear magnetic resonance spectroscopy using uniform {sup 15}N- or {sup 13}C-labeling of cyclosporin A and heteronuclear spectral editing techniques. With an input of 108 intramolecular NOEs and four vicinal {sup 3}J{sub HN{alpha}} coupling constants, the three-dimensional structure of cyclosporin A bound to cyclophilin was calculated with the distance geometry program DISMAN, and the structures resulting from 181 converged calculations were energy refined with the program FANTOM. A group of 120 conformers was selected on the basis of the residual constraint violations and energy criteria to represent the solution structure. The average of the pairwise root-mean-square distances calculated for the backbone atoms of the 120 structures was 0.58 {angstrom}. The structure represents a novel conformation of cyclosporin A, for which the backbone conformation is significantly different from the previously reported structures in single crystals and in chloroform solution. The structure has all peptide bonds in the trans form, contains no elements of regular secondary structure and no intramolecular hydrogen bonds, and exposes nearly all polar groups to its environment. The root-mean-square distance between the backbone atoms of the crystal structure of cyclosporin A and the mean of the 120 conformers representing the NMR structure of cyclosporin A bound to cyclophilin is 2.5 {angstrom}.

  6. Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

    PubMed

    Dixon, C Edward; Bramlett, Helen M; Dietrich, W Dalton; Shear, Deborah A; Yan, Hong Q; Deng-Bryant, Ying; Mondello, Stefania; Wang, Kevin K W; Hayes, Ronald L; Empey, Philip E; Povlishock, John T; Tortella, Frank C; Kochanek, Patrick M

    2016-03-15

    Operation Brain Trauma Therapy (OBTT) is a consortium of investigators using multiple pre-clinical models of traumatic brain injury (TBI) to bring acute therapies to clinical trials. To screen therapies, we used three rat models (parasagittal fluid percussion injury [FPI], controlled cortical impact [CCI], and penetrating ballistic-like brain injury [PBBI]). We report results of the third therapy (cyclosporin-A; cyclosporine; [CsA]) tested by OBTT. At each site, rats were randomized to treatment with an identical regimen (TBI + vehicle, TBI + CsA [10 mg/kg], or TBI + CsA [20 mg/kg] given intravenously at 15 min and 24 h after injury, and sham). We assessed motor and Morris water maze (MWM) tasks over 3 weeks after TBI and lesion volume and hemispheric tissue loss at 21 days. In FPI, CsA (10 mg/kg) produced histological protection, but 20 mg/kg worsened working memory. In CCI, CsA (20 mg/kg) impaired MWM performance; surprisingly, neither dose showed benefit on any outcome. After PBBI, neither dose produced benefit on any outcome, and mortality was increased (20 mg/kg) partly caused by the solvent vehicle. In OBTT, CsA produced complex effects with histological protection at the lowest dose in the least severe model (FPI), but only deleterious effects as model severity increased (CCI and PBBI). Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No positive treatment effects were seen on biomarker levels in any of the models, whereas significant increases in 24 h UCH-L1 levels were seen with CsA (20 mg/kg) after CCI and 24 h GFAP levels in both CsA treated groups in the PBBI model. Lack of behavioral protection in any model, indicators of toxicity, and a narrow therapeutic index reduce enthusiasm for clinical translation. PMID:26671075

  7. The in vivo effect of cyclosporine A on macrophages.

    PubMed

    Matsushima, Y; Baba, T

    1990-01-01

    The macrophage disappearance reaction (MDR) was induced when muramyl dipeptide (MDP) was injected intraperitoneally into guinea pigs bearing macrophage-rich peritoneal exudate cells. Heparin could inhibit the MDR induced by MDP. In the present study, we tested the effect of the immunosuppressive agent cyclosporine A (CsA) on MDR. The MDR was significantly suppressed in guinea pigs given 20 or 100 mg/kg of CsA, although 5 mg/kg of CsA had no effect. The number of macrophages elicited by liquid paraffin was significantly reduced in guinea pigs given with 20 or 100 mg/kg of CsA, but not in those given 5 mg/kg of CsA. These results indicate that CsA could directly affect macrophages in vivo, through a relatively high dose was required. Cyclosporine A (CsA), a cyclic peptide of 11 amino acids, is a fungal metabolite with potent immunosuppressive properties. Numerous experimental and clinical trials have demonstrated its effectiveness in organ transplantation. It has been suggested that primary target cells of CsA were T-lymphocytes, and macrophages were not directly affected. However, recent studies in an in vitro system have shown that some functions of macrophage are affected by CsA. These include chemotaxis (Drath & Kahan, 1983), interleukin-1 generation (Bunjes et al., 1981), prostaglandin E production (Whisler et al., 1984) and procoagulant activity (Carlsen et al., 1985). However, the effect of CsA on macrophages has not been elucidated in vivo. The macrophage disappearance reaction (MDR) is an in vivo manifestation of cell-mediated immunity and/or delayed type hypersensitivity (Sonozaki et al., 1975). Furthermore, our previous study demonstrated a possibility that MDR was an in vivo manifestation of macrophage activation (Ochiya et al., 1982). Muramyl dipeptide (MDP; N-acetyl-muramyl-L-alanyl-D-isoglutamine), a synthetic analogue of water soluble components of bacterial cell wall peptidoglycans, is known to have the ability to activate macrophages (Nagao et al

  8. Cyclosporin A renders target cells resistant to immune cytolysis.

    PubMed

    Hudnall, S D

    1991-01-01

    Exposure of cytolytically susceptible human target cells with therapeutic concentrations of the immunosuppressive drug cyclosporin A renders these cells highly resistant to T cell-mediated, natural killer (NK) cell-mediated, and complement-mediated cytolysis. The resistance is dose dependent, time dependent and reversible. The resistance is accompanied by target cell growth inhibition as measured by thymidine uptake. Surprisingly, target cell growth inhibition induced by serum depletion is associated with cell-mediated cytolytic resistance. These data suggest that cyclosporin A (CsA) may block some target cell biochemical pathway(s) important in the suicidal cytolytic process which is (are) linked to some G0/G1 cell cycle events. In addition, these results suggest that the increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in human organ transplant recipients may be contributed to by CsA-induced resistance of EBV-transformed B lymphocytes to immune cytolysis. In the post-transplant setting, CsA probably blocks T cell-dependent responses to EBV-transformed B lymphocytes (Bird, A.G., McLachlan, S.M. and Britton, S., Nature 1981, 289: 300) yet leaving the NK cell and antibody-dependent responses intact (Shao-Hsien, C. et al. Transplantation 1983. 35: 127). However, given the direct effect of CsA upon EBV-transformed B lymphocytes, these cells would be rendered resistant to nearly all forms of cytolytic immune control (cytotoxic T lymphocyte, natural killer, antibody-dependent cell-mediated cytotoxicity, complement). Unregulated EBV-transformed B lymphocytes may then proliferate in the CsA-treated host thus leading to a polyclonal B cell hyperplasia. Our data would suggest that this early pre-malignant process is likely to be reversible following CsA dose reduction. Indeed, EBV-dependent polyclonal B cell hyperplasia is seen in early post-transplant lymphoproliferative disorders (Hanto, D.W., et al., Transplantation 1989, 47: 458

  9. Infliximab versus Cyclosporine Treatment for Severe Corticosteroid-Refractory Ulcerative Colitis: A Korean, Retrospective, Single Center Study

    PubMed Central

    Kim, Eun Hye; Kim, Duk Hwan; Park, Soo Jung; Hong, Sung Pil; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee

    2015-01-01

    Background/Aims In patients with corticosteroid-refractory ulcerative colitis (UC), cyclosporine or infliximab may be added to the treatment regimen to induce remission. Here, we aimed to compare the efficacy of cyclosporine and infliximab. Methods Between January 1995 and May 2012, the medical records of 43 patients with corticosteroid-refractory UC who received either infliximab or cyclosporine as a rescue therapy at a tertiary care hospital in Korea were reviewed. Results Among the 43 patients, 10 underwent rescue therapy with cyclosporine and the remaining 33 patients received infliximab. A follow-up of 12 months was completed for all patients. The colectomy rate at 12 months was 30% and 3% in the cyclosporine and the infliximab groups, respectively (p=0.034). However, the Cox proportional hazard model indicated that the treatment of rescue therapy was not an independent associate factor for preventing colectomy (p=0.164). In the subgroup analysis, infliximab with azathioprine was superior to cyclosporine for preventing colectomy (hazard ratio of infliximab with azathioprine compared with cyclosporine only, 0.073; 95% confidence interval, 0.008 to 0.629). Conclusions No difference between infliximab and cyclosporine with respect to preventing colectomy was noted. However, infliximab with azathioprine may be more effective than cyclosporine alone for preventing colectomy. PMID:25473080

  10. Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding.

    PubMed

    Nagao, Kohjiro; Maeda, Minami; Mañucat, Noralyn B; Ueda, Kazumitsu

    2013-02-01

    ATP-binding cassette protein A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL). However, the detailed mechanism of HDL formation remains unclear; in order to reveal it, chemicals that specifically block each step of HDL formation would be useful. Cyclosporine A inhibits ABCA1-mediated cholesterol efflux, but it is not clear whether this is mediated via inhibition of calcineurin. We analyzed the effects of cyclosporine A and related compounds on ABCA1 function in BHK/ABCA1 cells. Cyclosporine A, FK506, and pimecrolimus inhibited ABCA1-mediated cholesterol efflux in a concentration-dependent manner, with IC(50) of 7.6, 13.6, and 7.0μM, respectively. An mTOR inhibitor, rapamycin also inhibited ABCA1, with IC(50) of 18.8μM. The primary targets for these drugs were inhibited at much lower concentrations in BHK/ABCA1 cells, suggesting that they were not involved. Binding of [(3)H] cyclosporine A to purified ABCA1 could be clearly detected. Furthermore, a non-immunosuppressive cyclosporine, PSC833, inhibited ABCA1-mediated cholesterol efflux with IC(50) of 1.9μM, and efficiently competed with [(3)H] cyclosporine A binding to ABCA1. These results indicate that cyclosporine A and PSC833 inhibit ABCA1 via direct binding, and that the ABCA1 inhibitor PSC833 is an excellent candidate for further investigations of the detailed mechanisms underlying formation of HDL. PMID:23153588

  11. Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

    PubMed

    Simon, N; Tillement, J P; Albengres, E; Jaber, K; Hestin, D; Roux, F; Olivier, P; d'Athis, P; Kessler, M; Berland, Y; Crevat, A

    1997-01-01

    Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection. PMID:9526174

  12. Alterations in rat pulmonary macrophage function by the immunosuppressive agents cyclosporine, azathioprine, and prednisolone.

    PubMed

    Drath, D B; Kahan, B D

    1983-06-01

    Disturbances of the immune response of the lung induced by the action of immunosuppressive agents on the functional abilities of rat pulmonary alveolar macrophages (PAM) were analyzed following in vitro incubation or in vivo administration (for 30 days) of cyclosporinea, (CsA) azathioprine (Az) or prednisolone (Pr). Two major parameters were analyzed: oxygen consumption and superoxide release as indices of the overall state of oxygen metabolism of these cells reflecting the integrity of PAM oxidative mechanisms of microbicidal activity, and chemotaxis, an event clinically important for normal defense to infection. In vitro incubation with cyclosporine at concentrations as low as 10(-9) M caused a 52% inhibition of PAM superoxide release, but Az had no effect at concentrations up to 10(-6) M. Prednisolone caused a 38% inhibition of superoxide release; comparable levels of inhibition with Pr required concentrations at least 10-fold greater than with cyclosporine. Further experiments indicated that cyclosporine induced a 40% inhibition after contact with PAM for only 30 min. In vivo experiments indicated that cyclosporine (5 mg/kg), Az (20 mg/kg), or Pr (2 or 0.5 mg/kg) administered intraperitoneally had no effect on the number of PAM available for host defense, PAM oxygen consumption, or PAM superoxide release. However, PAM from cyclosporine-treated animals demonstrated complete inhibition of active migration or chemotaxis in modified Boyden chambers upon incubation with formylmethionyl-leucyl-phenylalanine (FMLP). The effect was apparently dampened by simultaneous administration of Pr with cyclosporine. These experiments suggest that with the exception of a marked effect on chemotaxis the in vivo effects of physiologic amounts of cyclosporine on PAM function are modest compared with the marked depression after in vitro addition. PMID:6306880

  13. Exposure to Nerve Growth Factor Worsens Nephrotoxic Effect Induced by Cyclosporine A in HK-2 Cells

    PubMed Central

    Lofaro, Danilo; Toteda, Giuseppina; Lupinacci, Simona; Leone, Francesca; Gigliotti, Paolo; Papalia, Teresa; Bonofiglio, Renzo

    2013-01-01

    Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkANTR and p75NTR. Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 NTR and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75NTR down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A. PMID:24244623

  14. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis

    PubMed Central

    Danieli, M; Malcangi, G; Palmieri, C; Logullo, F; Salvi, A; Piani, M; Danieli, G

    2002-01-01

    Objective: To describe the treatment of polymyositis (PM) and dermatomyositis (DM) with prednisone (PRED) and cyclosporin A (CSA) alone or associated with intravenous immunoglobulin (IVIg) and plasmapheresis (PEX). Methods: Between 1992 and 1999 CSA and PRED were used to treat 20 patients with idiopathic myositis (12 with DM, eight with PM), diagnosed according to the Bohan and Peter criteria. In patients with refractory or relapsed disease, IVIg was added alone (seven cases) or synchronised with PEX (six cases). A standardised protocol was used to evaluate the patients, and assess disease activity and treatment response. Results: Despite a transient response to PRED and CSA in 16/20 cases, this combination did not induce full remission in 13/20 cases, which led to the IVIg trial with or without PEX. Patients receiving PRED and CSA plus IVIg had a significantly higher probability of maintaining complete remission at the end of the four year follow up period than those treated with PRED and CSA alone (p<0.001). No further benefit was added by the PEX. The presence of arthritis significantly correlated with a poorer response to treatment (p<0.05). Adverse effects were gingival hyperplasia (one patient) and transient renal dysfunction (one). Conclusions: This open study suggests that combined treatment with PRED, CSA, and IVIg is useful in patients with myositis, even those with refractory or relapsed disease; no increase in the number or type of side effects is seen. PMID:11779756

  15. Supersaturated polymeric micelles for oral cyclosporine A delivery.

    PubMed

    Yu, Hongzhen; Xia, Dengning; Zhu, Quanlei; Zhu, Chunliu; Chen, Dan; Gan, Yong

    2013-11-01

    Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81-3.53 (p < 0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6 ± 24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption. PMID:23954511

  16. Exacerbation of allergic contact dermatitis during immunosuppression with cyclosporine A.

    PubMed

    Prignano, F; Bonciolini, V; Bonciani, D; Lotti, T

    2010-08-01

    Allergic contact dermatitis (ACD) is one of the commonest occupational diseases in industrialized countries, where it comprises 20-70% of all occupational diseases. Recent studies found out the top ten allergens, but there are some differences in their frequency in relation to gender and age of patients: Myroxylon pereirae and Carba mix resulted the most prevalent allergens in men, while in women the most common sensitizers were nickel sulfate, PPD, fragrance mix and cobalt chloride. ACD is an inflammatory skin disease caused by repeated skin exposure to contact allergens, in which the lesions are due to T CD8+ cells in a type IV, delayed or cell-mediated, immune reaction. The typical skin lesions of ACD in general outburst in contact areas with the specific allergens and they are erythematosus-squamous lesions with other little differences in relation to localization, for example edema, vesicular-exuding lesions or onychodystrophy. Different treatment options exist and are applied according to the severity of the lesions. Topical treatments consist of bland emollients, corticosteroids ointments, topical immunomodulators such as tacrolimus and pimecrolimus ointments, coal tar and derivatives and irradiation with ultraviolet lights or X-rays; while azathioprine, methotrexate, cyclosporine A, oral retinoids or oral corticosteroids represent systemic options of therapy. Nevertheless, the control of chronic ACD is often difficult, overall in patients with chronic ACD. PMID:20823796

  17. Amelioration of cyclosporine induced nephrotoxicity by dipeptidyl peptidase inhibitor vildagliptin.

    PubMed

    Ateyya, Hayam

    2015-09-01

    Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases but its clinical uses may be limited due to its dose-related nephrotoxicity. This study was carried out to evaluate the possible protective effects of vildagliptin (VLD) against CsA-induced nephrotoxicity in rats. Animals were divided into four groups treated as follows: control group (CsA & VLD vehicle); VLD group (10mg/kg/day, orally); CsA group (20mg/kg in sunflower oil, S.C.); and CsA-VLD group (CsA &VLD). Induced nephrotoxicity was evidenced by a significant elevation of serum creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and urinary micro total proteins (MTP), while serum albumin and urinary creatinine clearance were significantly decreased compared to the control group. Moreover, renal dysfunction was further confirmed by a significant increase in renal lipid peroxide that was measured as renal malondialdehyde (MDA). Renal reduced glutathione (GSH) and superoxide dismutase (SOD) were significantly decreased. Nephrotoxicity was further confirmed by renal tissue histopathology. Also, a high protein expression of Bax with decreased Bcl-2 was revealed in the renal tissue of the CsA treated group. Administration of VLD significantly ameliorated the nephrotoxic effects of CsA suggesting antioxidant, anti-inflammatory and anti-apoptotic benefits of VLD in CsA-induced nephrotoxicity. PMID:26225924

  18. [Topical cyclosporine in ophthalmology: Pharmacology and clinical indications].

    PubMed

    Levy, O; Labbé, A; Borderie, V; Laroche, L; Bouheraoua, N

    2016-03-01

    Cyclosporine A (CsA) is a cyclic undecapeptide, which is an immunosuppressive drug in the calcineurin inhibitor class. CsA was initially used as a systemic immunosuppressant to minimize rejection of solid organ transplants. In ophthalmology, topically applied CsA was first used to inhibit corneal allograft rejection in the 1980s and later in various inflammatory ocular surface disorders (OSD). Currently, topical ophthalmic CsA is available as a licensed commercial emulsion or is prepared by hospital pharmacies with concentration ranging from 0.05 to 2%. Many of its pharmacological effects on the ocular surface are direct consequences of its ability to inhibit T ciclosporine activation and apoptosis. Topical CsA differs from topical steroids in its favourable local and systemic tolerability at the concentrations used. Most clinical studies have evaluated topical CsA in moderate to severe dry eye disease (DED) and demonstrated its efficacy for improvement of signs and symptoms, thus providing the sole indication for market approval and treatment protocols. For the other indications - corneal graft rejection, blepharitis, allergic or viral keratitis, and ocular surface disease due to graft versus host disease or post-operative DED - evidence-based medicine remains unclear due to the lack of major randomized controlled trials. Despite the lack of standardized protocols or market approval for these conditions, numerous studies suggest clinical efficacy. PMID:26997607

  19. Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation

    PubMed Central

    Li, Xuejuan; Ding, Fangrui; Wang, Suxia; Li, Baihong; Ding, Jie

    2015-01-01

    Accumulating evidence suggests that podocytes are direct targets of many classic antiproteinuric drugs. The immunosuppressive drug cyclosporine A (CsA), which is a calcineurin inhibitor, is used to treat proteinuric kidney diseases. One novel mechanism by which CsA reduces proteinuria is by directly stabilizing the podocyte cytoskeleton. Previous studies showed that calcineurin can directly regulate WAVE1 within mouse striatal slices. In this study, WAVE1 was expressed in podocytes and was localized in the podocyte cell bodies and foot processes (FPs). WAVE1 expression increased in both in vivo and in vitro models of puromycin aminonucleoside (PAN)-induced podocyte injury. CsA restored WAVE1 expression and also partially rescued the disordered F-actin arrangement after PAN injury. Co-immunoprecipitation assays showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes. Synaptopodin is a well-characterized target of CsA. WAVE1 overexpression and synaptopodin knockdown experiments directly demonstrated that WAVE1 expression is not dependent on synaptopodin expression, and vice versa. Overexpression of WAVE1 using a WAVE1 plasmid disrupted F-actin structure and promoted podocyte migration compared with the empty vector group. Therefore, WAVE1 may be a novel molecular target for the maintenance of podocyte FPs and for antiproteinuric treatment in the future. PMID:26634693

  20. Effect of cyclosporin on immune complex deposition in murine glomerulonephritis.

    PubMed Central

    Quinn, D G; Fennell, J S; Sheils, O; Gaffney, E F; Feighery, C F

    1991-01-01

    Chronic glomerulonephritis (GN) was induced in N/M mice by daily injections of human serum albumin (HSA). The glomerular lesion was similar to that observed in human membranous GN and was characterized by intense mesangial and capillary loop immunofluorescent staining for HSA, IgG and C3. Electron microscopic examination revealed numerous electron-dense deposits in the mesangium and along the subepithelial side of the glomerular basement membrane, the latter deposits being associated with membranous spikes. Chronically injected mice that had been treated with cyclosporin (CsA) from Day 1 had different patterns of immune complex deposition. Mesangial deposition was apparently unaltered but no subepithelial deposits or spikes were evident. In addition, only two out of 21 HSA-injected mice which began CsA treatment on Day 21 had subepithelial deposits. There was no significant difference in serum levels of HSA-specific IgG between the three groups of mice. CsA treatment would therefore appear to ameliorate the immunopathology of antigen-induced glomerulonephritis in this model without affecting serum antibody levels, and may be of therapeutic value in the treatment of human membranous GN. Images Figure 1 Figure 2 Figure 3 PMID:1828056

  1. Cyclosporin-A efficacy in chronic idiopathic urticaria.

    PubMed

    Di Leo, E; Nettis, E; Aloia, A M; Moschetta, M; Carbonara, M; Dammacco, F; Vacca, A

    2011-01-01

    Common drugs in the therapy of chronic idiopathic urticaria (CIU) include antihistamines alone or combined with corticosteroids, but severe unresponsive patients require alternative treatments. This retrospective study aims to evaluate clinical response and safety of low-dose and long-term oral Cyclosporin-A (CyA) in unresponsive patients. One hundred and ten CIU patients, unresponsive to a previous treatment (antihistamines plus prednisone 0.2 mg/kg/day), received additional oral CyA 1–3 mg/kg/day for 6 months. The patients were subdivided into three groups (A, B, C) according to the different CyA doses. Parameters of clinical efficacy including pruritus, and size and number of wheals were evaluated at baseline, after three and six months. All adverse events were recorded. The mean total symptom severity score decreased by 63% in Group A, 76% in Group B, and 85% in Group C after 6 months. Total disappearance of the symptoms was recorded in 43 patients (39.1%): 7 (28%) of Group A; 12 (37.5%) of Group B and 24 (45%) of Group C. After a mean of 2 months from CyA suspension, 14 patients (11%) had recurrence of symptoms. Minor side effects were noted in 8 patients (7%). Our study indicates that low-dose, long-term CyA therapy is efficacious and safe in severe unresponsive CIU. PMID:21496403

  2. Pharmacokinetic and pharmacodynamic interactions of morin and cyclosporin

    SciTech Connect

    Fang, S.-H. . E-mail: shfang@mail.cmu.edu.tw; Hou, Y.-C.; Chao, P.-D.L.

    2005-05-15

    Morin is a flavonoid present in mulberry and herbs. We have reported that morin exerted anti-inflammatory activity on the activated macrophages. Cyclosporin (CsA) is a potent immunosuppressive agent with narrow therapeutic range, which is widely used for the treatments of autoimmune diseases and transplantation rejection. This study aimed to measure the effects of morin on the disposition of CsA in lymphoid and non-lymphoid tissues, and on the functions of immune cells in mice. CsA (Neoral, 10 mg/kg) was orally administered with and without a concomitant dose of morin (0, 50, 100, 200 mg/kg) to mice once daily for 2 weeks. CsA concentrations in blood, liver, kidney, and spleen were determined by a specific monoclonal fluorescence polarization immunoassay. The decreased levels of CsA in tissues were found well correlated to increased doses of morin. The coadministration of 200 mg/kg morin significantly decreased CsA in blood, liver, kidney, and spleen by 33%, 17%, 38%, and 45%, respectively. On the other hand, coadministration of morin decreased dramatically the nitric oxide production by the activated macrophages when compared to CsA treatment alone. Moreover, morin maintained the level of CsA-suppressed T helper 1 (Th1) type cytokine, although the CsA concentration in spleen was markedly reduced. In conclusion, morin coadministration profoundly reduced CsA concentration but did not significantly alter the CsA-suppressed Th1 immune response in mice.

  3. Cyclosporine therapy of aplastic anaemia, congenital and acquired red cell aplasia.

    PubMed

    Leonard, E M; Raefsky, E; Griffith, P; Kimball, J; Nienhuis, A W; Young, N S

    1989-06-01

    We treated 22 patients with severe aplastic anaemia refractory to antithymocyte globulin (ATG) with cyclosporine, alone or in combination with prednisone. Eight patients showed significant clinical improvement, all but one to transfusion-independence. Although cyclosporine alone was effective, the addition of prednisone resulted in prompter and fuller haematologic improvement. No patient with an absolute granulocyte count less than 0.2 x 10(9)/l responded to treatment. Haematologic remissions were sustained beyond the treatment period. Of nine patients with Diamond-Blackfan syndrome, one showed a complete response to two separate courses of cyclosporine and relapse with withdrawal of therapy, and a second achieved significant reduction in corticosteroid dose without relapse; however, seven cases failed to respond. Two of three adults with acquired pure red cell aplasia recovered. A combination of cyclosporine and corticosteroids may be effective therapy in patients with aplastic anaemia who have failed ATG treatment. Occasional cases of congenital and acquired pure red cell aplasia may also respond to cyclosporine. PMID:2503027

  4. Effect of cyclosporine, total lymphoid irradiation, and cobra venom factor on hyperacute rejection

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Murphy, C.E.; Saad, T.; Abernethy, K.; Miller, D.; Bollinger, R.R.

    1985-09-01

    Transplantation into sensitized recipients is contraindicated due to the potential for hyperacute rejection. In order to study the mechanism of hyperacute rejection and the role of immunosuppression in the face of presensitization, we evaluated the effect of total lymphoid irradiation, cyclosporine, and cobra venom factor, alone and in combination, on hyperacute rejection of heterotopic rat heart allografts. Lewis rats were sensitized to strongly RT-1-incompatible ACI rats by three successive skin grafts. Heart allografts were then performed, and survived for a mean period of 15.7 +/- 7.4 hours. Neither preoperative treatment of hypersensitized rats with total lymphoid irradiation alone nor with cyclosporine (5 mg/kg/day) resulted in a prolongation of survival (20.4 +/- 16.6 hours and 35.6 +/- 6.2 hours, respectively). However, complement depletion using cobra venom factor significantly prolonged mean graft survival time to 114.4 +/- 31.0 hours (p less than 0.05). Cyclosporine (10 mg/kg/day) also significantly prolonged survival to 149 +/- 29 hours (p less than 0.01), but did not lower the antibody or complement levels. The addition of total lymphoid irradiation or cyclosporine to treatment with cobra venom factor did not result in longer survival than cobra venom factor alone. In conclusion, cobra venom factor and cyclosporine delay but do not prevent hyperacute rejection, while total lymphoid irradiation has no observable effect on hyperacute rejection.

  5. Beneficial effects of nilotinib, tyrosine kinase inhibitor on cyclosporine-A induced renal damage in rats.

    PubMed

    Nader, Manar A; Attia, Ghalia M

    2016-04-01

    Nilotinib is a known tyrosine kinase inhibitor that has been approved for treatment of leukemia. The possible protective effect of nilotinib on cyclosporine A-induced nephropathy was investigated in this study and the possible underlying mechanism was explored. Nilotinib (25mg/kg, orally) and cyclosporine A (15 mg/kg/day, subcutaneous) were given to male SD rats for 28 days. Cyclosporine A alone was found to significantly increase serum creatinine, blood urea nitrogen, lactate dehydrogenase, urinary micrototal protein, renal thiobarbituric acid reactive substance, Bax, cytosol cytochrome c release and nuclear factor kappa B activation. Moreover, cyclosporine A significantly reduced serum albumin, creatinine clearance, urinary total antioxidant, superoxide dismutase, glutathione and Bcl2 protein levels. Pathological results showed that in the model group; there was an obvious shrinkage and congestion of the glomeruli and widening of urinary spaces of renal corpuscles, in addition to marked renal tubular injury and fibrosis, while in the group pretreated with nilotinib all measured serum, renal and pathological changes were significantly reduced. This protective effect of nilotinib is linked to the enhanced antioxidant status and reduced inflammation and apoptosis induced by cyclosporine A. PMID:26844915

  6. Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.

    PubMed Central

    Rosenwirth, B; Billich, A; Datema, R; Donatsch, P; Hammerschmid, F; Harrison, R; Hiestand, P; Jaksche, H; Mayer, P; Peichl, P

    1994-01-01

    (Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug. PMID:7527198

  7. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy. PMID:27610174

  8. Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury

    PubMed Central

    Mbye, Lamin HAN; Singh, Indrapal N; Carrico, Kimberly M; Saatman, Kathryn E; Hall, Edward D

    2009-01-01

    Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (α-spectrin) degradation, neurodegeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated α-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased α-spectrin breakdown products observed in vehicle-treated animals (P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days (P < 0.005) and neurodegeneration at 7 days postinjury (P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce α-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA. PMID:18714331

  9. Fibroadenomatosis involving bilateral breasts and axillary accessory breast tissues in a renal transplant recipient given cyclosporin A.

    PubMed

    Bulakci, Mesut; Gocmez, Ahmet; Demir, Ali Aslan; Salmaslioglu, Artur; Tukenmez, Mustafa; Yavuz, Ekrem; Acunas, Gulden

    2014-10-01

    We present the mammographic and sonographic findings in a case of fibroadenomatosis involving both breasts and axillae in a renal transplant patient after 16 years of treatment with cyclosporin A. Awareness of the fact that cyclosporin A may induce the formation of fibroadenomas, including in accessory breast tissue, is important for correct diagnosis and preventing unnecessary intervention. PMID:25131521

  10. Cyclosporine A attenuates 3-nitropropionic acid-induced Huntington-like symptoms in rats: possible nitric oxide mechanism.

    PubMed

    Kumar, Puneet; Kalonia, Harikesh; Kumar, Anil

    2010-01-01

    Cyclosporine A is a well-known immunosuppressant drug that is currently used for prevention of allograft rejection. The current study was conducted to explore the therapeutic potential of cyclosporine A against 3-nitropropionic acid (3-NP)-induced neurotoxicity, an animal model of Huntington disease (HD). Systemic administration of 3-NP (10 mg/kg) for 14 days significantly impaired body weight, motor activity, biochemical parameters (raised lipid peroxidation, nitrite concentration, depletion of superoxide dismutase [SOD] and catalase), and mitochondrial enzymes. Cyclosporine A (2.5, 5, and 10 mg/kg) treatment significantly attenuated behavioral, biochemical, and cellular alterations. Furthermore, L-arginine pretreatment with cyclosporine A (5 mg/kg) significantly reversed the protective effect of cyclosporine A. However, L-nitro-arginine methyl ester (L-NAME; 10 mg/kg) pretreatment potentiated the protective effect of cyclosporine A (5 mg/kg). Study highlights the therapeutic potential of cyclosporine A in the treatment of HP. Study suggests that nitric oxide (NO) modulation is involved in the neuroprotective effect of cyclosporine A against 3-NP neurotoxicity. PMID:20448265

  11. The role of cyclosporine A on the periodontal tissues

    PubMed Central

    Jayasheela, Mallappa; Mehta, Dhoom Singh

    2013-01-01

    Background: Cyclosporin A (CsA) is a known immunosuppressive agent and can be considered as a lifesaving drug in the organ transplantation cases. However, it is associated with many side-effects on different tissues and body organs including the periodontal tissues. The present animal study was undertaken to evaluate the effects of CsA targeting the tissue triad of periodontal tissues, i.e., gingiva, alveolar bone and cementum in rats. Materials and Methods: Twelve 6-week-old male Wistar rats weighing 150-200 g were considered for the case-control study in rats. The rats were divided into 2 groups: (1) CsA (test) group (2) Saline (control) group and were administered the same subcutaneously daily once for 45 days. Impressions were taken and study casts were prepared on weekly basis for the morphometric analysis. At the end of 45 days, rats were sacrificed and specimens were analyzed for histomorphometric analysis. CsA and saline groups were analyzed to test of association using the Student t-test at 99% confidence interval. Results: The morphometric examination showed significant gingival overgrowth in the CsA group, whereas no such growth in the saline group. Similarly, on histomorphometric analysis, there was a significant loss of alveolar bone in CsA group as compared with control. Furthermore, there was large amount of cementum formation accompanied by insertion of new connective tissue fibers especially in the cervical region of the tooth in CsA group rats. Conclusion: CsA targets the periodontal tissues (gingiva, alveolar bone and cementum) in different pattern. Its role in cementogenesis can be utilized for periodontal regeneration, if its local application is testified and verified in the future animal studies. PMID:24379871

  12. Cyclosporin A Disrupts Notch Signaling and Vascular Lumen Maintenance

    PubMed Central

    Pandey, Raghav; Botros, Mark A.; Nacev, Benjamin A.; Albig, Allan R.

    2015-01-01

    Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA treatment and contrary to the anti-angiogenic activity ascribed to CSA, angiogenic sprouting of ISV vessels was normal in CSA treated embryos. Most strikingly, CSA treated embryos exhibited a progressive decline in blood flow that was associated with eventual collapse of vascular luminal structures. Vascular collapse in zebrafish embryos was partially rescued by global Notch inhibition with DAPT suggesting that disruption of normal Notch signaling by CSA may be linked to vascular collapse. However, multiple signaling pathways likely cause the vascular collapse phenotype since both cyclophilin A and calcineurin/NFAT were required for normal vascular function. Collectively, these results show that CSA is a novel inhibitor of Notch signaling and

  13. Accurate diagnosis of renal transplant rejection by indium-111 platelet imaging despite postoperative cyclosporin therapy

    SciTech Connect

    Collier, B.D.; Adams, M.B.; Kauffman, H.M.; Trembath, L.; Hoffmann, R.G.; Tisdale, P.L.; Rao, S.A.; Hellman, R.S.; Isitman, A.T.

    1988-08-01

    Previous reports indicate that In-111 platelet scintigraphy (IPS) is a reliable test for the early diagnosis of acute post-operative renal transplant rejection (TR). However, the recent introduction of cyclosporin for post-transplantation immunosuppression requires that the diagnostic efficacy of IPS once again be established. Therefore, a prospective IPS study of 73 post-operative renal transplant recipients was conducted. Fourty-nine patients received cyclosporin and 24 patients did not receive this drug. Between these two patient groups, there were no significant differences in the diagnostic sensitivities (0.86 vs 0.80) and specificities (0.93 vs 0.84) with which TR was identified. We conclude that during the first two weeks following renal transplantation the cyclosporin treatment regimen used at our institution does not limit the reliability of IPS as a test for TR.

  14. Cyclosporin A for the treatment of graft-versus-host disease in man.

    PubMed

    Powles, R L; Barrett, A J; Clink, H; Kay, H E; Sloane, J; McElwain, T J

    Cyclosporin A was given to five patients with acute leukaemia in whom graft-versus-host disease (G.V.H.D.) had developed after bone-marrow transplantation from sibling donors. In all instances the acute erythematous skin reaction of G.V.H.D. resolved within two days, but four of the five patients died. Cyclosporin A in high doses produced anorexia, nausea, and a reversible rise in blood-urea. The four patients who died all had liver damage, but the histological changes varied. Cyclosporin A modifies the acute skin reaction of G.V.H.D. In the management of liver and gut G.V.H.D., and in prophylaxis of G.V.H.D., its role needs to be determined. PMID:82837

  15. Kimura's disease with eosinophilic panniculitis - treated with cyclosporine: a case report

    PubMed Central

    2010-01-01

    Kimura's disease is a rare, benign, slow growing chronic inflammatory swelling with a predilection for the head and neck region and almost always with peripheral blood eosinophilia and elevated serum IgE levels. Here, we report a 25-year-old male patient with asthma, Reynaud phenomenon, eosinophilic panniculitis, bilateral inguinal lymphadenopathy and peripheral blood eosinophilia. He responded initially to oral prednisolone with the subsidence of peripheral blood eosinophilia, asthma and the Reynaud phenomenon. But with tapering of prednisolone symptoms reappeared and hereby he was treated with cyclosporine. He has been symptom free for 6 months of follow up while taking cyclosporine 25 mg orally per day. Eosinophilia has resolved. This case shows that in addition to previously reported associations, Kimura disease may be associated with eosinophilic panniculitis and that cyclosporine could be effective in its treatment. PMID:20236545

  16. The effect of systemic cyclosporin A on a hairless mouse model of photoaging.

    PubMed

    Moloney, S J; Learn, D B

    1992-10-01

    The mechanisms that cause skin wrinkling in response to chronic exposure to sunlight are unknown. We investigated the possibility that wrinkling of Skh-1 hairless mice is associated with an ultraviolet (UV) radiation-induced immunologic alteration. Exposing Skh-1 hairless mice to a regimen of nonerythemal UV-B (290-320 nm) radiation induced skin wrinkles after 6-7 weeks. Concomitant treatment with cyclosporin A decreased the time to the onset of wrinkles to approximately 4 weeks. Exposing HRS/J hairless mice or athymic nude mice to a similar nonerythemal UV-B radiation regimen for 10 weeks failed to induce skin wrinkles. Concomitant administration of cyclosporin A and UV-B radiation for 7 weeks to HRS/J hairless mice induced no skin wrinkles. Ultraviolet-B or UV-B plus cyclosporin A exposure caused increased immunohistochemical staining for Ia and F4/80 antigens in the upper dermis of tissue from Skh-1 mice, as compared to controls. Treating Skh-1 mice with UV-B radiation plus cyclosporin A was also associated with a large increase in the number of CD3+ cells in the dermis. These staining patterns were absent in similarly treated HRS/J hairless mice. Dermal mast cell numbers in Skh-1 mice were 2-3-fold higher than in HRS/J, athymic nude or NSA mice. Treatment with cyclosporin A increased Skh-1 dermal mast cell numbers approximately 2-fold but had no effect on the dermal mast cell numbers in HRS/J or NSA mice. Based on these findings we postulate that UV-B light and cyclosporin A exacerbate an immunological condition in Skh-1 mice, one consequence of which is manifested as skin wrinkles. Thus, the induction of skin wrinkles in this mouse strain may have no relevance to the wrinkles observed in human skin after chronic exposure to sunlight. PMID:1454879

  17. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

    PubMed

    Zavada, J; Pesickova, Ss; Rysava, R; Olejarova, M; Horák, P; Hrncír, Z; Rychlík, I; Havrda, M; Vítova, J; Lukác, J; Rovensky, J; Tegzova, D; Böhmova, J; Zadrazil, J; Hána, J; Dostál, C; Tesar, V

    2010-10-01

    Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) PMID:20605876

  18. Efficacy and safety of constant-rate intravenous cyclosporine infusion immediately after heart transplantation.

    PubMed

    Schroeder, T J; Myre, S A; Melvin, D B; Van der Bel-Kahn, J; Stephens, G W; Collins, J A; Wolf, R K; Brown, L L; Pesce, A J; First, M R

    1989-01-01

    Oral cyclosporine therapy immediately after heart transplantation is erratic and difficult to predict. The purpose of this study was to evaluate the relative efficacy and safety of cyclosporine when administered by constant-rate infusion immediately after transplantation. Nineteen patients (17 men and two women) aged 50 years (range 25 to 61 years) who weighed 71 +/- 9 kg, participated in the study and received cyclosporine, 7 to 10 mg/hr (117 +/- 15 micrograms/kg/hr). The infusions were initially maintained for 26 +/- 5 hours (range 18 to 42 hours) without adjustments in dosage. Whole blood samples were obtained at hourly intervals for the first 8 to 12 hours and then daily throughout the 7-day study period and were analyzed by high-performance liquid chromatography. Constant-rate cyclosporine infusion resulted in therapeutic blood levels (350 to 450 ng/ml) at 6 hours. These levels remained relatively steady throughout the 7-day infusion, requiring only minimal dosage adjustments. Kidney function was not altered significantly after 7 days of intravenous cyclosporine therapy as evidenced by a mean serum creatinine level of 1.3 mg/dl before therapy and 1.4 mg/dl after therapy. There, however, was a transient rise in serum creatinine level in most patients on the second or third day after transplantation that resolved without a reduction in cyclosporine dosage. The mean endomyocardial biopsy score at 1 week after transplantation was 0.1, and only four of the patients required additional immunosuppressive therapy to treat rejection during the first 6 weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2647932

  19. Preferential effectiveness of cyclosporin in patients receiving kidney transplants after glomerulonephritis.

    PubMed

    Cats, S; Terasaki, P I; Perdue, S; Mickey, M R

    1985-03-01

    Glomerulonephritis patients transplanted with cadaver kidneys had a significantly higher one-year graft survival when immunosuppressed with cyclosporin rather than standard therapy (80% versus 59%, p less than 10(-5]. For nephrosclerosis patients the corresponding rates were 70% and 59% (p greater than 0.05); and in those with antecedent diabetes mellitus, polycystic kidney, and pyelonephritis the differences were negligible. In glomerulonephritis patients, but not in the other groups, cyclosporin was additive to the effect of transfusions and of HLA-A, B and HLA-Dr matching. PMID:2857855

  20. Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen.

    PubMed

    Chocair, P; Duley, J; Simmonds, H A; Cameron, J S; Ianhez, L; Arap, S; Sabbaga, E

    1993-07-10

    Early rejection can still complicate renal transplantation even with cyclosporin. We added low-dose allopurinol (25 mg on alternative days) to "triple" immunosuppression with cyclosporin, prednisolone, and azathioprine for twelve recipients of cadaver renal grafts. The controls were fifteen patients on triple therapy alone. Only one rejection episode occurred among the allopurinol-treated patients, whereas eleven controls had rejections (seven with more than one episode). Allopurinol may be toxic when combined with azathioprine, yet the bone marrow tolerated the new regimen well. As expected, reduction of the azathioprine dose was necessary in the treated group. PMID:8100914

  1. Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats

    PubMed Central

    Kim, Ji Hong; Lee, Yeon Hee; Lim, Beom Jin; Jeong, Hyeon Joo; Kim, Pyung Kil; Shin, Jae Il

    2016-01-01

    The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction. PMID:26947764

  2. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

    PubMed

    Trompeter, Richard; Filler, Guido; Webb, Nicholas J A; Watson, Alan R; Milford, David V; Tyden, Gunnar; Grenda, Ryszard; Janda, Jan; Hughes, David; Ehrich, Jochen H H; Klare, Bernd; Zacchello, Graziella; Bjorn Brekke, Inge; McGraw, Mary; Perner, Ferenc; Ghio, Lucian; Balzar, Egon; Friman, Styrbjörn; Gusmano, Rosanna; Stolpe, Jochen

    2002-03-01

    This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the

  3. An underlying role for hepatobiliary dysfunction in cyclosporine A nephrotoxicity

    SciTech Connect

    Aleo, Michael D.

    2008-07-01

    Renal-derived cysteinyl leukotrienes (cysLT), such as leukotrienes C{sub 4} (LTC{sub 4}) and D{sub 4} (LTD{sub 4}) are thought to mediate acute and chronic cyclosporine A (CSA) nephrotoxicity. However, whole-body cysLT elimination is regulated primarily by hepatobiliary excretion. Since CSA is known to alter hepatobiliary function, the effects of CSA on whole-body cysLT elimination were investigated in vivo, with respect to hepatobiliary and renal function. Male rats were anesthetized and cannulated (jugular vein, bile duct, and urinary bladder). A tracer dose of tritiated LTC{sub 4} ({sup 3}H-LTC{sub 4}) was administered systemically (i.v.) immediately following vehicle and then 90 min later after vehicle or CSA. In vehicle/vehicle controls, hepatobiliary {sup 3}H-cysLT elimination predominated over renal elimination without altering glomerular filtration rate (GFR), bile flow, and urine production. {sup 3}H-cysLT elimination kinetics were comparable between each 90 min collection period. In vehicle/CSA-treated rats, an acutely nephrotoxic dose of CSA (20 mg/kg, i.v.) reduced urine flow 74 {+-} 9% and caused a transient reduction in GFR, while total bile flow decreased 40 {+-} 13%. Hepatobiliary and renal {sup 3}H-cysLT elimination was also impaired 59 {+-} 5 and 61 {+-} 18%, respectively. In contrast, a non-nephrotoxic dose (2 mg/kg i.v.) increased renal {sup 3}H-cysLT elimination due to impaired hepatobiliary elimination without affecting GFR, bile flow or urine production. Both doses caused {sup 3}H-cysLT retention in hepatic and renal tissue. These findings demonstrate that CSA alters whole-body handling of cysLT by disrupting hepatobiliary cysLT elimination. This disruption leads to increased renal exposure to systemically derived cysLT and renal cysLT tissue retention. Renal exposure to and accumulation of systemically derived cysLT products may be underlying factors in CSA nephrotoxicity.

  4. Cyclosporin C is the main antifungal compound produced by Acremonium luzulae.

    PubMed Central

    Moussaïf, M; Jacques, P; Schaarwächter, P; Budzikiewicz, H; Thonart, P

    1997-01-01

    A strain of Acremonium luzulae (Fuckel) W. Gams was selected in screening new microorganisms for biological control of fruit postharvest diseases, especially gray and blue mold diseases on apples and strawberries. This strain manifests a very strong activity against a large number of phytopathogenic fungi. In this work, the product responsible for this antifungal activity was isolated from modified Sabouraud dextrose broth cultures of A. luzulae. It was purified to homogeneity by reverse-phase column chromatography. On the basis of UV, infrared, and 1H and 13C nuclear magnetic resonance spectra, mass spectral analysis, and the amino acid composition of the acid hydrolysates, the antibiotic was determined to be cyclosporin C. Cyclosporin C showed a broad-spectrum activity against filamentous phytopathogenic fungi but no activity against bacteria or yeasts. Its antifungal activity is only fungistatic. In contrast to Tolypocladium inflatum, another cyclosporin-producing strain, A. luzulae, did not produce additional cyclosporins. This was confirmed by in vivo-directed biosynthesis. PMID:9143111

  5. Recalcitrant pyoderma gangrenosum--two cases successfully treated with cyclosporin A.

    PubMed

    Kavanagh, G M; Ross, J S; Cronin, E; Smith, N P; Black, M M

    1992-01-01

    The successful use of cyclosporin A (CSA) in organ transplantation is now well established. In recent years its usefulness has extended to the treatment of cutaneous autoimmune disorders, including pyoderma gangrenosum (P.G.). We report two further cases of recalcitrant P.G., both associated with rheumatoid arthritis (R.A.) which responded to low dose CSA. PMID:1424262

  6. Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion.

    PubMed

    Rahman, Ziyaur; Xu, Xiaoming; Katragadda, Usha; Krishnaiah, Yellela S R; Yu, Lawrence; Khan, Mansoor A

    2014-03-01

    Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products. PMID:24423028

  7. Effect of cyclosporin A particles of varying diameters on gastric cancer cell apoptosis.

    PubMed

    Xing, X L; Lu, Y; Qiu, H L

    2016-01-01

    Human health is significantly threatened by gastric cancer, which is the most common malignant tumor; although drastic, surgery is currently the only way to cure it. However, high recurrence rates and low survival rates are associated with the disease. Therefore, to improve the effectiveness of gastric cancer treatment and to increase the clinical cure rate, we investigated the effect of cyclosporin A particles of varying diameter on gastric cancer cell apoptosis. Flow cytometry was used to detect apoptosis induced by Annexin V-fluorescein isothiocyanate/propidium iodide-double labeling. We also determined the content of reactive oxygen species and the expression level of P-glycoprotein in cells after treatment with cyclosporin A. The results indicated that increases in the concentration and action time of cyclosporin A were associated with statistically significant increases in the apoptosis rate of gastric cancer cells when the experimental and control groups were compared (P < 0.05 and P < 0.01, respectively). In conclusion, during a certain action time and concentration range, cyclosporin A inhibits the proliferation of human gastric cancer cells and can induce their apoptosis. PMID:27173251

  8. [Polyneuropathy and central nervous system diseases before and after heart transplantation. Is cyclosporin neurotoxic?].

    PubMed

    Porschke, H; Strenge, H; Stauch, C

    1991-10-18

    In a cross-sectional study, 52 patients (44 men, 8 women, mean age 50.6 [19-68] years) were investigated clinically and electrophysiologically for evidence of peripheral and central nervous system damage before and after heart transplantation. 20 patients were investigated before heart transplantation (group 1), 16 at 7 days to 5 months after transplantation (early post-operative group; group 2) and 16 at 6 to 32 months after transplantation (late post-operative group; group 3). Nerve conduction studies (median, peroneal and sural nerves) revealed polyneuropathy in 14 out of 16 patients in group 2, significantly more than in group 1 (11 out of 19) and group 3 (9 out of 16). The mean blood cyclosporin concentration was 656 ng/ml in group 2 and 409 ng/ml in group 3 (P less than 0.001). Patients in group 3 with polyneuropathy had significantly higher cyclosporin concentrations than patients without polyneuropathy (505 vs 284 ng/ml; P less than 0.01). Among patients who had undergone operations, there were no noteworthy differences between the mean cyclosporin concentrations and clinical data in those with or without central nervous system lesions. There is preliminary evidence of a neurotoxic effect of cyclosporin on the peripheral but not the central nervous system. PMID:1935623

  9. Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil

    PubMed Central

    Guerra, Augusto Afonso; Silva, Grazielle Dias; Andrade, Eli Iola Gurgel; Cherchiglia, Mariângela Leal; Costa, Juliana de Oliveira; Almeida, Alessandra Maciel; Acurcio, Francisco de Assis

    2015-01-01

    OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. However, regimens containing cyclosporine were more cost-effective. PMID:25741648

  10. Effects of immunosuppressive drugs on gastrointestinal transit of rats: effects of tacrolimus, cyclosporine, and prednisone.

    PubMed

    Dall'Agnol, D J R; Hauschildt, A T; Lima, M B; Corá, L A; Teixeira, M C B; Américo, M F

    2014-01-01

    Triple immunosuppressive therapy after organ transplantation may cause several gastrointestinal disturbances. It is difficult to identify which drug causes more complications, requiring an appropriate animal model. The aim was to compare the gastrointestinal transit in immunosuppressed rats under triple immunosuppressive therapy. Male rats were immunosuppressed by gavage during 14 days with tacrolimus (n = 10), cyclosporine (n = 12), and prednisone (n = 9). Animals received a magnetic pellet before (control) and after treatment that was monitored at predetermined intervals by AC biosusceptometry, a noninvasive and radiation-free technique. The following parameters were measured: creatinine serum, mean time of gastric emptying (MGET), mean time to reach cecum (MCAT), and mean transit time through small bowel (MSBTT). The differences were analyzed by ANOVA (Tukey). Our results showed that MGET of animals treated with prednisone, cyclosporine, and tacrolimus were reduced compared with control subjects (P < .03, P < .009, and P < .002, respectively). There was no difference in MCAT, whereas MSBTT was longer for tacrolimus and prednisone compared with control subjects (P < .004 and P < .004, respectively). Also, prednisone and tacrolimus presented a reduced MGET (P < .05 and P < .01, respectively) compared with cyclosporine. Our data showed a low serum creatinine level and no difference among groups regarding renal function. In summary, cyclosporine has less effect on the gastrointestinal transit; however, all of these drugs should be carefully prescribed to prevent gastrointestinal symptoms and improve quality of life after transplantation. PMID:25131057

  11. The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphates

    PubMed Central

    Serkova, Natalie; Litt, Lawrence; Leibfritz, Dieter; Hausen, Bernard; Morris, Randall E; James, Thomas L; Benet, Leslie Z; Christians, Uwe

    2000-01-01

    SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-effect of cyclosporine. We studied the effect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31P-magnetic resonance spectroscopy (MRS). Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 μg l−1: 93±3% of control (NTP), 91±3% (PCr); 500 μg l−1: 84±2% (NTP), 73±2 (PCr); 5000 μg l−1: 68±3% (NTP), 55±5% (PCr); n=6; P<0.02). In contrast, after perfusion for 2 h, SDZ-RAD (500 μg l−1 and 5000 μg l−1) significantly increased high-energy phosphate concentrations in the brain slices (P<0.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 μg l−1 SDZ-RAD+5000 μg l−1 cyclosporine: 86±3% (NTP), 83±7% (PCr), n = 3, P<0.03 compared to cyclosporine alone. 5As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ-RAD/ cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD. PMID:10711346

  12. Effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis in rats.

    PubMed

    Cannon, G W; McCall, S; Cole, B C; Radov, L A; Ward, J R; Griffiths, M M

    1993-03-01

    The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically. PMID:8213350

  13. A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression.

    PubMed

    Shima, Tomoko; Yamamoto, Yuki; Okuhira, Hisako; Mikita, Naoya; Furukawa, Fukumi

    2016-01-01

    We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine. PMID:27462222

  14. Cyclosporine A affects the in vitro expression of T cell activation-related molecules and cytokines in dogs.

    PubMed

    Fellman, C L; Stokes, J V; Archer, T M; Pinchuk, L M; Lunsford, K V; Mackin, A J

    2011-04-15

    Cyclosporine is a powerful immunosuppressive drug that is being used with increasing frequency to treat a wide range of immune-mediated diseases in the dog. To date, ideal dosing protocols that will achieve immunosuppression with cyclosporine in dogs remain unclear, and standard methods that can measure effectiveness of immunosuppression have not been established. The aim of our study was to evaluate the effects of in vitro cyclosporine exposure on a panel of molecules expressed by activated T cells to ascertain their potential as biomarkers of immunosuppression in dogs. Blood was drawn from six healthy dogs, and peripheral blood mononuclear cells (PBMC) were isolated and activated. Half of the cells were incubated with 200 ng/mL cyclosporine prior to activation, and the other half were not exposed to cyclosporine. Samples were analyzed using flow cytometry, and the expression of intracellular cytokines IL-2, IL-4, and IFN-γ was evaluated after 6, 12, and 24h of drug exposure. Each cytokine exhibited a time-dependent suppression profile, and all but two samples activated in the presence of cyclosporine showed lower cytokine expression than untreated controls. We also evaluated the expression of the surface T cell activation molecules CD25 and CD95 by flow cytometry after 36 h of drug exposure. Expression of these surface molecules decreased significantly when activated in the presence of cyclosporine. Our results suggest that suppressed expression of the markers related to T cell activation could potentially be utilized as an indicator of the efficacy of cyclosporine therapy in dogs. PMID:21227512

  15. A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression

    PubMed Central

    Shima, Tomoko; Yamamoto, Yuki; Okuhira, Hisako; Mikita, Naoya; Furukawa, Fukumi

    2016-01-01

    We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine. PMID:27462222

  16. Atypical dissemination of the highly neurotropic Borna disease virus during persistent infection in cyclosporine A-treated, immunosuppressed rats.

    PubMed Central

    Stitz, L; Schilken, D; Frese, K

    1991-01-01

    In adult rats infected with Borna disease virus, the virus was found exclusively in the brain, whereas in cyclosporine A-treated rats, infectious virus was also detected in peripheral nerve fibers and, unexpectedly, in adjacent organ-specific cells. In contrast to untreated virus-infected rats, no major histocompatibility complex class II expression was found in the brain of cyclosporine A-treated animals. Images PMID:1985209

  17. Morphometric and ultrastructural analysis of the effect of bromocriptine and cyclosporine on the vasospastic femoral artery of rats

    PubMed Central

    Tokmak, Mehmet; Başocak, Kahan; Canaz, Hüseyin; Canaz, Gökhan; İplikçioğlu, Celal

    2015-01-01

    Vasospasm is the main causes of mortality and morbidity in patiens with subarachnoid hemorrhage (SAH). The arterial narrowing mechanism that develops after SAH is not yet fully understood but many studies showed that hypotension, neurogenic reflexes, clots in the subarachnoidal space, spasmogenic agents, humoral and celluler immunity play a role in the etiology. In this study we investigate the effects of Bromocriptine and Cyclosporine A in vasospasm secondary to SAH on rat femoral artery from ultrastructural and morphometric perspectives. 120 male Sprague-Dawley rats divided into 12 groups: Vasospasm (V), control (K), surgical control (CK) groups, vasospasm+Bromocriptine and/or Cyclosporine-A groups (VCyA, VBr, VBr+CyA), Bromocriptine and/or Cyclosporine-A control groups (CK, BK, Br+CyAK), Bromocriptine and/or Cyclosporine-A surgical control groups (BCK, CyCK, Br+CyACK). In order to create SAH model, 0, 1 cm3 blood injected into silastic sheath wrapped rat femoral artery. Bromocriptine (2 mg/kg/d) and Cyclosporine A (10 mg/kg/d) combinations applied to control, surgical control and vasospastic models. Light microscopy, transmission electron microscopy and scanning electron microscopy used during this study. Statistical evaluation of the morphometric measurement data concerning vascular wall thickness and luminal cross-sectional areas of all groups were performed using Mann-Whitney U, Wilcoxon-signed rank, and Student-t tests. Cyclosporine A, whose effects in the prevention of vasospasm have been demonstrated in previous studies. In this study we discovered that Bromocriptine demonstrated strong effects similar to Cyclosporine-A. Bromocriptine and Cyclosporine A markedly prevent the development of chronic morphologic vasospasm following SAH. The combined use of both drugs does not change this preventive effect. PMID:26770311

  18. Methotrexate and Cyclosporine Treatments Modify the Activities of Dipeptidyl Peptidase IV and Prolyl Oligopeptidase in Murine Macrophages

    PubMed Central

    Olivo, R. A.; Nascimento, N. G.; Teixeira, C. F. P.; Silveira, P. F.

    2008-01-01

    Analysis of the effects of cyclosporine A (25–28 mgkg−1) and/or methotrexate (0.1 mgkg−1) treatments on dipeptidyl peptidase IV (DPPIV) and prolyl oligopeptidase (POP) activities and on algesic response in two distinct status of murine macrophages (Mφs) was undertaken. In resident Mφs, DPPIV and POP were affected by neither individual nor combined treatments. In thioglycolate-elicited Mφs, methotrexate increased DPPIV (99–110%) and POP (60%), while cyclosporine inhibited POP (21%). Combined treatment with both drugs promoted a rise (51–84%) of both enzyme activities. Only cyclosporine decreased (42%) the tolerance to algesic stimulus. Methotrexate was revealed to exert prevalent action over that of cyclosporine on proinflammatory Mφ POP. The opposite effects of methotrexate and cyclosporine on POP activity might influence the availability of the nociceptive mediators bradykinin and substance P in proinflammatory Mφs. The exacerbated response to thermally induced algesia observed in cyclosporine-treated animals could be related to upregulation of those mediators. PMID:18354729

  19. Safety and Efficacy of Cyclosporine in the Treatment of Chronic Dry Eye

    PubMed Central

    Schultz, Clyde

    2014-01-01

    Dry-eye syndrome (DES) is a multifactorial disease affecting millions of individuals worldwide. Various factors, including age, hormonal status, genetics, sex, immune status, innervation status, nutrition, pathogens, and environmental stress, can alter the cellular and molecular structure or function of components of the ocular surface system. The resulting imbalance increases susceptibility to desiccation and epithelial damage, leading to a vicious circle in which inflammation amplifies and sustains further damage by chronic deregulation of the system. Lubricating agents and steroids have been used as treatment options. However, as the causes of the disease become better elucidated, the more chemically complex cyclosporine A has become an increasingly useful treatment option and in the United States is currently the only Food and Drug Administration (FDA)-approved prescription drug for the treatment of dry eye. The safety and efficacy of cyclosporine have been shown in numerous studies. PMID:25002818

  20. Cyclosporine in the management of impetigo herpetiformis: a case report and review of the literature.

    PubMed

    Patsatsi, Aikaterini; Theodoridis, Theodoros D; Vavilis, Dimitrios; Tzevelekis, Vasilios; Kyriakou, Aikaterini; Kalabalikis, Dimitrios; Sotiriadis, Dimitrios

    2013-01-01

    A 27-year-old female, gravida 1, para 0, in week 22 of pregnancy, presented with an eruption consisting of annular erythematosquamous plaques with an active polycyclic elevated border comprised of superficial micropustules. Clinical and histological features were typical of impetigo herpetiformis (IH). Systemic steroids resulted in an unstable condition, with no resolution of lesions. Resistance to the above therapeutic scheme served as a stimulus to discuss the use of cyclosporine as a therapeutic option in this condition. Reviewing the limited literature, cyclosporine seems to serve not as a monotherapy in the management of IH but as an additional medication, in order to achieve a stable course of the disease and avoid high doses of systemic steroids. PMID:23626548

  1. [Use of cyclosporine 0.05% in various ocular surface disorders].

    PubMed

    Maĭchuk, D Iu; Vasil'eva, O A; Shokirova, M M

    2014-01-01

    It is proved that chronic ocular surface inflammatory disease (including allergic blepharitis, recurrent chalyazia, punctuate keratitis, recurrent herpetic corneal erosions, late stages of adenoviral keratoconjunctivitis, etc.) takes part in the development of secondary dry eye syndrome (DES). However, therapies for inflammation-induced impairment of tear production do not provide long-term control of inflammatory process. Cyclosporine 0.05% eye drops are an option. Their effect is well-studied in foreign practice. Local application experience of cyclosporine 0.05% eye drops was summarized at a meeting of the Russian expert group on DES and conclusions were made on their effectiveness in treatment of dry eye syndrome associated with certain ocular surface inflammatory disorders, such as allergic blepharoconjunctivitis, late stages of adenoviral keratoconjunctivitis, and others. PMID:24864503

  2. Cyclosporine for the Treatment of HTLV-1-Induced HAM/TSP

    PubMed Central

    Sánchez-Montalvá, Adrián; Salvador, Fernando; Caballero, Estrella; Molina, Israel

    2015-01-01

    Abstract HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) remains a challenging disease. Treatment options are scarce, and their safety and efficacy are currently a matter of concern. We present a case report describing our experience using cyclosporine in a patient with early HAM/TSP who started with a gait disturbance at Vall d’Hebron University Hospital (Barcelona) from August 2012 to October 2013. After 62 weeks of treatment, clinical improvement was observed and proviral load diminished. No safety concerns were observed. Cyclosporine seems to be effective in new-onset HAM/TSP or in chronic HAM/TSP that develops a relapse. However, the duration and safety profile of this steroid-sparing therapy remain unknown and should be further investigated. PMID:25569667

  3. [Hair-like hyperkeratoses in patients with kidney transplants. A new cyclosporin side-effect].

    PubMed

    Izakovic, J; Büchner, S A; Düggelin, M; Guggenheim, R; Itin, P H

    1995-12-01

    We report a 31-year-old renal transplant patient treated with cyclosporin A who developed an unusual sebaceous gland hyperplasia accompanied by a disseminated follicular spiny hyperkeratosis. Those alterations were most evident on his face and limbs. In some locations hairy hyperkeratosis with authentic hair neogenesis was found. The histology of these alterations showed a marked hyperkeratosis of the hair follicles with formation of hair-like spikes either alone or in connection with hairs. The presence of true hairs distinguishes our case from the morphologically similar disseminated spiked hyperkeratosis and other spiny keratinization disorders. Scanning electron microscopy helped to demonstrate the hair-like structure of these keratoses. Some of the sebaceous glands showed cystic widening of their lumina, which were filled with abundant amorphous eosinophilic material, a finding similar to earlier observations. Our case demonstrates that these skin alterations should be classified as side effects of cyclosporin A and that they are apparently dose-dependent. PMID:8567267

  4. The influence of cyclosporin A on experimental autoimmune thyroid disease in the rat

    SciTech Connect

    McGregor, A.M.; Rennie, D.P.; Weetman, A.P.; Hassman, R.A.; Foord, S.M.; Dieguez, C.; Hall, R.

    1983-01-01

    Female PVG/c rats, thymectomised on weaning and given 4 courses of whole body irradiation to a total dose of 1000 rads, developed experimental autoimmune thyroid disease (EAITD) as assessed by histological evidence of thyroiditis and circulating levels of antithyroglobulin antibodies. Hypothyroidism resulted. Induction of the disease was associated with a highly significant fall in T lymphocyte numbers. Eight weeks after their last dose of irradiation the animals commenced treatment with cyclosporin A (10 mg/kg rat/day, intragastrically) and were treated for varying time intervals thereafter. The reversal of the T lymphocyte helper: suppressor ratio on cyclosporin A therapy was associated with a significant improvement in the disease process. The alterations in the T cell subsets and in the disease lasted only as long as the drug was administered and thereafter reverted towards that seen in the control groups of animals receiving no treatment.

  5. Tacrolimus Versus Cyclosporine as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

    PubMed

    Liu, Jin-Yu; You, Ru-Xu; Guo, Min; Zeng, Lu; Zhou, Pu; Zhu, Lan; Xu, Gang; Li, Juan; Liu, Dong

    2016-01-01

    Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period. PMID:25299636

  6. Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers.

    PubMed Central

    Gottsch, J D; Akpek, E K

    2000-01-01

    OBJECTIVE: To report the successful use of topical cyclosporin for treatment of central sterile corneal ulcers associated with rheumatoid disease. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS/INTERVENTION: Five patients (7 eyes) with collagen vascular disorders presented with central, sterile corneal ulcers. An extensive medical evaluation did not reveal active underlying rheumatoid disease in any patient. Inadequate clinical response with use of topical steroids and lubricants led to corneal perforations requiring multiple tectonic procedures. Systemic immunosuppressive therapy either could not be initiated owing to a systemic contraindication or was discontinued owing to intolerance and side effects. The patients were ultimately treated with topical cyclosporin. RESULTS: Six of the 7 eyes responded favorably. An intense limbal vascularization began within 48 hours of treatment. The neovascularization progressed centrally with the simultaneous arresting of epithelial and stromal ulceration. Over a 2-week period, re-epithelization occurred with vascularization proceeding throughout the cornea. After several months, the corneal vessels attenuated, and all signs of inflammation subsided. Intrastromal bleeding with corneal blood staining occurred in 1 patient; this resolved over several months. No recurrences of corneal ulceration occurred in a mean follow-up period of 28 months (range, 7 to 60 months). None of the 5 patients have had a reactivation of their rheumatoid disease in the follow-up period. CONCLUSION: The clinical response in these patients contrasts with previous animal studies demonstrating an anti-angiogenic property of cyclosporin. We report that an immediate intense neovascularization is the first sign of a favorable clinical response. Treatment with topical cyclosporin alone may be considered in patients with sterile corneal ulcers associated with rheumatoid disease in the absence of systemic activation. Images FIGURE 1 FIGURE 2

  7. Localization of gingival overgrowth in heart transplant patients undergoing cyclosporin therapy.

    PubMed

    Somacarrera, M L; Hernández, G; Acero, J; Moskow, B S

    1994-07-01

    This research was aimed at determining and comparing the pattern of localization of both cyclosporin-induced gingival overgrowth and associated periodontal variables in heart transplant patients. Thirty-nine patients undergoing cyclosporin treatment were studied for 6 months following transplant surgery. Oral hygiene and gingivitis were evaluated using the Silness-Löe and Löe-Silness indices. Gingival overgrowth was measured using a periodontal probe to determine the height of the gingiva at six points per tooth. Statistical hypothesis testing was applied to calculate the significance of the results. Overgrowth average showed a steady and significant growth. The graphs depicting average overgrowth localization, "standard periodontograms," showed remarkable symmetry, and a significantly anterior mandibular papillary distribution. No overgrowth was observed in edentulous areas. The localization of plaque and gingivitis followed a similar pattern; a highly significant correlation was found with the overgrowth localization pattern. It was concluded that the elimination of plaque is an important preventive measure for cyclosporin-induced gingival overgrowth, and that tooth or periodontium related factors have a significant impact on its pathogenesis. PMID:7608842

  8. Cyclosporin A and tissue antigen matching in bone transplantation. Fibular allografts studied in the dog.

    PubMed

    Welter, J F; Shaffer, J W; Stevenson, S; Davy, D T; Field, G A; Klein, L; Li, X Q; Zika, J M; Goldberg, V M

    1990-12-01

    We studied the mechanical, metabolic, and histologic properties of short-term nonvascularized cortical bone grafts in a canine fibular graft model. Sham operated nonvascularized autotransplanted and allotransplanted bones were compared. The allografts were performed between dog leukocyte antigen (DLA) class I and II matched; DLA class I and II mismatched; and cyclosporin A (CsA) treated, DLA class I and II mismatched animals. Cyclosporin was given for 1 month, and all the animals were followed for 3 months after surgery. Mechanical properties were investigated using standard torsional tests, metabolic kinetics were assessed using isotopic prelabeling techniques, and histomorphometric analysis of cross-sectional area properties and sequential fluorochrome labels were performed. Autografts were mechanically stronger and stiffer than all the types of allograft. CsA-treated, DLA-mismatched allografts performed better than matched allografts. These in turn were stronger than non-CsA-treated, mismatched allografts, which underwent nearly complete resorption. These relationships were preserved in the metabolic and histologic analyses. In this short-term animal study, although DLA matching resulted in a slight improvement in graft outcome, mismatched grafts in dogs receiving a short course of cyclosporin A fared even better. PMID:2281759

  9. Development and characterization of mucoadhesive chitosan films for ophthalmic delivery of cyclosporine A.

    PubMed

    Hermans, Kris; Van den Plas, Dave; Kerimova, Sabina; Carleer, Robert; Adriaensens, Peter; Weyenberg, Wim; Ludwig, Annick

    2014-09-10

    Ocular chitosan films were prepared in order to prolong ocular delivery of cyclosporine A. The mucoadhesive films were prepared using the solvent casting evaporation method. A 2(4) full factorial design was used to evaluate the effect of 4 preparation parameters on the film thickness, swelling index and mechanical properties. Moreover, uniformity of content and in vitro drug release were investigated. Possible interactions between the film excipients were studied by FTIR analysis. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the chitosan films. Film thickness, water uptake, mechanical properties and in vitro release of cyclosporine A were dependent on film composition, especially on the amount of plasticizer. Lower drug release was measured from chitosan films containing a higher amount of plasticizer as glycerol decreased the swelling of chitosan films. FTIR spectra suggest a reorganization of hydrogen bonds between chitosan chains in the presence of glycerol and cyclodextrins. None of the film formulations showed significant cytotoxicity as compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A dispersed in the various film formulations remained anti-inflammatorily active as significant suppression of interleukin-2 secretion in concanavalin A stimulated Jurkat T cells was measured. PMID:24929014

  10. Use of Cyclosporine Therapy in Steroid Resistant Nephrotic Syndrome (SRNS): A Review

    PubMed Central

    Shah, Syed Raza; Altaf, Areeba; Arshad, Mohammad Hussham; Mari, Anum; Noorani, Sahir; Saeed, Eraj; Mevawalla, Areesh Amir; Haq, Zaiyn Ul; Faquih, Muhammad Ehsan

    2016-01-01

    A chronic, progressive disorder Steroid Resistant Nephrotic Syndrome (SRNS) accounts for 10-20% of all children with Nephrotic Syndrome. It is a heterogeneous disorder comprised of persistent edema, proteinuria, hypoalbuminemia and hyperlipidemia. Treatment for steroid-resistant nephrotic syndrome (SRNS) is challenging and children who suffer from SRNS require aggressive treatment to achieve remission. Calcineurin inhibitors have been used more in an empirical manner than on the basis of clear rationale. It was in 1984 when cyclosporine was first considered for the treatment of steroid resistant nephrotic syndrome. Cyclosporin is a calcineurin inhibitor that suppresses immune response by downregulating the transcription of various cytokine genes. Till now many studies have been conducted to determine dosages, duration of therapy, side effects and advantages of cyclosporine. Treatment of SRNS remains a difficult challenge in pediatric nephrology. Treatment should be individualized according to the underlying histopathology, and clinical and environmental conditions of the children. There is an urgent need to distinguish as soon as possible those patients who may benefit from prolonged immunosuppressive treatment from those who will not benefit from such treatment and who will just suffer from its major side effects. The emerging evidence that the majority of genetic forms of SRNS should receive symptomatic treatment only, should also be clinically tested and studies baring its significance should be evaluated in the future. PMID:26573045

  11. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth

    PubMed Central

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities. PMID:26759584

  12. Anorexia nervosa in a pediatric renal transplant recipient and its reversal with cyclosporine.

    PubMed

    Okechuku, Gyongyi; Boulos, Andrew K; Herman, Lettie; Upadhyay, Kiran

    2015-05-01

    We report a 16-yr-old female who developed AN within a month after renal transplantation and its resolution after switching from tacrolimus to cyclosporine. Her initial maintenance immunosuppressive regimen after renal transplantation consisted of tacrolimus, mycophenolate, and steroid. She had 7 kg weight loss within the first month of transplant with subsequent 10, 12, 17, and 19 kg loss after three, five, seven, and nine months of transplant, respectively. Besides weight loss and disturbances in body image, the patient developed alopecia, bradycardia, and persistent secondary amenorrhea. Upon switching to cyclosporine from tacrolimus nine months after transplant, she started regaining weight with 5 kg gain within two months and 10 kg after four months. She restarted her menstrual cycle, alopecia and bradycardia resolved, and her body image disturbance improved. Here, we describe a very unusual neuropsychiatric side effect of tacrolimus and its resolution with another calcineurin inhibitor, cyclosporine, in an adolescent renal transplant recipient. PMID:25661468

  13. Effect of Cyclosporin A on the Uptake of D3-Selective PET Radiotracers in Rat Brain

    PubMed Central

    Tu, Zhude; Li, Shihong; Xu, Jinbin; Chu, Wenhua; Jones, Lynne A.; Luedtke, Robert R.; Mach, Robert H.

    2011-01-01

    Introduction Four benzamide analogs having a high affinity and selectivity for D3 versus D2 receptors were radiolabeled with 11C or 18F for in vivo evaluation. Methods Precursors were synthesized and the four D3 selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. MicroPET imaging was carried out for [11C]6 in a control and a cyclosporin A pre-treated rat. Results All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-i.v. injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other ABC transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters. PMID:21718948

  14. Measurement of cyclosporine concentrations in whole blood: HPLC and radioimmunoassay with a specific monoclonal antibody and /sup 3/H- or /sup 125/I-labeled ligand compared

    SciTech Connect

    Wolf, B.A.; Daft, M.C.; Koenig, J.W.; Flye, M.W.; Turk, J.W.; Scott, M.G.

    1989-01-01

    We compared cyclosporine concentrations in whole blood as measured by HPLC and by RIA with a monoclonal antibody specific for cyclosporine with /sup 3/H- or /sup 125/I-labeled cyclosporine ligand. The /sup 3/H-RIA kit slightly underestimated cyclosporine concentrations (greater than 600 micrograms/L) in comparison with HPLC. Over a wide range of concentrations, cyclosporine measured with the /sup 125/I-RIA kit correlated well with HPLC (slope = 0.99, n = 301, r = 0.98), observed for samples from recipients of kidney, heart, or liver allografts (respective slopes: 1.01, 0.93, and 1.00). The /sup 125/I-RIA standard curve was linear to 1000 micrograms of cyclosporine per liter. Inter- and intra-assay CVs for /sup 125/I-RIA measurements of cyclosporine were less than or equal to 7%. Evidently, the /sup 125/I-RIA kit involving a monoclonal antibody specific for cyclosporine is equivalent to the HPLC assay and can replace it for therapeutic drug monitoring of cyclosporine therapy.

  15. Cyclosporine Treatment Reduces Oxygen Free Radical Generation and Oxidative Stress in the Brain of Hypoxia-Reoxygenated Newborn Piglets

    PubMed Central

    Liu, Jiang-Qin; Chaudhary, Hetal; Brocks, Dion R.; Bigam, David L.; Cheung, Po-Yin

    2012-01-01

    Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H2O2) production and markers of oxidative stress. Piglets (1–4 d, 1.4–2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation)(n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40–48% of baseline), hypotension (mean arterial pressure 27–31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H2O2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H2O2 production and minimizes oxidative stress in newborn piglets following hypoxia

  16. Gelatin-stabilised microemulsion-based organogels facilitates percutaneous penetration of Cyclosporin A in vitro and dermal pharmacokinetics in vivo.

    PubMed

    Liu, Hongzhuo; Wang, Yongjun; Han, Fei; Yao, Huimin; Li, Sanming

    2007-11-01

    Gelatin-stabilised microemulsion-based organogels (MBGs) are very useful in transdermal and topical delivery of hydrophobic drugs because of their lipophilic nature. MBGs systems possessing a potentially improved skin bioavailability of Cyclosporin A were designed and explored for some characteristics. The release characteristics of drug from MBGs were studied according to drug concentration. As the concentration of drug increased, the release of drug from gel increased, showing concentration dependency. Percutaneous penetration studies using rat skin in vitro showed that the deposition of Cyclosporin A was significantly improved by MBGs compared to the control. We also evaluated the therapeutic advantage of dermal administration of Cyclosporin A in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the MBGs containing Cyclosporin A, the deposition of the drug into skin and subcutaneous fat was, respectively, almost 55- and 3-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical than following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical applied MBGs loaded with Cyclosporin A might deliver maximal therapeutic effect to local tissue while avoiding the side effects seen with systemic therapy. The histopathological findings revealed that the new MBGs vehicle was a safe vehicle for topical drug delivery systems. PMID:17705159

  17. NMR studies of (U- sup 13 C)cyclosporin A bound to cyclophilin: Bound conformation and protions of cyclosporin involved in binding

    SciTech Connect

    Fesik, S.W.; Gampe, R.T. Jr.; Eaton, H.L.; Gemmecker, G.; Olejniczak, E.T.; Neri, P.; Holzman, T.F.; Egan, D.A.; Edalji, R.; Simmer, R.; Helfrich, R.; Hochlowski, J.; Jackson, M. )

    1991-07-02

    Cyclosporin A (CsA), a potent immunosuppressant, is known to bind with high specificity to cyclophilin (CyP), a 17.7 kDa protein with peptidyl-prolyl isomerase activity. In order to investigate the three-dimensional structure of the CsA/CyP complex, the authors have applied a variety of multidimensional NMR methods in the study of uniformly {sup 13}C-labeled CsA bound to cyclophilin. The {sup 1}H and {sup 13}C NMR signals of cyclosporin A in the bound state have been assigned, and, from a quantitative interpretation of the 3D NOE data, the bound conformation of CsA has been determined. Three-dimensional structures of CsA calculated from the NOE data by using a distance geometry/simulated annealing protocol were found to be very different form previously determined crystalline and solution conformations of uncomplexed CsA. In addition, from CsA/CyP NOEs, the portions of CsA that interact with cyclophilin were identified. For the most part, those CsA residues with NOEs to cyclophilin were the same residues important for cyclophilin binding and immunosuppressive activity as determined from sturcture/activity relationships. The structural information derived in this study together with the known structure/activity relationships for CsA analogues may prove useful in the design of improved immunosuppressants. Moreover, the approach that is described for obtaining the structural information is widely applicable to the study of small molecule/large molecule interactions.

  18. Cyclosporine-impregnated allograft bone sterilized with low-temperature plasma.

    PubMed

    Lu, Haibo; Pei, Guoxian; Zhao, Peiran; Liang, Shuangwu; Jin, Dan; Jiang, Shan

    2010-12-01

    Deep-freezing, freeze-drying and gamma (γ)-irradiation have deleterious effects on bone healing and mechanical properties of allograft bones. We tried preparing bone allografts using cyclosporine plus low-temperature-plasma sterilization. To explore the feasibility of this method of preparation, segmental defects in the right radii of rabbits were repaired with cyclosporine-impregnated allograft bones (CABs) sterilized with low-temperature-plasma (in the study group) and deep-frozen/freeze-dried irradiated allograft bones (D/FIABs) (in the control group). X-ray and quantitative histological analysis, peripheral blood T lymphocyte subset analysis and CD₂₅ molecule immunohistochemistry stain, the four-point bending test and safety evaluations were respectively conducted to compare bone-healing, immunosuppression, mechanical properties and safety between the two groups. X-ray scores were higher in the study group than those in the control (p = 0.032). There were significant differences in new bone areas at most repairs in both groups (p < 0.05). There were no significant differences in the percentages of CD₄(+) T, CD₈(+) T, ratios of CD₄(+) T:CD₈(+) T or serum concentrations of GPT/Cr in both groups (p > 0.05). At 16 weeks postoperatively, the density of CD₂₅ molecules in the control group was higher than that in the study group. The ultimate loading in the study group was significantly higher than that in the control (p = 0.048). Bone marrow stromal cells (BMSCs) grew thickly around and on the surface of a cyclosporine-impregnated allograft. Livers and kidneys in the study and control groups remained histologically normal at 7 days postoperatively. These results indicate that the CAB might be a better material than the D/FIAB in terms of bone healing, preservation of mechanical properties and immunosuppression without severe side-effects. PMID:20665654

  19. A novel calcineurin-independent activity of cyclosporin A in Saccharomyces cerevisiae.

    PubMed

    Singh-Babak, Sheena D; Shekhar, Tanvi; Smith, Andrew M; Giaever, Guri; Nislow, Corey; Cowen, Leah E

    2012-10-01

    Fungi rely on regulatory networks to coordinate sensing of environmental stress with initiation of responses crucial for survival. Antifungal drugs are a specific type of environmental stress with broad clinical relevance. Small molecules with antifungal activity are ubiquitous in the environment, and are produced by a myriad of microbes in competitive natural communities. The echinocandins are fungal fermentation products and the most recently developed class of antifungals, with those in clinical use being semisynthetic derivatives that target the fungal cell wall by inhibiting 1,3-β-D-glucan synthase. Recent studies implicate the protein phosphatase calcineurin as a key regulator of cellular stress responses required for fungal survival of echinocandin-induced cell wall stress. Pharmacological inhibition of calcineurin can be achieved using the natural product and immunosuppressive drug cyclosporin A, which inhibits calcineurin by binding to the immunophilin Cpr1. This drug-protein complex inhibits the interaction between the regulatory and catalytic subunits of calcineurin, an interaction necessary for calcineurin function. Here, we report on potent activity of cyclosporin A when combined with the echinocandin micafungin against the model yeast Saccharomyces cerevisiae that is independent of its known mechanism of action of calcineurin inhibition. This calcineurin-independent synergy does not involve any of the 12 immunophilins known in yeast, individually or in combination, and is not mediated by any of the multidrug transporters encoded or controlled by YOR1, SNQ2, PDR5, PDR10, PDR11, YCF1, PDR15, ADP1, VMR1, NFT1, BPT1, YBT1, YNR070w, YOL075c, AUS1, PDR12, PDR1 and/or PDR3. Genome-wide haploinsufficiency profiling (HIP) and homozygous deletion profiling (HOP) strongly implicate the cell wall biosynthesis and integrity pathways as being central to the calcineurin-independent activity of cyclosporin A. Thus, systems level chemical genomic approaches implicate

  20. Skeletal muscle ischemia-reperfusion injury and cyclosporine A in the aging rat.

    PubMed

    Pottecher, Julien; Kindo, Michel; Chamaraux-Tran, Thiên-Nga; Charles, Anne-Laure; Lejay, Anne; Kemmel, Véronique; Vogel, Thomas; Chakfe, Nabil; Zoll, Joffrey; Diemunsch, Pierre; Geny, Bernard

    2016-06-01

    Old patients exhibit muscle impairments and increased perioperative risk during vascular surgery procedures. Although aging generally impairs protective mechanisms, data are lacking concerning skeletal muscle in elderly. We tested whether cyclosporine A (CsA), which protects skeletal muscle from ischemia-reperfusion (IR) in young rats, might reduce skeletal muscle mitochondrial dysfunction and oxidative stress in aging rats submitted to hindlimb IR. Wistar rats aged 71-73 weeks were randomized to IR (3 h unilateral tourniquet application and 2 h reperfusion) or IR + CsA (10 mg/kg cyclosporine IV before reperfusion). Maximal oxidative capacity (VM ax ), acceptor control ratio (ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV (VS ucc ), and IV (VTMPD /Asc ), together with calcium retention capacity (CRC) a marker of apoptosis, and tissue reactive oxygen species (ROS) production were determined in gastrocnemius muscles from both hindlimbs. Compared to the nonischemic hindlimb, IR significantly reduced mitochondrial coupling, VMax (from 7.34 ± 1.50 to 2.87 ± 1.22 μMO2 /min/g; P < 0.05; -70%), and VS ucc (from 6.14 ± 1.07 to 3.82 ± 0.83 μMO2 /min/g; P < 0.05; -42%) but not VTMPD /Asc . IR also decreased the CRC from 15.58 ± 3.85 to 6.19 ± 0.86 μMCa(2+) /min/g; P < 0.05; -42%). These alterations were not corrected by CsA (-77%, -49%, and -32% after IR for VM ax, VS ucc , and CRC, respectively). Further, CsA significantly increased ROS production in both hindlimbs (P < 0.05; +73%). In old rats, hindlimb IR impairs skeletal muscle mitochondrial function and increases oxidative stress. Cyclosporine A did not show protective effects. PMID:26787364

  1. Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants.

    PubMed

    Clardy, C W; Schroeder, T J; Myre, S A; Wadhwa, N K; Pesce, A J; First, M R; McEnery, P T; Balistreri, W F; Harris, R E; Melvin, D B

    1988-10-01

    The most important limitation associated with the clinical use of cyclosporine is the narrow therapeutic range between its efficacy and toxicity. Effective treatment is further complicated by significant variation in intrapatient and interpatient pharmacokinetics of the drug. We describe a practical approach to pharmacokinetic analysis that does not interfere with the cyclosporine dosage regimen or with clinical management of the patient. To optimize therapy, we individualized patient management by using noncompartmental pharmacokinetic analysis. Mean residence time (MRT) and volume of distribution at steady-state were calculated from data on concentration vs time after dose. We applied this approach to 24 kidney, 12 heart, 8 bone-marrow, 7 liver, and 5 pancreas transplants. Individualized requirements for cyclosporine dose and dosage interval can be predicted from these parameters. MRT is the most useful pharmacokinetic parameter, because it allows prediction of the optimal dosage interval. PMID:3048779

  2. Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation

    PubMed Central

    Hibberd, Adrian D; Clark, David A; Trevillian, Paul R; Mcelduff, Patrick

    2016-01-01

    AIM: To investigate the interaction between castanospermine and cyclosporin A (CsA) 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 (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure 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 CsA in the prolongation of cardiac allograft survival for dose ranges of CsA 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 CsA. On the contrary, cessation of castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA 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 CsA in rat cardiac transplantation. Neither the mixed lymphocyte

  3. SUCCESSFUL SMALL BOWEL ALLOTRANSPLANTATION IN DOGS WITH CYCLOSPORINE AND PREDNISONE1

    PubMed Central

    Diliz-Perez, Hector S.; McClure, John; Bedetti, Carlos; Hong, He-Qun; de Santibanes, Eduardo; Shaw, Byers W.; Van Thiel, David; Iwatsuki, Shunzaburo; Starzl, Thomas E.

    2010-01-01

    Twelve dogs had transplantation of almost the entire small intestine in the orthotopic location; immunosuppression was with cyclosporine and prednisone. Half the dogs had survival of at least one month, and a third lived for at least four months. Two of the animals are still living after 550 and 555 days. Maintenance of nutrition, and absorption of D-xylose and fat were better than in control animals with an iatrogenic short gut syndrome, but distinctly worse than that of normal dogs. PMID:6695451

  4. Conversion from Tacrolimus to Cyclosporine A Improves Glucose Tolerance in HCV-Positive Renal Transplant Recipients

    PubMed Central

    Handisurya, Ammon; Kerscher, Corinna; Tura, Andrea; Herkner, Harald; Payer, Berit Anna; Mandorfer, Mattias; Werzowa, Johannes; Winnicki, Wolfgang; Reiberger, Thomas; Kautzky-Willer, Alexandra; Pacini, Giovanni; Säemann, Marcus; Schmidt, Alice

    2016-01-01

    Background Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. Methods In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). Results After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82–441.92) vs. 468.80 (414.27–488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032–0.106) vs. 0.083 (0.054–0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. Conclusions HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV

  5. Induction therapy with a combination of fumarates and cyclosporine: A benefit for the patient?

    PubMed

    Fallah Arani, S; Neumann, H A M; Thio, H B

    2016-08-01

    Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance. PMID:26651839

  6. Successful treatment of severe arthralgia associated with palmoplantar pustulosis with low-dose oral cyclosporine A.

    PubMed

    Yamamoto, T; Kimura, K; Katayama, I; Nishioka, K

    1995-07-01

    Two patients with severe arthralgia associated with palmoplantar pustulosis (PPP) were treated with oral cyclosporine A (CsA). Clinical efficacy was assessed on a 0-4 point scale for erythema, desquamation, infiltration, and pustulation, and on a 0-3 point pain scale. Skin lesions and arthralgia improved within twelve weeks with low dose CsA ranging from 2.1 to 2.2 mg/kg/day. High levels of plasma interleukin-6 (IL-6) were reduced to the normal range. PMID:7560444

  7. The effect of cyclosporin A on peripheral blood T cell subpopulations in renal allografts.

    PubMed Central

    Sweny, P; Tidman, N

    1982-01-01

    Treatment with cyclosporin A (CyA) produces a reversal of the normal ratio of OKT4+ (inducer type) to OKT84 (suppressor-cytotoxic type) cells so that renal allograft recipients on CyA alone develop a four-fold increase in the absolute number of circulating OKT8 positive cells. Conventional immunosuppression with azathioprine and prednisolone reduces both populations of T cells without altering the ratio of OKT4+ to OKT8+ cells. This effect of CyA may help to explain its action as an immunosuppressive agent. PMID:6210475

  8. Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine

    PubMed Central

    Kim, Kwi Suk; Moon, Aree; Kang, Hyoung Jin; Shin, Hee Young; Choi, Young Hee; Kim, Hyang Sook; Kim, Sang Geon

    2016-01-01

    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 cyclosporine were 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 (aGVHD) and VOD. Although the incidences of aGVHD 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/dL 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/dL, suggestive of more sensitive VOD indication in this age group. PMID:27358786

  9. Abbott’s Fluorescence Polarization Immunoassay for Cyclosporine and Metabolites Compared with the Sandoz “Sandimmune” RIA

    PubMed Central

    Sanghvi, Ajit; Diven, Warren; Seltman, Howard; Starzl, Thomas

    2010-01-01

    A new procedure for measuring cyclosporine in plasma has been introduced by Abbott Laboratories, involving their TDx instrumentation and fluorescence polarization immunoassay. Radioimmunoassay (RIA) and high-performance liquid chromatography are currently the conventional methods for measuring cyclosporine in plasma and whole blood. In an effort to find a method that will decrease the radioactive hazard, the reagent and supply cost, and the labor requirements associated with RIA procedures, we used specimens from transplantation patients to compare the Abbott assay with the Sandoz Sandimmune assay. We believe that the Abbott assay offers some advantages over the Sandimmune RIA procedure, providing a reliable but simpler and less hazardous technology. PMID:3416444

  10. Differential effects of cyclosporin A on transport of bile acids by rat hepatocytes: relationship to individual serum bile acid levels.

    PubMed

    Azer, S A; Stacey, N H

    1994-02-01

    Cyclosporin A treatment has been reported to induce hepatotoxicity marked by a rise in total serum bile acid and total bilirubin. The mechanism of cyclosporin A-induced hepatotoxicity seems to be related to interference with hepatocellular transport of these substrates although this remains to be fully substantiated. The purpose of this study was to investigate whether the hepatocellular uptake of the different bile acids, in the presence of cyclosporin A, is consistent with the changes in their respective individual serum bile acid concentrations. High-performance liquid chromatography has been used to assay individual serum bile acids in cyclosporin A-treated rats at doses of 0.1, 1, and 10 mg/kg/day for 4 days. Control rats were treated with Cremophor (1 ml/kg/day). At the higher doses, cyclosporin A produced a significant increase in levels of cholic acid, taurocholic acid, chenodeoxycholic acid, and deoxycholic acid compared with controls. Serum glycocholate was unaffected even at the highest dose. Inhibition of initial rate of uptake and accumulation of [14C]cholic acid, [14C]chenodeoxycholic acid, and [14C]deoxycholic acid by isolated rat hepatocytes was consistent with the changes in their respective serum bile acids. Coincubation of rat hepatocytes with unlabeled cholic acid (100 microM), the major serum bile acid in cyclosporin A-treated rats, showed a further inhibitory effect on [14C]cholic acid and [14C]deoxycholic acid accumulation. The initial rate of uptake of [14C]glycocholate was also inhibited. However, accumulation of glycocholic acid did not show significant changes at the longer incubation times (2-30 min). In addition, coincubation of rat hepatocytes with unlabeled cholic acid (100 microM) plus cyclosporin A did not induce any inhibition of glycocholate accumulation. Together, these differences provide an explanation for the unchanged serum levels of glycocholate. In conclusion, the changes in individual serum bile acids in cyclosporin A

  11. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity

    PubMed Central

    Czechowska, Grażyna; Irla-Miduch, Joanna

    2016-01-01

    Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity. PMID:27298826

  12. Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

    PubMed Central

    Rodrigues-Diez, Raquel; González-Guerrero, Cristian; Ocaña-Salceda, Carlos; Rodrigues-Diez, Raúl R.; Egido, Jesús; Ortiz, Alberto; Ruiz-Ortega, Marta; Ramos, Adrián M.

    2016-01-01

    The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4−/− mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2−/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation. PMID:27295076

  13. Canine mammary carcinoma cell line are resistant to chemosensitizers: verapamil and cyclosporin A.

    PubMed

    Król, M; Pawłowski, K M; Majchrzak, K; Mucha, J; Motyl, T

    2014-01-01

    Cancer chemotherapy can fail in many ways. One of the most significant is the development of multiple drug resistance (MDR), which constitutes a serious clinical problem. The development of MDR relates to the expression of a major membrane pump, P-glycoprotein (P-gp). Thus, currently one of the goals of experimental and clinical oncology is to decrease its activity. So far, many different P-gp inhibitors are available, but their efficacy is still questionable and requires further study. The aim of our study was to assess an impact of classical P-gp inhibitors (verapamil and cyclosporin A) in the reversion of multidrug resistance in canine mammary cancer cells. We used two cell lines isolated from mammary tumors and two cell lines isolated from their lung metastases. All of them showed P-gp over-expression confirmed using Real-time rt-PCR, Skan(R) screening station and confocal microscopy. The FACS analysis showed that in three of the examined cell lines, treatment with verpamil/cyclosporin A was ineffective to reverse cancer chemoresistance. However, more studies in this field are required. PMID:24724465

  14. Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients

    PubMed Central

    Baek, Hyunjeong; Han, Seunghoon; Yim, Dong-Seok; Kim, Sung Joo; Lee, Soo-Youn; Jang, Hye Ryoun; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Oh, Ha Young; Huh, Wooseong

    2014-01-01

    This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time–concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period. PMID:25422583

  15. Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling.

    PubMed

    Rodrigues-Diez, Raquel; González-Guerrero, Cristian; Ocaña-Salceda, Carlos; Rodrigues-Diez, Raúl R; Egido, Jesús; Ortiz, Alberto; Ruiz-Ortega, Marta; Ramos, Adrián M

    2016-01-01

    The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4(-/-) mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2(-)/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation. PMID:27295076

  16. Biological conversion of a water-soluble prodrug of cyclosporine A.

    PubMed

    Lallemand, F; Varesio, E; Felt-Baeyens, O; Bossy, Leila; Hopfgartner, G; Gurny, R

    2007-09-01

    UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) designed for topical ocular delivery. The pro-moiety is grafted via an ester function to CsA and the solubilizing group is a phosphate ion. The aim of this study was to elucidate the conversion mechanisms by which UNIL088 generates CsA. UNIL088 was incubated in rabbit tears at physiological temperature to study its enzymatic and chemical conversion, respectively. Metabolites and intermediates were identified using a quadrupole-time of flight (QqTOF) mass spectrometer, which allowed biotransformation pathways to be deduced. Conversion is activated by the chemical or enzymatic hydrolysis of the terminal ester function of the pro-moiety, leading to the phospho-serine-sarcosine-cyclosporine A that spontaneously converts into CsA. In addition to the main biotransformation pathway, a secondary reaction involved hydrolysis of the phosphate ester group of the pro-moiety, probably by phosphatases present in tears. PMID:17475453

  17. Expression of amelogenin and effects of cyclosporin A in developing hair follicles in rats.

    PubMed

    Yoo, Hong-Il; Lee, Gye-Hyeok; Lee, Su-Young; Kang, Jee-Hae; Moon, Jung-Sun; Kim, Min-Seok; Kim, Sun-Hun

    2016-01-01

    Amelogenin, an enamel matrix protein has been considered to be exclusively expressed by ameloblasts during odontogenesis. However, burgeoning evidence indicates that amelogenin is also expressed in non-mineralizing tissues. Under the hypothesis that amelogenin may be a functional molecule in developing hair follicles which share developmental features with odontogenesis, this study for the first time elucidated the presence and functional changes of amelogenin and its receptors during rat hair follicle development. Amelogenin was specifically localized in the outer epithelial root sheath of hair follicles. Its expression appeared in the deeper portion of hair follicles, i.e. the bulbar and suprabulbar regions rather than the superficial region. Lamp-1, an amelogenin receptor, was localized in either follicular cells or outer epithelial sheath cells, reflecting functional changes during development. The expression of amelogenin splicing variants increased in a time-dependent manner during postnatal development of hair follicles. Amelogenin expression was increased by treatment with cyclosporin A, which is an inducer of anagen in the hair follicle, whereas the level of Lamp-1 and -2 was decreased by cyclosporin A treatment. These results suggest that amelogenin may be a functional molecule involved in the development of the hair follicle rather than an inert hair shaft matrix protein. PMID:26426935

  18. A pilot study of medium-dose cyclosporine for the treatment of palmoplantar pustulosis complicated with pustulotic arthro-osteitis.

    PubMed

    Hayama, Koremasa; Inadomi, Toru; Fujisawa, Daisuke; Terui, Tadashi

    2010-01-01

    Pustulotic arthro-osteitis (PAO), which is one of the most intractable complications of palmoplantar pustulosis (PPP), is resistant to conventional therapies such as oral administration of NSAIDs. The main purpose of this study was to assess the effectiveness of cyclosporine for treating PPP with PAO. Seven patients affected by PPP with PAO were enrolled, and were treated with cyclosporine at medium doses ranging from 2 to 3 mg/kg/day. The severity of the skin lesions was scored by the modified PASI and pain scores at 0, 2, 4 and 8 weeks after the initiation of treatment, were assessed. QoL was assessed by SF-8TM at 0 and 8 weeks. The average dose of cyclosporine used was 2.48 mg/kg/day. Each pain score improved statistically significantly at the indicated times after the initiation of treatment (P < 0.05). The QoL score improved significantly with a good correlation with the relevant pain scores. The modified PASI scores also decreased gradually, but were not statistically significant. No serious adverse events were observed in this study. These results suggest that a medium dose of cyclosporine is effective for treating PPP with PAO and markedly improves the patient QoL. PMID:21047721

  19. Factors related to the incidence and severity of cyclosporin-induced gingival overgrowth in transplant patients. A longitudinal study.

    PubMed

    Somacarrera, M L; Hernández, G; Acero, J; Moskow, B S

    1994-07-01

    A longitudinal study was conducted during the first 6 months following transplant surgery in 100 heart, liver, or kidney transplant patients to assess the incidence and severity of cyclosporin-induced gingival overgrowth, as well as the most important associated factors. Gingival overgrowth, plaque, and gingivitis indices, in addition to cyclosporin blood concentration, were assessed monthly. Statistical analysis was applied to evaluate the relationship between gingival overgrowth and other study variables and to test the influence of age, sex, time, and transplant type. Forty-three percent (43%) of the patients developed gingival overgrowth. Gingival overgrowth increased significantly during the study, while plaque and gingivitis, subject to an oral hygiene training and motivation program, decreased significantly. The findings from this study would suggest that the basic factor influencing gingival overgrowth is cyclosporin blood concentration, followed by plaque/gingivitis level. The significant differences observed among transplant types, as well as among age groups, might be attributed to the differences in cyclosporin concentrations. An oral hygiene program prior to the transplant surgery is recommended. PMID:7608843

  20. Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.

    PubMed Central

    Back, D J; Tjia, J F

    1991-01-01

    Four antimycotic drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine have been studied for their effect on the metabolism of cyclosporin by human liver microsomes (n = 3) in vitro. Ketoconazole caused marked inhibition of cyclosporin hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and 0.022 +/- 0.004 microM, respectively. Based on IC50 values, itraconazole was ten times less potent (IC50 value of 2.2 +/- 0.2 microM) and both fluconazole and terbinafine had values above 100 microM. Ki values for itraconazole and fluconazole were 0.7 +/- 0.2 and 40 +/- 5.6 microM, respectively. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Based on these data, ketoconazole is confirmed as being a potent inhibitor of cyclosporin metabolism and this has clinical relevance. Although inhibition by fluconazole was much less than that by itraconazole at equimolar concentrations, it should be noted that in patients plasma concentrations of fluconazole are much greater than those of itraconazole. Clinical interactions of cyclosporin with both fluconazole and itraconazole have been reported. In contrast to the azoles, terbinafine does not have the same potential for interaction. PMID:1659439

  1. Simple, rapid /sup 125/I-labeled cyclosporine double antibody/polyethylene glycol radioimmunoassay used in a pediatric cardiac transplant program

    SciTech Connect

    Berk, L.S.; Webb, G.; Imperio, N.C.; Nehlsen-Cannarella, S.L.; Eby, W.C.

    1986-01-01

    We modified the Sandoz cyclosporine radioimmunoassay because of our need for frequent clinical monitoring of cyclosporine drug levels in allo- and xenograft pediatric cardiac transplant patients. With application of a commercially available (/sup 125/I)cyclosporine label in place of (/sup 3/H)cyclosporine and a second antibody/polyethylene glycol (PEG) method of separation in place of charcoal separation, we simplified and enhanced the speed and precision of assay performance. Studies of 140 whole blood samples comparing this new method to the (/sup 3/H)cyclosporine radioimmunoassay (RIA) method of Berk and colleagues yielded a coefficient of correlation of 0.96 (p less than 0.00001) with means of 626 and 667 ng/ml for (/sup 3/H)RIA and (/sup 125/I)RIA, respectively, and a regression equation of y = 28 + 1.02x. The major advantages are that total assay time is reduced to approximately 1 h; (/sup 125/I)cyclosporine label is used, avoiding the problems associated with liquid scintillation counting; and precision is enhanced by separating bound and free fractions with second antibody/PEG. These modifications should provide for greater ease of assay performance and improved clinical utility of cyclosporine monitoring not only in the pediatric but also in the adult transplant patient.

  2. Cyclosporine Injection

    MedlinePlus

    ... hours before transplant surgery and once a day after the surgery until medication can be taken by ... Mevacor), pravastatin (Pravachol), and simvastatin (Zocor); cimetidine (Tagamet);ciprofloxacin (Cipro); clarithromycin (Biaxin); colchicine; dalfopristin and quinupristin combination ( ...

  3. Cyclosporine Injection

    MedlinePlus

    ... diuretics ('water pills') including amiloride (in Hydro-ride), spironolactone (Aldactone), and triamterene (Dyazide, Dyrenium, in Maxzide); erythromycin ( ... or growth of extra tissue on the gums acne uncontrollable shaking of a part of your body ...

  4. Safety of Eplerenone for Kidney-Transplant Recipients with Impaired Renal Function and Receiving Cyclosporine A

    PubMed Central

    Barbe, Coralie; Lavaud, Sylvie; Toupance, Olivier; Nazeyrollas, Pierre; Jaisser, Frederic; Rieu, Philippe

    2016-01-01

    Background Animal studies have highlighted the role of vascular mineralocorticoid receptor during Cyclosporine A-induced nephrotoxicity. Mineralocorticoid receptor antagonists could improve kidney survival but are not commonly used during renal impairment and in association with several immunosuppressive drugs due to a supposed higher risk of adverse events. We tested the tolerance of eplerenone according to its expected adverse events: hyperkalemia, metabolic acidosis, hypotension, acute kidney failure, or any other adverse event. Methods We conducted a single-center, prospective, open-label study in 31 kidney-transplant recipients with impaired renal function (30 and 50 mL/min/1.73m2) and receiving cyclosporine A. All patients received eplerenone 25 mg/d for 8 weeks. Serum potassium, renal function and expected adverse events were closely monitored. Results Eight patients experienced mild hyperkalemia (>5 mmol/L), one moderate hyperkalemia (>5.5 mmol/L) and had to receive potassium-exchange resin. No severe hyperkalemia (>6 mmol/L) occurred. One acute kidney failure was observed, secondary to diarrhea. Basal serum potassium and bicarbonate were independently associated with a higher risk of developing mild hyperkalemia (>5 mmol/L) under treatment (OR 6.5, p = 0.003 and 0.7, p = 0.007, respectively). A cut-off value of 4.35 mmol/L for basal serum potassium was the best factor to predict the risk of developing mild hyperkalemia (>5 mmol/L). Conclusions Until eGFR falls to 30 mL/min/1.73m2, eplerenone could be safely given to kidney-transplant recipients receiving cyclosporine A, if kalemia is closely monitored. When renal function is impaired and if basal kalemia is >4.35 mmol/L, then clinicians should properly balance risk and benefit of eplerenone use and offer dietary advice. An adequately powered prospective randomized study is now needed to test its efficiency (and safety) in this population. Trial Registration ClinicalTrials.gov NCT01834768 PMID:27088859

  5. The new immunosuppressant, isogarcinol, binds directly to its target enzyme calcineurin, unlike cyclosporin A and tacrolimus.

    PubMed

    Cen, Juren; Wang, Mengqi; Jiang, Guohua; Yin, Yanxia; Su, Zhenyi; Tong, Li; luo, Jing; Ma, Yipeng; Gao, Yadan; Wei, Qun

    2015-04-01

    Isogarcinol, a bioactive polyisoprenylated benzophenone derivative isolated from Garcinia mangostana L., has been shown previously to exert a strong inhibitory effect on calcineurin and is thus a potential oral, low-toxicity immunomodulatory drug. In the present study, enzyme kinetic analysis showed that inhibition of calcineurin by isogarcinol was competitive. Fluorescence spectroscopy indicated that isogarcinol bound to calcineurin. Isothermal titration calorimetry showed that binding was mainly driven by enthalpy, and was exothermic because the enthalpy change exceeded the entropy reduction. The interaction force is either hydrogen bonding or Van der Waals forces. Fluorescence resonance energy transfer and molecular docking experiments indicated that there were two potential binding sites for isogarcinol in the catalytic domain of calcineurin. In summary, isogarcinol binds directly to calcineurin in vitro, unlike the classical calcineurin inhibitors cyclosporin A and tacrolimus. PMID:25701551

  6. Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

    PubMed Central

    Tjia, J F; Back, D J; Breckenridge, A M

    1989-01-01

    The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine. PMID:2789931

  7. Schnitzler's syndrome with monoclonal IgG kappa gammopathy: good response to cyclosporin.

    PubMed

    Pascual-López, M; Hernández-Núñez, A; Sánchez-Pérez, J; Fernández-Herrera, J; García-Díez, A

    2002-05-01

    Schnitzler's syndrome (SS) is a rare entity characterized by the association of chronic urticaria and monoclonal IgM gammopathy. Usually, intermittent fever, arthralgia and elevation of erythrocyte sedimentation rate also occur. We report a patient with the same symptoms, but with monoclonal IgG instead of IgM paraproteinaemia. Histological examination of the urticarial lesions showed signs of leucocytoclastic vasculitis. After 20 years of therapeutic failure, cyclosporin has achieved a total clearance of urticarial lesions in our patient. Two previous similar cases with clinical features of SS and monoclonal IgG immunoglobulin have been described. We suggest our case also represents a variant of SS with IgG gammopathy. PMID:12195569

  8. Protective effects of 2-deoxy-D-glucose on nephrotoxicity induced by cyclosporine A in rats

    PubMed Central

    Ouyang, Zizhang; Cao, Weiwei; Zhu, Shaohua; Liu, Xiaoping; Zhong, Zhihua; Lai, Xiangmao; Deng, Huirong; Jiang, Sheng; Wang, Yan

    2014-01-01

    Objective: This study aims to explore the protective effect mechanism of 2-deoxy-D-glucose on nephrotoxicity of cyclosporin A in vivo. Method: Renal toxicity of SD rats model induced by CsA was established. Serum creatinine, blood urea nitrogen, urine NAG, GSH and MDA were determined and the histopathological changes of rat renal cortex were observed to explore the protective effects of 2-DG on CsA-induced nephrotoxicity. Results: Serum creatinine, BUN and urinary NAG of rats were significantly changed in experimental groups. Pathological results showed that there was obvious renal tubular injury in model group, however, the renal injury was significantly reduced in pre-treated with 2-DG. Conclusions: 2-DG had obvious protective effect on nephrotoxicity especially with high dose. This protective effect could be related to the reduction of ROS induced by CsA. However, 2-DG had no effect on the expression of RIP3. PMID:25197331

  9. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A.

    PubMed

    Steiner, J P; Connolly, M A; Valentine, H L; Hamilton, G S; Dawson, T M; Hester, L; Snyder, S H

    1997-04-01

    We show that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neuronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 of cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases. PMID:9095176

  10. Efficacy of AZM therapy in patients with gingival overgrowth induced by Cyclosporine A: a systematic review

    PubMed Central

    Clementini, Marco; Vittorini, Gianluca; Crea, Alessandro; Gualano, Maria Rosaria; Macrì, Ludovica Antonella; Deli, Giorgio; La Torre, Giuseppe

    2008-01-01

    Background In daily clinical practice of a dental department it's common to find gingival overgrowth (GO) in periodontal patients under treatment with Cyclosporine A (CsA). The pathogenesis of GO and the mechanism of action of Azithromycin (AZM) are unclear. A systematic review was conducted in order to evaluate the efficacy of Azithromycin in patients with gingival overgrowth induced by assumption of Cyclosporine A. Methods A bibliographic search was performed using the online databases MEDLINE, EMBASE and Cochrane Central of Register Controlled Trials (CENTRAL) in the time period between 1966 and September 2008. Results The literature search retrieved 24 articles; only 5 were Randomised Controlled Trials (RCTs), published in English, fulfilled the inclusion criteria. A great heterogeneity between proposed treatments and outcomes was found, and this did not allow to conduct a quantitative meta-analysis. The systematic review revealed that a 5-day course of Azithromycin with Scaling and Root Planing reduces the degree of gingival overgrowth, while a 7-day course of metronidazole is only effective on concomitant bacterial over-infection. Conclusion Few RCTs on the efficacy of systemic antibiotic therapy in case of GO were found in the literature review. A systemic antibiotic therapy without plaque and calculus removal is not able to reduce gingival overgrowth. The great heterogeneity of diagnostic data and outcomes is due to the lack of precise diagnostic methods and protocols about GO. Future studies need to improve both diagnostic methods and tools and adequate classification aimed to determine a correct prognosis and an appropriate therapy for gingival overgrowth. PMID:19087331

  11. Topical, Aqueous, Clear Cyclosporine Formulation Design for Anterior and Posterior Ocular Delivery

    PubMed Central

    Cholkar, Kishore; Gilger, Brian C.; Mitra, Ashim K.

    2015-01-01

    Purpose: The main objective of this study was to optimize cyclosporine (CsA) nanomicellar solution and study in vivo ocular CsA tissue distribution with a topical drop. Methods: An optimized blend of hydrogenated castor oil-40 and octoxynol-40 was prepared to entrap CsA within nanomicelles. In vivo studies were conducted in New Zealand White albino rabbits with topical drop instillation. Results: Average size of CsA-loaded nanomicelles was approximately 22.4 nm. Ocular tissue CsA quantification with single and multiple dosing revealed that CsA levels followed as cornea → iris-ciliary body → aqueous humor → lens. Cyclosporine levels were also found to be in the following order: conjunctiva → sclera → retina/choroid → vitreous humor. High CsA level was detected in retina/choroid (53.7 ng/g tissue). Conclusions: Ocular tissue CsA distribution studies revealed high CsA concentrations in anterior ocular tissues. Moreover, it appears that nanomicelles are transported through a conjunctival–scleral pathway and deliver CsA to the retina/choroid. Results suggest polymeric blend to be a safe carrier for anterior and posterior ocular tissues. Translational Relevance: This study has significant translational relevance, disclosing results that suggest that aqueous nanomicellar approach can provide high corneal and conjunctival CsA concentrations. Aqueous nanomicelles can deliver high drug concentrations not only to anterior but also to back of the eye tissues, including retina. This article provides a platform for noninvasive back of the eye drug delivery with topical eye drops. Aqueous CsA nanomicelles have no perceptible toxicity such as cell membrane damage or cytotoxicity to corneal and retinal pigment epithelial cells. Clear aqueous nanomicellar solution can be translated to human conditions for keratoconjunctivitis sicca and other anti-inflammatory conditions. PMID:25964868

  12. Heteropterys tomentosa (A. Juss.) infusion counteracts Cyclosporin a side effects on the ventral prostate

    PubMed Central

    2013-01-01

    Background Cyclosporin A (CsA) is an immunosuppressive drug widely used in treatment of auto-immune diseases or after organ transplants. However, several side effects are commonly associated with CsA long term intake, some regarding to loss of reproductive organ function due to oxidative damage. Considering that phytotherapy is an important tool often used against oxidative stress, we would like to describe the beneficial effects of Heteropterys tomentosa intake to minimize the damage caused by CsA to the ventral prostate tissue of Wistar rats under laboratorial conditions. Methods Thirty adult Wistar rats (Rattus norvegicus albinus) were divided into: control group (water); CsA group (Cyclosporin A); Ht group (H. tomentosa infusion) and CsA + Ht group (CsA and H. tomentosa infusion). Plasmic levels of hepatotoxicity markers, triglycerides, cholesterol and glucose were quantified. The ventral prostate tissue was analyzed under light microscopy, using stereological, morphometrical and immunohistochemical techniques. Results H. tomentosa did not cause any alterations either of the plasmic parameters or of the ventral prostate structure. CsA caused alterations of GOT, total and indirect bilirubin, cholesterol, triglycerides and glucose levels in the plasma; CsA-treated rats showed alterations of the ventral prostate tissue. There were no alterations regarding the plasma levels of GOT, triglycerides and glucose of CsA + Ht animals. The same group also showed normalization of most of the parameters analyzed on the ventral prostate tissue when compared to the CsA group. The treatments did not alter the pattern of AR expression or the apoptotic index of the ventral prostate epithelium. Conclusions The results suggest a protective action of the H. tomentosa infusion against the side effects of CsA on the ventral prostate tissue, which could also be observed with plasmic biochemical parameters. PMID:23406403

  13. An animal model of testicular toxicity by cyclosporine: evaluation and protection.

    PubMed

    Ali, Ridha Ben; Klouz, Anis; Boubaker, Samir; Lakhal, Mohamed; Belkahia, Chalbi

    2009-04-01

    CyclosporineA (CsA) improves the survival of patients who benefited from transplantation. However, its use is generally limited by its side effects. The aim of our study was to measure, in an experimental model, the changes of the testosterone plasma levels after 21 days of CsA treatment and to explain the mechanism of this modification. After treatment, the levels of CsA, testosterone, corticosterone, transaminases were measured. The cytotoxic effect of CsA was evaluated by microscopic observation. The experimental study showed that CsA had no effect on the plasmatic levels of hepatic enzymes - alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl-transferase - because their plasma concentrations in treated rats did not differ from those of the sham group. The plasma concentration of corticosterone was not modified, the plasma level of testosterone decreased when the dose of cyclosporine was increased to 4 mg/kg/day. The photonic microscope observation showed that the number of Leydig cells was increased and the electronic microscope observation showed mitochondria alteration. The treatment by CsA and trimetazidine did not correct the alteration caused by CsA. N-benzyl-N'-(2-hydrox-3, 4-dimethyloxybenzyl)-pipeazine did not protect the mitochondrial function but partially protected mitochondria structure from the deleterious effect induced by CsA. The decrease of the plasma level of testosterone induced by CsA was due to the inhibition of the mitochondrial 20-22 desmolase which blocked the formation of the testosterone precursor and the destruction of the mitochondria structure. PMID:19645818

  14. A Retrospective Comparison of Mycophenolate Mofetil with Low-Exposure Cyclosporine Versus Standard Cyclosporine Therapy in De Novo Liver Transplant Patients.

    PubMed

    Senft, Jonas D; Gotthardt, Daniel N; Frischbier, Lina; Bruns, Helge; Schemmer, Peter

    2015-01-01

    BACKGROUND Data on low-exposure calcineurin inhibitor therapy with mycophenolate mofetil (MMF) in de novo liver transplant patients are limited and restricted to tacrolimus. MATERIAL AND METHODS Twenty-eight patients receiving cyclosporine and MMF at a single center were identified retrospectively and categorized as low-exposure or standard-exposure CsA (median concentration <80 ng/mL [n=16] or ≥80 ng/mL [n=12] during days 1-7) and analyzed to 12 weeks post-transplant. RESULTS Biopsy-proven acute rejection (Banff ≥4) occurred in 3 low-CsA patients and no standard-CsA patients (p=0.238); graft failure occurred in 4 and zero patients, respectively (p=0.113); no graft loss was attributable to rejection. Mean (SD) estimated GFR at baseline and week 12 was 79.5 (45.3) and 79.3 (24.5) mL/min/1.73 m2 in the low-CsA group (p=0.508), and 106.0 (66.9) and 86.7 (23.2) mL/min/1.73 m2 in the standard-CsA group (p=0.093). Estimated GFR decreased significantly in patients with good baseline renal function (≥80 mL/min/1.73 m2) in the standard-CsA (p=0.028) and increased markedly in patients with poor function (≤60 mL/min/1.73 m2) given low-CsA (p=0.043). There was no significant between-group difference regarding incidence of infections. CONCLUSIONS These preliminary findings suggest that immunosuppressive efficacy is maintained with low-exposure CsA and MMF in de novo liver transplant patients and good baseline renal function may be better preserved, but no benefit for infections was observed. PMID:26364728

  15. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

    PubMed

    Pestana, J O Medina; Grinyo, J M; Vanrenterghem, Y; Becker, T; Campistol, J M; Florman, S; Garcia, V D; Kamar, N; Lang, P; Manfro, R C; Massari, P; Rial, M D C; Schnitzler, M A; Vitko, S; Duan, T; Block, A; Harler, M B; Durrbach, A

    2012-03-01

    Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population. PMID:22300431

  16. Effectiveness and Optical Quality of Topical 3.0% Diquafosol versus 0.05% Cyclosporine A in Dry Eye Patients following Cataract Surgery

    PubMed Central

    Lee, Jang Hoon; Song, In Seok; Kim, Kyoung Lae; Yoon, Sam Young

    2016-01-01

    Purpose. To evaluate the effectiveness and optical quality of 3.0% topical diquafosol versus 0.05% cyclosporine A in dry eye patients following cataract surgery. Methods. In total, 40 eyes of 40 patients newly diagnosed with dry eye syndrome 1 week after cataract surgery were randomized to receive either 3.0% diquafosol ophthalmic solution six times daily or 0.05% cyclosporine A twice daily for 3 months. Outcome measures were tear film break-up time (TBUT), results on Schirmer 1 test, ocular surface staining score, the ocular surface disease index (OSDI) score, and higher-order aberrations (HOAs). Measurements were taken at baseline and at 1, 2, and 3 months. Results. In the diquafosol group, TBUT showed higher outcomes than the cyclosporine A group at 1 and 3 months. Both groups showed increased scores on Schirmer 1 test. The ocular surface staining score decreased in all periods in both groups. Vertical coma and total HOAs decreased more in the cyclosporine A group than in the diquafosol group at 3 months. Conclusion. Both 3.0% diquafosol and 0.05% cyclosporine A were effective in treating dry eye after cataract surgery. Diquafosol was more effective in increasing the tear secretion, but cyclosporine A was more effective in improving optical aberrations. PMID:26989503

  17. Oral Cyclosporin A Inhibits CD4 T cell P-glycoprotein Activity in HIV-Infected Adults Initiating Treatment with Nucleoside Reverse Transcriptase Inhibitors

    PubMed Central

    Hulgan, Todd; Donahue, John P.; Smeaton, Laura; Pu, Minya; Wang, Hongying; Lederman, Michael M.; Smith, Kimberly; Valdez, Hernan; Pilcher, Christopher; Haas, David W.

    2010-01-01

    Purpose P-glycoprotein limits tissue penetration of many antiretroviral drugs. We characterized effects of the P-glycoprotein substrate cyclosporin A on T cell P-glycoprotein activity in HIV-infected AIDS Clinical Trials Group study A5138 participants. Methods We studied P-glycoprotein activity on CD4 and CD8 T cells in 16 participants randomized to receive oral cyclosporin A (n=9) or not (n=7) during initiation antiretroviral therapy (ART) that did not include protease or non-nucleoside reverse transcriptase inhibitors. Results CD4 T cell P-glycoprotein activity decreased by a median of 8 percentage points with cyclosporin A/ART (difference between cyclosporin A/ART versus ART only P=0.001). Plasma trough cyclosporin A concentrations correlated with change in P-glycoprotein activity in several T cell subsets. Conclusions Oral cyclosporin A can inhibit peripheral blood CD4 T cell P-glycoprotein activity. Targeted P-glycoprotein inhibition might enhance delivery of ART to T cells. PMID:19779705

  18. Effectiveness and Optical Quality of Topical 3.0% Diquafosol versus 0.05% Cyclosporine A in Dry Eye Patients following Cataract Surgery.

    PubMed

    Lee, Jang Hoon; Song, In Seok; Kim, Kyoung Lae; Yoon, Sam Young

    2016-01-01

    Purpose. To evaluate the effectiveness and optical quality of 3.0% topical diquafosol versus 0.05% cyclosporine A in dry eye patients following cataract surgery. Methods. In total, 40 eyes of 40 patients newly diagnosed with dry eye syndrome 1 week after cataract surgery were randomized to receive either 3.0% diquafosol ophthalmic solution six times daily or 0.05% cyclosporine A twice daily for 3 months. Outcome measures were tear film break-up time (TBUT), results on Schirmer 1 test, ocular surface staining score, the ocular surface disease index (OSDI) score, and higher-order aberrations (HOAs). Measurements were taken at baseline and at 1, 2, and 3 months. Results. In the diquafosol group, TBUT showed higher outcomes than the cyclosporine A group at 1 and 3 months. Both groups showed increased scores on Schirmer 1 test. The ocular surface staining score decreased in all periods in both groups. Vertical coma and total HOAs decreased more in the cyclosporine A group than in the diquafosol group at 3 months. Conclusion. Both 3.0% diquafosol and 0.05% cyclosporine A were effective in treating dry eye after cataract surgery. Diquafosol was more effective in increasing the tear secretion, but cyclosporine A was more effective in improving optical aberrations. PMID:26989503

  19. Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine

    PubMed Central

    Darwich, A S; Pade, D; Rowland-Yeo, K; Jamei, M; Åsberg, A; Christensen, H; Ashcroft, D M; Rostami-Hodjegan, A

    2013-01-01

    An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual “post-bariatric surgery” population was evaluated through mimicking clinical investigations on cyclosporine and atorvastatin after bariatric surgery. Cyclosporine simulations displayed a reduced fraction absorbed through gut wall (fa) and Foral after surgery, consistent with reported observations. Simulated atorvastatin Foral postsurgery was broadly reflective of observed data with indications of counteracting interplay between reduced fa and an increased fraction escaping gut wall metabolism (FG). Inability to fully recover observed atorvastatin exposure after biliopancreatic diversion with duodenal switch highlights the current gap regarding the knowledge of associated biological changes. PMID:23903405

  20. Cyclosporine in psoriasis: comparison of a 25-year real-world Italian experience to current European guidelines.

    PubMed

    Altomare, Gianfranco; Ayala, Fabio; Bardazzi, Federico; Bellia, Gilberto; Chimenti, Sergio; Colombo, Delia; Flori, Maria L; Girolomoni, Giampiero; Micali, Giuseppe; Parodi, Aurora; Peris, Ketty; Vena, Gino A

    2016-08-01

    Cyclosporine (CsA) is an effective and safe therapeutic option in various dermatoses in both adults and children. Over the last 25 years, Italian dermatologists have gained relevant experience about the use of CsA in the treatment of psoriasis and atopic dermatitis, and an Italian Consensus Conference has recently provided recommendations in adult patients. A comparison between these real-world indications and current European guidelines is hereby provided. PMID:25786483

  1. Early adoption of cyclosporine and recombinant human erythropoietin: clinical, economic, and policy issues with emergence of high-cost drugs.

    PubMed

    Powe, N R; Eggers, P W; Johnson, C B

    1994-07-01

    The discovery of new drugs and their introduction into US markets will become an intense area of focus should health care reform result in Medicare insurance coverage for prescription drugs. Particular attention will be focused on high-cost drugs. Two high-cost drugs, cyclosporine and recombinant human erythropoietin (rHuEPO), introduced into the clinical management of patients with kidney disease during the past decade, provide some experience concerning the forces affecting the use of expensive drugs in a cost-conscious health care system. The decision to prescribe a drug will depend on provider's judgements of the drug's clinical benefits and costs compared with those of other possible therapies. It may also depend on payment policy. Both cyclosporine and rHuEPO were adopted rapidly and extensively by providers of end-stage renal disease care following US Food and Drug Administration approval, despite their high costs. Both drugs were remarkably effective, relatively safe, and able to be administered without great difficulty compared with the therapies they have replaced. There was no additional payment to hospitals for the initial use of cyclosporine, which was introduced in 1983 at the time when Medicare's prospective payment was established, since choice of immunosuppressive agent did not affect the fixed, per-admission payment determined by the diagnosis-related group for kidney transplantation. Medicare coverage for continuing outpatient use of cyclosporine was not initially provided, in contrast to rHuEPO, which was introduced in 1989 with Medicare outpatient coverage and payment of 80% of the allowed charge. Despite their high costs and different methods of insurance payment both drugs achieved a rather quick and high penetration rate into their respective populations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8023822

  2. Inhibition of Human Immunodeficiency Virus and Growth of Infected T Cells by the Immunosuppressive Drugs Cyclosporin A and FK 506

    NASA Astrophysics Data System (ADS)

    Karpas, Abraham; Lowdell, Mark; Jacobson, S. Kim; Hill, Fergal

    1992-09-01

    The effects of the immunosuppressive drugs cyclosporin A and FK 506 were studied on cells chronically infected with human immunodeficiency virus type 1 (HIV-1) as well as on uninfected and newly infected cells. When cells chronically infected with HIV-1 or with HIV-2 were cocultivated with uninfected cells in the presence of cyclosporin A or FK 506 there was a delay in the formation of syncytia and of cytopathic effects. This inhibitory effect was not due to decreased membrane expression of CD4. In addition, there was an ≈100-fold reduction in the yield of infectious HIV-1 when the infected cells were grown in the presence of these drugs, a finding consistent with other evidence of decreased HIV expression. Both drugs were found to inhibit the growth of chronically infected cells at concentrations that did not inhibit the growth of the uninfected cells. These results, demonstrating that cyclosporin A and FK 506 interfere with HIV production and selectively inhibit the growth of infected cells, suggest that they may be useful in the treatment of this infection and indicate further cellular targets for antiviral agents.

  3. Protective effects of cyclophosphamide, cyclosporin A and FK506 against antigen-induced lung eosinophilia in guinea-pigs.

    PubMed Central

    Norris, A A; Jackson, D M; Eady, R P

    1992-01-01

    A close association has been recognized between activated T cells and eosinophils in asthma, albeit circumstantial. The present study attempted to investigate this relationship in an animal model of lung eosinophilia using the new generation of T cell-selective immunosuppressants, cyclosporin A and FK506, compared with the myelotoxic immunosuppressive agent cyclophosphamide. Antigen challenge of ovalbumin-sensitized guinea-pigs resulted in a lung eosinophilia which was assessed by bronchoalveolar lavage. All three agents caused a marked suppression of lung eosinophilia at 24 h post-challenge when the compounds were administered at the time of sensitization but not when administered for 3 days before lavage. However, the lung eosinophilia at 72 h post-challenge was reduced significantly by FK506 and by cyclophosphamide, but not by cyclosporin A, when the drugs were administered for 3 days, before lavage. These results strongly suggest the involvement of T cells in antigen-induced late phase (72 h) eosinophilia in guinea-pigs but not at 24 h. The effects of cyclophosphamide were always associated with a reduction in circulating white cell counts, whereas cyclosporin A and FK506 showed no myelotoxic properties. These results suggest the potential therapeutic use of selective, non-cytotoxic immunosuppressive agents in asthma. PMID:1381297

  4. Effects of beauverolide L and cyclosporin A on humoral and cellular immune response of the greater wax moth, Galleria mellonella.

    PubMed

    Vilcinskas, A; Jegorov, A; Landa, Z; Götz, P; Matha, V

    1999-01-01

    The effects of beauverolide L and cyclosporin A, cyclic peptidic metabolites, produced by several genera of entomopathogenic fungi on immune responses of last instar larvae of the greater wax moth Galleria mellonella have been examined. Intrahemocoelic injection of either metabolite-coated silica particles or dissolved metabolites in a concentrations ranging between 10 and 30 micrograms per larvae caused no mortality but activated humoral responses in G. mellonella larvae. The challenge induced a significant release of lysozyme and cecropin-like activity into the hemolymph, suggesting stimulatory activity on humoral immune responses. Injected metabolite-coated particles were rapidly surrounded by hemocytes which subsequently accomplished formation of melanized nodules, which increased in size and number compared with controls. In vitro assays with dissolved metabolites indicated no adverse effects of beauverolide L or cyclosporin A on attachment or spreading of isolated plasmatocytes but dose-dependent inhibition of their phagocytic activity. Isolated plasmatocytes incubated with cyclosporin A or beauverolide L exhibited cytoskeleton alterations that differed from those observed in plasmatocytes from infected G. mellonella larvae or reported from other fungal secondary metabolites. The experiments provided further data to elucidate the role of fungal secondary metabolites in development of mycoses in insects. PMID:10190031

  5. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    PubMed

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant. PMID:27429515

  6. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

    SciTech Connect

    Luo, Yi Rana, Payal; Will, Yvonne

    2012-06-01

    Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity attenuated

  7. Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD

    PubMed Central

    Kirchner, Gabriele I; Winkler, Michael; Mueller, Lueke; Vidal, Christian; Jacobsen, Wolfgang; Franzke, Anke; Wagner, Siegfried; Blick, Stefan; Manns, Michael P; Sewing, Karl-Friedrich

    2000-01-01

    Aims The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels. Methods SDZ RAD was administered orally in different doses (0.25–15 mg day−1) to seven patients, who were on standard cyclosporin-based immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray-mass spectrometry. Results The mean area under the blood concentration-time curve to 12 h (AUC(0,12 h)) was 4244 ± 1311 µg l−1 h for cyclosporin before SDZ RAD treatment and 4683 ± 1174 µg l−1 h (P = 0.106) on the day of SDZ RAD treatment (95% CI for difference -126, 1003). On both study days Cmax, and tmax of cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-normalized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4 ± 13.1 µg l−1 h, Cmax: 7.9 ± 2.7 µg l−1 and tmax: 1.5 ± 0.9 h. The metabolites of SDZ RAD found in blood were hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demethyl-SDZ RAD, and a ring-opened form of SDZ RAD. Conclusions A single dose of SDZ RAD did not influence significantly the pharmacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy-SDZ RAD, its AUC(0,24 h) being nearly half that of the parent compound SDZ RAD. PMID:11069439

  8. Adjunct cyclosporine therapy for refractory Kawasaki disease in a very young infant.

    PubMed

    Okada, Seigo; Azuma, Yoshihiro; Suzuki, Yasuo; Yamada, Hiroko; Wakabayashi-Takahara, Midori; Korenaga, Yuno; Akase, Hideaki; Hasegawa, Shunji; Ohga, Shouichi

    2016-04-01

    Herein we describe the case of a 6-week-old boy who developed complete Kawasaki disease (KD). The cytokine profile and activation of monocytes and subsequent T cells matched the typical feature of refractory KD. The patient received a total of three courses of i.v. immunoglobulin (IVIG), but did not achieve clinical relief. Adjunctive therapy with oral cyclosporine A (CsA) led to prompt defervescence. This was continued for 7 days without serious adverse events. Coronary artery dilatations regressed within 3 months of follow up. KD infants <3 months of age are at higher risk of coronary artery aneurysm than the older ones. To our knowledge, oral CsA treatment has not been reported in such young infants with KD. The diagnosis and treatment of very young infants with KD are challenging. Adjunctive use of CsA in IVIG treatment could be effective for refractory KD in infants <3 months of age. PMID:26670024

  9. Bioconversion of FR901459, a novel derivative of cyclosporin A, by Lentzea sp. 7887.

    PubMed

    Sasamura, Satoshi; Kobayashi, Motoo; Muramatsu, Hideyuki; Yoshimura, Seiji; Kinoshita, Takayoshi; Ohki, Hidenori; Okada, Kazuki; Deai, Yoko; Yamagishi, Yukiko; Hashimoto, Michizane

    2015-08-01

    FR901459, a product of the fungus Stachybotrys chartarum No. 19392, is a derivative of cyclosporin A (CsA) and a powerful immunosuppressant that binds cyclophilin. Recently, it was reported that CsA was effective against hepatitis C virus (HCV). However, FR901459 lacks active moieties, which are essential for synthesizing more potent and safer derivatives of this anti-HCV agent. Here we identified an actinomycete strain (designated 7887) that was capable of efficient bioconversion of FR901459. Structural elucidation of the isolated bioconversion products (1-7) revealed that compounds 1-4 were mono-hydroxylated at the position of 1-MeBmt or 9-MeLeu, whereas compounds 5-7 were bis-hydroxylated at both positions. The results of morphological and chemical characterization, as well as phylogenetic analysis of 16S ribosomal DNA (rDNA), suggested that strain 7887 belonged to the genus Lentzea. Comparison of the FR901459 conversion activity of strain 7887 with several other Lentzea strains revealed that although all examined strains metabolized FR901459, strain 7887 had a characteristic profile with respect to bioconversion products. Taken together, these findings suggest that strain 7887 can be used to derivative FR901459 to produce a chemical template for further chemical modifications that may provide more effective and safer anti-HCV drugs. PMID:25783225

  10. A prospective study on treatment of hypercholesterolemia with lovastatin in renal transplant patients receiving cyclosporine.

    PubMed

    Cheung, A K; DeVault, G A; Gregory, M C

    1993-06-01

    Hypercholesterolemia occurs commonly in renal transplant recipients and may contribute to the high cardiovascular morbidity and mortality in these patients. Although an effective hypolipidemic agent, lovastatin has been associated with rhabdomyolysis and acute renal failure in patients on cyclosporin A (CsA). In this study, lovastatin was administered at 10 mg/day for 8 wk followed by 20 mg/day for 12 wk to six renal transplant recipients who were receiving CsA concomitantly. The 10-mg/day dose was effective, but an additional lipid-lowering effect was seen with the 20-mg/day dose. Both serum total cholesterol and low-density lipoprotein cholesterol levels decreased by 27% at the end of the 20 wk of lovastatin administration. Serum high-density lipoprotein cholesterol and triglyceride levels remained unchanged. No significant clinical or laboratory adverse effects were observed, including muscular symptoms, ophthalmologic abnormalities, or alterations in serum creatine kinase, urea nitrogen, creatinine, transaminases, and CsA levels. Peak and trough plasma concentrations of active lovastatin were comparable to those reported in normal subjects receiving a higher lovastatin dose without CsA. It was concluded that the administration of low-dose (10 to 20 mg/day) lovastatin to renal transplant recipients receiving concomitant CsA can be safe and effective in lowering serum cholesterol. PMID:8338920

  11. Preparation, characterization and in silico modeling of biodegradable nanoparticles containing cyclosporine A and coenzyme Q10

    NASA Astrophysics Data System (ADS)

    Ankola, D. D.; Durbin, E. W.; Buxton, G. A.; Schäfer, J.; Bakowsky, U.; Kumar, M. N. V. Ravi

    2010-02-01

    Combination therapy will soon become a reality, particularly for those patients requiring poly-therapy to treat co-existing disease states. This becomes all the more important with the increasing cost, time and complexity of the drug discovery process prompting one to look at new delivery systems to increase the efficacy, safety and patient compliance of existing drugs. Along this line, we attempted to design nano-scale systems for simultaneous encapsulation of cyclosporine A (CsA) and coenzyme Q10 (CoQ10) and model their encapsulation and release kinetics. The in vitro characterization of the co-encapsulated nanoparticles revealed that the surfactant nature, concentration, external phase volume, droplet size reduction method and drug loading concentration can all influence the overall performance of the nanoparticles. The semi-quantitative solubility study indicates the strong influence of CoQ10 on CsA entrapment which was thought to be due to an increase in the lipophilicity of the overall system. The in vitro dissolution profile indicates the influence of CoQ10 on CsA release (64%) to that of individual particles of CsA, where the release is faster and higher (86%) on 18th day. The attempts to model the encapsulation and release kinetics were successful, offering a possibility to use such models leading to high throughput screening of drugs and their nature, alone or in combination for a particular polymer, if chi-parameters are understood.

  12. The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A

    2016-03-01

    The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation. PMID:26632647

  13. Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt

    PubMed Central

    Guan, Peipei; Lu, Yi; Qi, Jianping; Niu, Mengmeng; Lian, Ruyue; Hu, Fuqiang; Wu, Wei

    2011-01-01

    The main purpose of this study was to evaluate liposomes containing a bile salt, sodium deoxycholate (SDC), as oral drug delivery systems to enhance the oral bioavailability of the poorly water-soluble and poorly permeable drug, cyclosporine A (CyA). Liposomes composed of soybean phosphatidylcholine (SPC) and SDC were prepared by a thin-film dispersion method followed by homogenization. Several properties of the liposomes including particle size, polydispersity index, and entrapment efficiency were characterized. The in vitro release of CyA from these liposomes was less than 5% at 12 hours as measured by a dynamic dialysis method. The pharmacokinetic results in rats showed improved absorption of CyA in SPC/SDC liposomes, compared with CyA-loaded conventional SPC/cholesterol (Chol) liposomes and microemulsion-based Sandimmune Neoral®. The relative oral bioavailability of CyA-loaded SPC/SDC and SPC/Chol liposomes was 120.3% and 98.6%, respectively, with Sandimmun Neoral as the reference. The enhanced bioavailability of CyA was probably due to facilitated absorption by the liposomes containing SDC rather than improved release rate. PMID:21720508

  14. Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism.

    PubMed Central

    Shaw, P M; Barnes, T S; Cameron, D; Engeset, J; Melvin, W T; Omar, G; Petrie, J C; Rush, W R; Snyder, C P; Whiting, P H

    1989-01-01

    A form of human hepatic microsomal cytochrome P-450 (P450hA7) with subunit Mr 50,400 has been purified from an epileptic who had been receiving long-term treatment with anticonvulsant drugs. P450hA7 metabolized the immunosuppressant drug cyclosporin A and the dihydropyridine calcium channel antagonist nifedipine, but did not metabolize a similar dihydropyridine drug, nicardipine, nor a series of alkoxyresorufin model substrates. The hepatic microsomal concentration of P450hA7 was higher in five individuals who had been receiving long-term anticonvulsant treatment than in any of 21 individuals who had not been similarly treated. The mean P450hA7 concentration in the treated individuals was 5-fold higher than the mean concentration in the untreated individuals. It is concluded that P450hA7 is a member of the cytochrome P450III family which is induced by anticonvulsant drugs in man. Images Fig. 1. Fig. 4. Fig. 5. Fig. 6. PMID:2688634

  15. Xenograft survival in two species combinations using total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Bollinger, R.R.

    1987-02-01

    Total lymphoid irradiation (TLI) has profound immunosuppressive actions and has been applied successfully to allotransplantation but not xenotransplantation. Cyclosporine (CsA) has not generally permitted successful xenotransplantation of organs but has not been used in combination with TLI. TLI and CsA were given alone and in combination to rats that were recipients of hamster or rabbit cardiac xenografts. Combined TLI and CsA prolonged survival of hamster-to-rat cardiac xenografts from three days in untreated controls to greater than 100 days in most recipients. TLI alone significantly prolonged rabbit to rat xenograft survival with doubling of survival time. However, combined treatment did not significantly prolong rabbit-to-rat cardiac xenograft survival compared with TLI alone. The hamster and rat are phylogenetically closely related. Transplants from hamsters to rat are concordant xenografts since the time course of unmodified rejection is similar to first-set rejection of allografts. Although the rabbit-to-rat transplant is also between concordant species (average survival of untreated controls: 3.2 days) the rabbit and rat are more distantly related. These results suggest that TLI is an effective immunosuppressant when applied to cardiac xenotransplants in these animal models; that the choice of species critically affects xenograft survival when TLI and/or CsA are used for immunosuppression; and that the closely related species combination tested has markedly prolonged (greater than 100 days) survival using combined TLI and CsA.

  16. Optimizing the formulation of cyclosporine A electret patch and the controlled release of drug

    NASA Astrophysics Data System (ADS)

    Liu, H. Y.; Wang, P.; Liang, Y. Y.; Guo, X.; Jiang, J.; Cui, L. L.

    2013-03-01

    The polypropylene (PP) film coated with/without aluminum electrode were charged with the gird voltages of -500 V, -1000 V and -2000 V to prepare the electrets and produce electric field for control of drug release. The model drug of cyclosporine A (CsA) was loaded on a patch and ethyl oleate was used as the chemical enhancer in the manufacturing process. The formulation of the CsA drug patch enhanced by chemical was optimized, and the in vitro release behaviours of drug in the patches were studied to explore the enhancing effect of the external electrostatic field on the CsA release from the patch. Besides, the piezoelectric d33 coefficient was also determined to study the polarization of the drug in the patch under the action of the internal electrostatic field of the electret. The results indicate that the electrostatic field produced by the electret could polarize the drug in patch and enhance the release of CsA from the patch, and the effect depended on the electrode coating condition and charging voltage of the electret.

  17. Cyclosporine-associated leukoencephalopathy in organ transplant recipients: experience of three clinical cases.

    PubMed

    Muñoz, R; Espinoza, M; Espinoza, O; Andrade, A; Bravo, E; González, F

    2006-04-01

    Leukoencephalopathy is a structural alteration of cerebral white matter mainly involving damage to myelin. Several reports have linked cyclosporine (CsA) with this alteration. The clinical features vary from qualitative alterations of consciousness to neurological deficits. Magnetic resonance imaging (MRI) of the brain demonstrates the damage to the white matter, which is essential for the differential diagnosis. We describe three clinical cases of leukoencephalopathy. The first case is a 43-year-old man received a cadaveric kidney transplant using immunosuppression with of mycophenolate mofetil, prednisone, and CsA. Four months later he developed meningism and bilateral sixth nerve palsy. The second case is a 50-year-old man with a cadaveric kidney transplant received immunosuppressive treatment with azathioprine and prednisone. As a result of gouty arthritis of the ankle, azathioprine was replaced with CsA to allow addition of allopurinol. Two weeks later he developed confusion and personality changes. The third case is a 16-year-old man received a orthotopic liver transplant. Postoperatively he suffered generalized tonic-clonic seizures. In all patients the CsA levels were toxic and signs of neurological alterations were present on MRI. All patients recovered rapidly after CsA withdrawal. PMID:16647511

  18. Attenuation of Cyclosporine-Induced Sperm Impairment and Embryotoxicity by Crataegus monogyna Fruit Aqueous Extract

    PubMed Central

    Zahra, Armand; Gholamreza, Najafi; Farokhi, Farah; Shalizar Jalali, Ali

    2013-01-01

    Objective: Cyclosporine (Cs), a cyclic undecapeptide with potent immuno suppressive activity, causes several adverse effects including reproductive toxicity. This study aims to examine the ability of Crataegus monogyna aqueous fruit extract as an antioxidant to protect against Cs-induced reproductive toxicity. Materials and Methods: In this experimental study, 32 adult male Wistar rats were divided into four groups of eight animals each. Rats in two groups received 40 mg/kg/day Cs for 45 days by oral gavage. In addition, one of the two groups received Crataegus monogyna aqueous extract at a dose of 20 mg/kg/day orally four hours after Cs administration. The remaining two groups consisted of a vehicle treated control (Cont) group and a Crataegus monogyna control (Cr) group. Differences between groups were assessed by analysis of variance (ANOVA) using the SPSS software package for Windows. Results: Cs treatment caused a signiifcant decrease in sperm count and viability with an increase in DNA damage and protamine deifciency of the sperm cells. We observed signiifcant decreases in fertilization rate and embryonic development, in addition to an increased rate of embryo arrest in Cs-treated rats. Crataegus monogyna co-administration attenuated all Cs-induced negative changes in the above-mentioned parameters. Conclusion: Supplementation with Crataegus monogyna a queous fruit extract could be useful against reproductive toxicity during Cs treatment in a rat model PMID:24027659

  19. Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides.

    PubMed

    Tracey, D E; Hardee, M M; Richard, K A; Paslay, J W

    1988-01-01

    The effects of a panel of hormones and pharmacological agents on the activation of T cells by a combination of interleukin-1 and phytohemagglutinin (IL-1/PHA) was studied. Pharmacological effects on various stages of IL-1/PHA-induced interleukin-2 (IL-2) production by the cloned murine thymoma cell line LBRM-33-1A5.7 were dissected using a multi-step assay procedure. A 4-h lag phase in the kinetics of IL-2 production allowed the operational definition of an early, IL-1-dependent programming stage, followed by an IL-2-production stage of the assay. A cell-washing procedure between these stages was introduced in order to distinguish IL-1 receptor antagonists from functional IL-1/PHA antagonists. Hydrocortisone and cyclosporine were potent inhibitors (active in the nM range) of both stages of IL-2 production, suggesting that neither is an IL-1 receptor antagonist. The cyclic adenosine monophosphate (cAMP)-elevating agents prostaglandin E2, dibutyryl cAMP, and theophylline inhibited IL-2 production during the early, IL-1-dependent programming stage. By contrast, prostaglandin F2 alpha and dibutyryl cyclic guanosine monophosphate did not appreciably inhibit IL-1/PHA activity. These results are discussed in relationship to the effects of these test agents in thymocyte IL-1 assays or mitogenesis assays and the implications toward understanding the mechanisms underlying IL-1/PHA activation of T cells. PMID:3258857

  20. Cremophor EL, the cyclosporine vehicle, suppresses in vitro natural killer cell cytotoxicity(NKCC)

    SciTech Connect

    Berk, L.; Nehlsen-Cannarella, S.; Eby, W.; Tan, S.; Kramer, J.; Hirokane, J.

    1986-03-01

    Cyclosporine I.V. (CIV), in its vehicle, Cremophor EL, (CEL), is a potent immunosuppressive agent which prolongs survival of allogeneic transplants. NKCC is postulated to be involved in allograft rejection. This study was designed to investigate the effect of CEL, a polyoxyethylated castor oil, on in vitro spontaneous cytotoxicity induced by human natural killer cells. NKCC was measured by a standard /sup 51/Cr release assay with K562 target cells. After a 4 hr NKCC assay, both CIV at 10/sup -3/M to 10/sup -7/M and CEL at the equivalent dilution, suppressed NKCC 46 to 6%, relative to control lysis (p 0.05). There was no significant suppression of NKCC at dilutions greater than 10/sup -7/M. The differences in NKCC between CIV and CEL at all dilutions tested were not significant. Both CIV and CEL with increasing dilutions correlated negatively with NKCC (r = -0.67, p < 0.0001; r = -0.74, p < 0.0001, respectively). With a 4 hr preincubation, both CIV at 10/sup -4/M and CEL at the equivalent dilution suppressed NKCC (p < 0.01). However, after a 24 hr preincubation of CIV and CEL, NKCC did not differ from control lysis. These data suggest that the CIV vehicle CEL transiently suppresses in vitro NKCC and, therefore, may play a role in the survival of allogeneic transplants.

  1. Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.

    PubMed

    Rovira, J; Renner, P; Sabet-Baktach, M; Eggenhofer, E; Koehl, G E; Lantow, M; Lang, S A; Schlitt, H J; Campistol, J M; Geissler, E K; Kroemer, A

    2016-04-01

    Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors. PMID:26855194

  2. Formulation Strategy for the Delivery of Cyclosporine A: Comparison of Two Polymeric Nanospheres.

    PubMed

    Goyal, Ritu; Macri, Lauren; Kohn, Joachim

    2015-01-01

    A wide range of nanoparticles has been explored for the delivery of highly hydrophobic drugs, but very few publications provide comparative data of the performance of different nanoparticles. To address this need, this publication compares poly(lactic-co-glycolic acid) (PLGA) nanoparticles and nanospheres made from tyrosine-derived tri-block copolymers (termed TyroSpheres) for their respective performance as carriers for cyclosporine A (CSA). Using previously reported data on PLGA, we followed similar experimental protocols to evaluate the in vitro characteristics of TyroSpheres. Although there are some similarities between the two particle systems for the delivery of CSA, such as effective encapsulation and epidermal skin penetration, several differences were notable. First, the methods of preparation were different, i.e., self-assembly and emulsion-diffusion-evaporation process for TyroSpheres and PLGA, respectively. Second, TyroSpheres provided 7-day diffusion-controlled release, whereas PLGA nanoparticles provided >21-day erosion-controlled release. Third, the size of TyroSpheres was measured to be ~60-70 nm irrespective of drug loading, whereas the size of PLGA nanoparticles (~100-250 nm) was dependent on drug loading and the method of preparation. Overall, this publication provides a direct comparison between two different types of nanoparticles and illuminates the respective advantages and disadvantages, using CSA as a model for the release of highly hydrophobic drugs. PMID:26268451

  3. Treatment of Severe Alopecia Areata: Combination Therapy Using Systemic Cyclosporine A with Low Dose Corticosteroids

    PubMed Central

    Lee, Deborah; Oh, Doo Jin; Kim, Jung Wook; Park, Sung Wook; Oh, Min Kyung; Sung, Ho Suk

    2008-01-01

    Background Combination therapy using cyclosporine A (CsA) together with low-dose corticosteroids has adequate efficacy with little toxicity for the treatment of severe alopecia areata (AA). Objective We wanted to evaluate the clinical efficacy of combination therapy using CsA with low-dose corticosteroid for the treatment of severe AA and we also wanted to determine the safe therapeutic concentration of CsA in the peripheral blood. Methods We treated 34 cases of severe AA with combination therapy for 24 weeks and we evaluated the efficacy at 12 and 24 weeks. We monitored the peripheral blood concentration of CsA to determine the therapeutic range of CsA that has the fewest side effects. Results Of the patients, 77.4% (n=24) and 22.6% (n=10) were classified in the responder and poor-responder groups, respectively. The mean trough concentration of CsA was 95.1 and 101.2 ng/ml in the responder and poor-responder groups, respectively. For the patients with side effects associated with CsA, the mean CsA concentration was 195.8 ng/ml. Conclusion We found that combination therapy with systemic CsA and low-dose corticosteroids effectively treats severe AA and this therapy results in a safe, therapeutic concentration of CsA in the peripheral blood. PMID:27303186

  4. Rats taste-aversive learning with cyclosporine a is not affected by contextual changes.

    PubMed

    Tuerkmen, Akin; Bösche, Katharina; Lückemann, Laura; Engler, Harald; Schedlowski, Manfred; Hadamitzky, Martin

    2016-10-01

    In conditioned taste aversion (CTA) rats associate a novel taste (conditioned stimulus; CS) with a treatment (unconditioned stimulus; US) that induces symptoms of malaise. During retrieval, animals learn that the CS no longer predicts the US, with the consequence that the behavior elicited by the CS extinguishes. Importantly, CTA data with lithium chloride (LiCl) as US indicate that extinction learning is affected by changing the physical context. However, if this is also the case in different taste-aversion paradigms employing compounds other than LiCL as US is unknown. Against this background the present study investigated in a CTA paradigm with saccharin as CS and the immunosuppressant cyclosporine A (CsA) as US the influence of contextual changes on CTA extinction. Our results show, that extinction of a learned CS-US association with CsA is not prone to contextual changes. Due to the direct effects of CsA on CNS functioning, CTA with this immunosuppressant apparently operates under different mechanisms compared to other drugs, such as LiCl. These data indicate that taste aversive learning and its extinction are not necessarily specific to the context in which it is learned but also depends, at least in part, on the physiological and neuropharmacological effects of the drug employed as US. PMID:27316343

  5. Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model

    SciTech Connect

    O'Connell, Sein; Slattery, Craig; Ryan, Michael P.; McMorrow, Tara

    2011-04-15

    The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However, nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsA-induced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased {alpha}-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.

  6. Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Els, D.; Du Toit, L.B.; Weideman, A.; Davids, H.; van der Merwe, E.

    1987-09-01

    The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

  7. Segmental pancreatic allograft survival in baboons treated with combined irradiation and cyclosporine: a preliminary report

    SciTech Connect

    du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Laker, L.; Els, D.; Weideman, A.; Wolfe-Coote, S.; van der Merwe, E.A.

    1985-04-01

    The present study was undertaken to evaluate the effectiveness of cyclosporine (CS) alone, total lymphoid irradiation (TLI) alone, and CS in combination with total body irradiation (TBI) in suppressing segmental pancreatic allograft rejection in totally pancreatectomized outbred chacma baboons. The administration of CS 25 mg/kg/day and 50 mg/ kg/day resulted in mean graft survival of 21.5 days and 24.5 days, respectively. CS 85 mg/kg/day resulted in median graft survival of 9 days. There was a wide daily fluctuation of CS serum trough levels exhibited between primates receiving the same oral dose. TBI in excess of 300 rads resulted in irreversible bone marrow suppression. Modest results were achieved in recipients of TBI-76 rads (38 x 2 rads), with median graft survival of 21 days, results not different from recipients treated with CS. TLI recipients of 600 rads (150 x 4 rads) resulted in median pancreatic graft survival of 16 days. TBI together with oral CS administration exhibited no synergistic or additive effect and a single peroperative donor-specific blood transfusion did not enhance pancreatic allograft survival in this model. However, of 10 primates receiving TBI 100 rads (50 x 2 rads) and CS 25 mg/kg/day administered orally indefinitely, four remained normoglycemic for more than 60 days. TBI 100 rads (50 x 2 rads) together with oral and parenteral CS resulted in necrotizing enterocolitis in four of six recipients.

  8. Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.

    PubMed

    Gupta, S K; Legg, B; Solomon, L R; Johnson, R W; Rowland, M

    1987-10-01

    1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance. PMID:3318898

  9. Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer.

    PubMed

    Lopes, Luciana B; Collett, John H; Bentley, M Vitória L B

    2005-05-01

    Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5-70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20-70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery. PMID:15848052

  10. Maintenance of new cementum formed during cyclosporin A administration after suspension of the treatment.

    PubMed

    Ayanoglou, C M; Lesty, C

    1997-10-01

    The aim of the present investigation was to examine if new cementum (NC) formed during cyclosporin A (CsA) administration was maintained after suspension of the treatment. Thirty mg/kg/d of CsA were given to 3 male Sprague-Dawley rats. Three control rats received oil-based vehicle solution. Nine wk later the drug and vehicle administration were stopped and the rats continued to be fed with the same standard laboratory diet and water ad libitum for 5 months. The rats were anaesthetized, the tissues fixed by intracardiac perfusion of fixative solution and the mandibles processed for Epon inclusion. Histological, histomorphometric and ultrastructural analysis revealed that (a) NC covered extensive areas of the root surfaces; its structural characteristics were identical to those observed in the rats killed during CsA administration. (b) collagen fibres of the adjacent connective tissue were functionally inserted into the NC. (c) In the presence of cervical NC spurs the extent of the apical downgrowth of the junctional epithelium, measured parallel to the cemento-dentinal junction, was decreased (up to 64%) compared to the one occurring in areas devoid of NC deposits. These results suggest that (a) NC deposition and its functional relations with the adjacent connective tissue are not reversible after cessation of CsA treatment and (b) in the presence of cervical NC spurs the amount of connective tissue attachment on the root surfaces is increased. PMID:9401934

  11. Cyclosporin A-induced new cementum formation: a morphometric evaluation in the periapical region of rats.

    PubMed

    Spolidorio, Luis Carlos; Spolidorio, Denise Madalena Palomari; Holzhausen, Marinella; Nassar, Carlos Augusto; Nassar, Patricia Oehlmeyer

    2007-01-01

    Cyclosporin A (CsA) is a potent immunosuppressor used in organ transplantation and in the management of various autoimmune diseases. Recent studies have shown that CsA stimulates deposition of cementum on root surfaces. The aim of this study was to evaluate the periapical cementum thickness and the apical foramen width in CsA-treated rats. Rats weighing 50 g were treated with a daily injection of 10 mg/kg body weight of CsA in the chow for 60 days. The cementum of the mandibular 1st molars was histologically and morphometricaly examined by analysis of 5-microm-thick serial buccolingual paraffin sections stained with hematoxylin and eosin. Histometric and stereologic analyses revealed the presence of large amounts of cementum in all root surfaces, particularly abundant in the periapical region and obliterating the foramen. The volume density of cementoblasts did not increase. Five to 90 days after the termination of CsA therapy, there was no reduction of cementum thickness. These results suggest that cementum deposition is not reversible after cessation of CsA treatment. PMID:17639196

  12. Evaluation of cyclosporine nephrotoxicity in rats with various renal radioactive agents

    SciTech Connect

    McAfee, J.G.; Thomas, F.D.; Subramanian, G.; Roskopf, M.; Hellwig, B.

    1988-09-01

    The efficacy of different radiodiagnostic agents for demonstrating the decline in renal function from cyclosporine (CyA) nephrotoxicity was assessed in rats receiving a standard dose of the drug for 2 wk, compared with control rats. The agents included (/sup 99m/Tc)DTPA, (/sup 131/I)hippuran, (/sup 111/In)lysozyme, (/sup 99m/Tc)glucoheptonate (GHA), (/sup 99m/Tc)dimercaptosuccinate (DMS) and (/sup 111/In)aminated dextran (amdex). A small dose of (/sup 99m/Tc)- or (/sup 111/In)DTPA was administered simultaneously to normalize the results for variations in drug response from one animal to another. There were statistically significant differences in the detectability of the renal functional impairment by plasma clearance, early and 2-hr renal uptake among the different agents. However, none was clearly superior to DTPA. This conclusion is consistent with previous studies which showed a parallel decline in glomerular filtration rate (GFR) and effective renal plasma flow in acute CyA toxicity probably due primarily to vasoconstriction.

  13. Effect of Cyclosporine-A on Paraoxonase Activity in Wistar Rats

    PubMed Central

    Argani, H.; Ghorbanihaghjo, A.; Rashtchizadeh, N.; Seifirad, S.; Rahbarfar, Y.

    2011-01-01

    Background: Many adverse effects have been reported on using cyclosporine (CSA) in organ transplantation. Objective: To investigate the effects of CSA on paraoxonase (PON) activity and lipid peroxidation metabolites in early and late-stage of peroxidation and also total antioxidant (TA). Methods: Twenty 220-250 g adult male Wistar rats were included in the study. The animals were stored for one week in the animal room before the initial injection to habituate with temperature, humidity, and circadian rhythm of day (12 h) and night (12 h). The temperature was kept at 23 °C. Animals had access to food and water ad libitum. Results: A significant (p=0.002) increase in the serum levels of conjugated diones was observed in the case compared to the control group. At the end of the study, malondialdehyde (MDA) levels in CSA group was significantly (p=0.01) higher than the control group. Serum PON1 activity was significantly (p=0.004) lower in the case than the control group. Conclusion: CSA administration could impair oxidant-antioxidant pathways and increase oxidative stress. Antioxidant therapy could be beneficial in patients treated with CSA. PMID:25013591

  14. Taste-masked orodispersible tablets of cyclosporine self-nanoemulsion lyophilized with dry silica.

    PubMed

    Zidan, Ahmed S; Aljaeid, Bader M; Mokhtar, Mahmoud; Shehata, Tamer M

    2015-01-01

    The aim of the current study was to investigate the effects of formulation parameters on the disintegration, water absorption and dissolution characteristics of cyclosporine A (CyA) loaded self-emulsifying drug delivery system (SEDDS) in an orodispersible compacts. Its taste masking efficiency was also attempted using an electronic tongue. ODTs were prepared by freeze-drying liquid SEDDS and synthetic amorphous silica suspension followed by direct compression. The influences of the compression forces and super-disintegrant were evaluated to optimize tablet characteristics. The liquid SEDDS was characterized by vesicular size of 48.5 nm, polydispersity index of 0.95, turbidity of 40.7 NTU and rapid CyA dissolution and emulsification rate. The results of micrometric studies demonstrated an acceptable flow, hardness and friability to indicate good mechanical strength of ODTs. The interaction and Pareto charts demonstrated a greater effect of low compression force to increase the porosity and facilitate the disintegration rather than the deformation action of the super-disintegrant. Super-disintegrant level was the most important factor affecting the dissolution parameter followed by the compression force then their interaction effect. Moreover, as indicated by Euclidean distance values and discrimination indices, the unpalatable taste and aversion taste of CyA to stimuli were masked in its optimized SEDDS incorporated ODTs. PMID:25069592

  15. Formulation Strategy for the Delivery of Cyclosporine A: Comparison of Two Polymeric Nanospheres

    PubMed Central

    Goyal, Ritu; Macri, Lauren; Kohn, Joachim

    2015-01-01

    A wide range of nanoparticles has been explored for the delivery of highly hydrophobic drugs, but very few publications provide comparative data of the performance of different nanoparticles. To address this need, this publication compares poly(lactic-co-glycolic acid) (PLGA) nanoparticles and nanospheres made from tyrosine-derived tri-block copolymers (termed TyroSpheres) for their respective performance as carriers for cyclosporine A (CSA). Using previously reported data on PLGA, we followed similar experimental protocols to evaluate the in vitro characteristics of TyroSpheres. Although there are some similarities between the two particle systems for the delivery of CSA, such as effective encapsulation and epidermal skin penetration, several differences were notable. First, the methods of preparation were different, i.e., self-assembly and emulsion-diffusion-evaporation process for TyroSpheres and PLGA, respectively. Second, TyroSpheres provided 7-day diffusion-controlled release, whereas PLGA nanoparticles provided >21-day erosion-controlled release. Third, the size of TyroSpheres was measured to be ~60–70 nm irrespective of drug loading, whereas the size of PLGA nanoparticles (~100–250 nm) was dependent on drug loading and the method of preparation. Overall, this publication provides a direct comparison between two different types of nanoparticles and illuminates the respective advantages and disadvantages, using CSA as a model for the release of highly hydrophobic drugs. PMID:26268451

  16. The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex.

    PubMed

    Cordeiro, Rossana de Aguiar; Macedo, Ramila de Brito; Teixeira, Carlos Eduardo Cordeiro; Marques, Francisca Jakelyne de Farias; Bandeira, Tereza de Jesus Pinheiro Gomes; Moreira, José Luciano Bezerra; Brilhante, Raimunda Sâmia Nogueira; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2014-07-01

    Candida parapsilosis complex comprises three closely related species, C. parapsilosis sensu stricto, Candida metapsilosis and Candida orthopsilosis. In the last decade, antifungal resistance to azoles and caspofungin among C. parapsilosis sensu lato strains has been considered a matter of concern worldwide. In the present study, we evaluated the synergistic potential of antifungals and the calcineurin inhibitor cyclosporin A (Cys) against planktonic and biofilms of C. parapsilosis complex from clinical sources. Susceptibility assays with amphotericin, fluconazole, voriconazole, caspofungin and Cys were performed by microdilution in accordance with Clinical and Laboratory Standards Institute guidelines. Synergy testing against planktonic cells of C. parapsilosis sensu lato strains was assessed by the chequerboard method. Combinations formed by antifungals with Cys were evaluated against mature biofilms in microtitre plates. No differences in the antifungal susceptibility pattern among species were observed, but C. parapsilosis sensu stricto strains were more susceptible to Cys than C. orthopsilosis and C. metapsilosis. Synergism between antifungals and Cys was observed in C. parapsilosis sensu lato strains. Combinations formed by antifungals and Cys were able to prevent biofilm formation and showed an inhibitory effect against mature biofilms of C. parapsilosis sensu stricto, C. metapsilosis and C. orthopsilosis. These results strengthen the potential of calcineurin inhibition as a promising approach to enhance the efficiency of antifungal drugs. PMID:24722799

  17. Rationale for monitoring cyclosporine concentration at 2 hours after administration in infants posttransplantation.

    PubMed

    Furlan, V; Lykavieris, P; Maubert, M A; Habes, D; Debray, D

    2009-10-01

    Therapeutic drug monitoring is critical to avoid overimmunosuppression or underimmunosuppression in young pediatric transplant recipients. The objective of this study was to examine cyclosporine (CsA) trough (C0) and 2-hour post-dose (C2) concentrations in the early period after liver transplantation (OLT) to determine whether CsA C2 monitoring is justified. Seventeen infants younger than 2 years treated with CsA (Neoral) were monitored at C0. The biopsy-proved acute rejection rate was 65% at 3 months post-OLT. No correlation was observed between values at C0 and C2. Poor absorption of CsA was observed in most infants during the first 2 weeks post-OLT, as well as interindividual variability in CsA clearance. Exposure to CsA could not be estimated using either C0 or C2 determinations in the early post-OLT period. As a marker of poor absorption, C2 is useful but does not indicate delayed or rapid clearance of drug without simultaneous measurement of concentration at C0. We suggest the use of both C0 and C2 monitoring, or AUC monitoring on an individual basis during at least the first 2 weeks post-OLT. PMID:19857744

  18. The influence of the cyclosporine vehicle, cremophor EL, on renal microvascular blood flow in the rat.

    PubMed

    Abraham, J S; Bentley, F R; Garrison, R N; Cryer, H M

    1991-07-01

    Cyclosporine nephrotoxicity may be due to glomerular hypoperfusion. Previous experimental and clinical studies have demonstrated a decrease in renal blood flow and an increase in renal vascular resistance. Cremophor EL, which is the vehicle in which CsA is dissolved, is thought to be a factor involved in intrarenal arteriolar vasoconstriction. To determine the relative contributions of the vehicle and CsA to intrarenal arteriolar vasoconstriction, we used in vivo videomicroscopy and Doppler velocimetry to measure changes in renal microvascular blood flow in the rat. A 5-min intravenous infusion of 20 mg/kg of CsA resulted in a 17% mean reduction (P less than 0.05) in the diameter of preglomerular interlobular arterioles and an associated 60% reduction (P less than 0.05) in microvascular blood flow by 15 min. Cremophor EL/ethanol equivalent caused less vasoconstriction (up to 10%) but resulted in a 42% mean decrease (P less than 0.05) in microvascular blood flow, probably secondary to a 38% mean decrease (P less than 0.05) in cardiac output and 13% decrease in arterial pressure. We conclude that cremophor EL does contribute to in vivo reduction of preglomerular microvascular blood flow in the rat. This may be particularly important when using this intravenous preparation in the study of CsA nephrotoxicity. PMID:1858136

  19. Methotrexate, Cyclosporine A, and Biologics Protect against Atherosclerosis in Rheumatoid Arthritis

    PubMed Central

    Kruszewski, Robert; Juszkiewicz, Aleksandra; Raczkiewicz, Anna; Bachta, Artur; Tłustochowicz, Małgorzata; Staniszewska-Varga, Jadwiga; Kłos, Krzysztof; Duda, Krzysztof; Bogusławska-Walecka, Romana; Płoski, Rafał; Tłustochowicz, Witold

    2015-01-01

    Introduction. The risk of cardiovascular disease is increased in rheumatoid arthritis (RA). A meta-analysis showed increased intima media thickness (IMT) in RA. It has been shown that disease modifying antirheumatic drugs (DMARDs) may influence the progression of atherosclerosis. However, it was suggested that biologics may be more efficient than other DMARDs (including methotrexate—MTX) in protecting against atherosclerosis. Objectives. The aim of this study was to assess the influence of different RA characteristics and treatment regimens on IMT and atherosclerotic plaques. Patients and Methods. 317 RA patients and 111 controls were included in the study. IMT was measured in carotid (CIMT) and femoral (FIMT) arteries. Arteries were screened for the presence of plaques. Results. CIMT, FIMT, and prevalence of plaques were lower in patients treated with methotrexate (MTX) ≥ 20 mg/wk, cyclosporine (CsA), or biologics than in patients treated with lower doses of MTX and other disease modifying antirheumatic drugs. No differences in IMT between patients treated with MTX ≥ 20 mg/wk, biologics, or CsA were found. Conclusions. We found a beneficial effect of MTX ≥ 20 mg/wk, biologics, and CsA on atherosclerosis. We do not confirm a stronger influence of biologics on IMT compared with therapeutic doses of MTX. PMID:26090499

  20. Management of cyclosporine-induced gingival hyperplasia by use of an argon laser

    NASA Astrophysics Data System (ADS)

    Blankenau, Richard J.; Triolo, P.; Powell, G. L.

    1994-09-01

    This is a report of a case study with interesting laser applications. A 7 year old female was referred to us for treatment of hyperplastic tissue. At age two the patient had successfully undergone a liver transplant. She had undergone two periodontal surgeries under general anesthetic for the same soft tissue problem. Other possible complications were chronic sinusitis and frequent headaches. She has allergies to penicillin and sulfa. Her daily medications are Predisone and Cyclosporin. We consulted with her transplant team and they had no contraindication for the proposed dental surgery. The doctor placed her on prophylactic erythromycin for the procedure, as a preventive measure. The patient desired not to have any more general anesthetics administered. Clinical examination revealed electric pulp tests were normal for all teeth tested. No visible carious lesions were observed and there was no need for radiographs at this time. Soft tissue revealed red inflamed fibrous tissue consistent with gingival hyperplasia. Probing demonstrated 4 - 6 mm pockets around the anterior teeth.

  1. Effects of cyclosporine A on biomembranes. Vibrational spectroscopic, calorimetric and hemolysis studies.

    PubMed Central

    O'Leary, T J; Ross, P D; Lieber, M R; Levin, I W

    1986-01-01

    Cyclosporine A (CSA)-dipalmitoylphosphatidylcholine (DPPC) interactions were investigated using scanning calorimetry, infrared spectroscopy, and Raman spectroscopy. CSA reduced both the temperature and the maximum heat capacity of the lipid bilayer gel-to-liquid crystalline phase transition; the relationship between the shift in transition temperature and CSA concentration indicates that the peptide does not partition ideally between DPPC gel and liquid crystalline phases. This nonideality can be accounted for by excluded volume interactions between peptide molecules. CSA exhibited a similar but much more pronounced effect on the pretransition; at concentrations of 1 mol % CSA the amplitude of the pretransition was less than 20% of its value in the pure lipid. Raman spectroscopy confirmed that the effects of CSA on the phase transitions are not accompanied by major structural alterations in either the lipid headgroup or acyl chain regions at temperatures away from the phase changes. Both infrared and Raman spectroscopic results demonstrated that CSA in the lipid bilayer exists largely in a beta-turn conformation, as expected from single crystal x-ray data; the lipid phase transition does not induce structural alterations in CSA. Although the polypeptide significantly affects DPPC model membrane bilayers, CSA neither inhibited hypotonic hemolysis nor caused erythrocyte hemolysis, in contrast to many chemical agents that are believed to act through membrane-mediated pathways. Thus, agents, such as CSA, that perturb phospholipid phase transitions do not necessarily cause functional changes in cell membranes. PMID:3755063

  2. Two-dimensional /sup 1/H NMR studies on cyclophilin, a cytosolic cyclosporin A binding protein

    SciTech Connect

    Dalgarno, D.C.; Harding, M.W.; Lazarides, A.; Handschumacher, R.E.; Armitage, I.M.

    1986-05-01

    Cyclophilin (CyP) is a specific cytosolic cyclosporin A (CsA) binding protein (163 residues) that has been implicated in the pharmacological action of this potent immunosuppressant. One and two-dimensional /sup 1/H NMR methods are being employed to elucidate the solution structural properties of CyP particularly as they relate to the binding site of CsA. The focal point for these studies is the single Trp (residue number120) in CyP which, in the 1:1 CyP:CsA complex (K/sub d/approx.2 x 10/sup -7/M), shows a 2 fold enhancement in its intrinsic fluorescence. Using 2D /sup 1/H NMR methods, a low resolution structure has been derived for a very hydrophobic domain containing the Trp residue using interresidue n.O.e. data between assigned spin systems and a distance geometry algorithm. The structure of this hydrophobic domain will be discussed in relation to the predicted ..cap alpha../..beta.. secondary structure of this protein and comparisons made between its structure in the drug free and complexed form of the protein.

  3. Beneficial effect of shallot (Allium ascalonicum L.) extract on cyclosporine nephrotoxicity in rats.

    PubMed

    Wongmekiat, O; Leelarugrayub, N; Thamprasert, K

    2008-05-01

    The clinical use of an immunosuppressive cyclosporine A (CsA) is limited by its serious nephrotoxic effect. Evidences have suggested the role of oxidative stress in its pathogenesis. Shallot (Allium ascalonicum L.) has recently been shown to possess antioxidative and free radical scavenging abilities. The present study was undertaken to investigate the possible beneficial effect of shallot extract on renal injury caused by CsA. Male Wistar rats were treated orally with vehicle, CsA (25 mg/kg), shallot extract (1 g/kg), and CsA plus shallot extract for 21 days. Renal function, histopathology, tissue malondialdehyde (MDA) and glutathione (GSH) levels were evaluated 24 h after the last treatment. CsA-induced nephrotoxicity was evidenced by increased blood urea nitrogen and serum creatinine, but decreased urea and creatinine clearance. The kidney of CsA treated rats exhibited severe vacuolations and tubular necrosis. CsA also induced oxidative stress, as indicated by increased renal MDA and reduced GSH concentrations. Administration of shallot extract along with CsA counteracted the deleterious effects of CsA on renal dysfunction, oxidative stress markers, and morphological changes. These data indicate the protective potential of shallot extract against CsA nephrotoxicity and suggest a significant contribution of its antioxidant property to this beneficial effect. PMID:18308444

  4. An Overview on Dry Eye Treatment: Approaches for Cyclosporin A Delivery

    PubMed Central

    Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Ünlü, Nurşen

    2012-01-01

    Dry eye syndrome (DES, Keratoconjunctivitis sicca) is a common disorder of the tear film caused by decreased tear production or increased evaporation. Changes in tear composition also promote inflammation on the ocular surface by various mechanisms. Artificial tear drops, tear retention treatment, stimulation of tear secretion, or anti-inflammatory drugs may be used for dry eye treatment according to the severity of the disease. For untreated patients, the risk of ocular infection increases at considerable level and clinical course of the disease may proceed up to infection, corneal ulcer, and blindness. Artificial tears and/or punctual occlusions are used for tear replacement or preservation. New treatment approaches are designed to modify the underlying disease process. For the treatment of severe dry eye disease, cyclosporin A (CsA), the first one of the new generation immunomodulatory drugs, which has an anti-inflammatory effect, is frequently used. CsA has immunosuppressive effects following systemic application. Following local administration of CsA, it is expected to obtain effective drug concentration at the target area and to avoid the various side effects associated with systemic delivery. Microspheres, implants, and liposomes have been developed for administration of CsA subconjunctivally in order to enhance its efficiency. PMID:22619624

  5. Influence of cyclosporine A on molecular interactions in lyotropic reverse hexagonal liquid crystals.

    PubMed

    Ben Ishai, Paul; Libster, Dima; Aserin, Abraham; Garti, Nissim; Feldman, Yuri

    2010-10-14

    We present a dielectric study of H(II) mesophases (H(II)) based on a GMO/tricaprylin/phosphatidylcholine/water system seeded with the peptide Cyclosporine A (CSA). The study covers a frequency range 0.01 Hz to 1 MHz and a temperature range of 293 to 319 K, with a 3 K temperature step. Three dielectric relaxation processes are observed and discussed. This picture is further elucidated by comparison with a dielectric study of the empty H(II) mesophase system, previously published, where the same three processes were involved. A complex picture emerges whereby the CSA is intercalated between the surfactant tails yet protrudes into the interface as well. Whereas the CSA remains hydrophobic, it still influences the relaxation behavior of the GMO head and counterion movement along the interface in a nontrivial manner. The third dipolar species, the tricaprylin molecule, is also influenced by the presence of CSA. A critical temperature T(0) = 307 K is recognized and identified as the dehydration temperature of the surfactant heads. This induces a conformal transition in the CSA, drastically changing its effect on the three dielectric processes evident in the raw data. The implications of this behavior are discussed in detail. PMID:20857961

  6. Cyclosporine-induced immune suppression alters establishment of HTLV-1 infection in a rabbit model

    PubMed Central

    Haynes, Rashade A. H.; Ware, Evan; Premanandan, Christopher; Zimmerman, Bevin; Yu, Lianbo; Phipps, Andrew J.

    2010-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia and several lymphocyte-mediated inflammatory diseases. Persistent HTLV-1 infection is determined by a balance between host immune responses and virus spread. Immunomodulatory therapy involving HTLV-1–infected patients occurs in a variety of clinical settings. Knowledge of how these treatments influence host-virus relationships is not understood. In this study, we examined the effects of cyclosporine A (CsA)–induced immune suppression during early infection of HTLV-1. Twenty-four New Zealand white rabbits were split into 4 groups. Three groups were treated with either 10 or 20 mg/kg CsA or saline before infection. The fourth group was treated with 20 mg/kg CsA 1 week after infection. Immune suppression, plasma CsA concentration, ex vivo lymphocyte HTLV-1 p19 production, anti–HTLV-1 serologic responses, and proviral load levels were measured during infection. Our data indicated that CsA treatment before HTLV-1 infection enhanced early viral expression compared with untreated HTLV-1–infected rabbits, and altered long-term viral expression parameters. However, CsA treatment 1 week after infection diminished HTLV-1 expression throughout the 10-week study course. Collectively, these data indicate immunologic control is a key determinant of early HTLV-1 spread and have important implications for therapeutic intervention during HTLV-1–associated diseases. PMID:19965683

  7. A Cyclosporine-Sensitive Psoriasis-Like Disease Produced in Tie2 Transgenic Mice

    PubMed Central

    Voskas, Daniel; Jones, Nina; Van Slyke, Paul; Sturk, Celina; Chang, Wing; Haninec, Alex; Babichev, Yael Olya; Tran, Jennifer; Master, Zubin; Chen, Stephen; Ward, Nicole; Cruz, Maribelle; Jones, Jamie; Kerbel, Robert S.; Jothy, Serge; Dagnino, Lina; Arbiser, Jack; Klement, Giannoula; Dumont, Daniel J.

    2005-01-01

    Psoriasis is a common, persistent skin disorder characterized by recurrent erythematous lesions thought to arise as a result of inflammatory cell infiltration and activation of keratinocyte proliferation. Unscheduled angiogenic growth has also been proposed to mediate the pathogenesis of psoriasis although the cellular and molecular basis for this response remains unclear. Recently, a role for the angiopoietin signaling system in psoriasis has been suggested by studies that demonstrate an up-regulation of the tyrosine kinase receptor Tie2 (also known as Tek) as well as angiopoietin-1 and angiopoietin-2 in human psoriatic lesions. To examine temporal expression of Tie2, we have developed a binary transgenic approach whereby expression of Tie2 can be conditionally regulated by the presence of tetracycline analogs in double-transgenic mice. A psoriasis-like phenotype developed in double-transgenic animals within 5 days of birth and persisted throughout adulthood. The skin of affected mice exhibited many cardinal features of human psoriasis including epidermal hyperplasia, inflammatory cell accumulation, and altered dermal angiogenesis. These skin abnormalities resolved completely with tetracycline-mediated suppression of transgene expression, thereby illustrating a complete dependence on Tie2 signaling for disease maintenance and progression. Furthermore, the skin lesions in double-transgenic mice markedly improved after administration of the immunosuppressive anti-psoriatic agent cyclosporine, thus demonstrating the clinical significance of this new model. PMID:15743796

  8. Effects of oral cyclosporine on canine T-cell expression of IL-2 and IFN-gamma across a 12-h dosing interval

    PubMed Central

    FELLMAN, C. L.; ARCHER, T. M.; STOKES, J. V.; WILLS, R. W.; LUNSFORD, K. V.; MACKIN, A. J.

    2016-01-01

    The duration of immunosuppressive effects following oral cyclosporine in dogs is unknown. This study used flow cytometry and quantitative reverse transcription–polymerase chain reaction (qRT-PCR) to evaluate the effects of high-dose oral cyclosporine across a 12-h dosing interval. Expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) was compared before and after 8 days of cyclosporine at 10 mg/kg every 12 h in six healthy dogs. Samples were collected at 0, 2, 4, and 8 h postdosing for analysis of unactivated and activated T-cell and whole blood cytokine expression using flow cytometry and qRT-PCR, respectively, and at 0, 2, 4, 6, 8, and 10 h postdosing for measurement of cyclosporine concentrations. Flow cytometry and qRT-PCR both demonstrated significant marked reductions in IL-2 and IFN-γ levels at 0, 2, 4, and 8 h after dosing compared to pretreatment levels (P < 0.05) for activated samples, with less consistent effects observed for unactivated samples. Both flow cytometry and qRT-PCR are viable techniques for measuring cyclosporine pharmacodynamics in dogs, yielding comparable results with activated samples. Two hours postdrug administration is the preferred time for concurrent assessment of peak drug concentration and cytokine expression, and T-cell activation is needed for optimal results. PMID:26676223

  9. Effects of oral cyclosporine on canine T-cell expression of IL-2 and IFN-gamma across a 12-h dosing interval.

    PubMed

    Fellman, C L; Archer, T M; Stokes, J V; Wills, R W; Lunsford, K V; Mackin, A J

    2016-06-01

    The duration of immunosuppressive effects following oral cyclosporine in dogs is unknown. This study used flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to evaluate the effects of high-dose oral cyclosporine across a 12-h dosing interval. Expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) was compared before and after 8 days of cyclosporine at 10 mg/kg every 12 h in six healthy dogs. Samples were collected at 0, 2, 4, and 8 h postdosing for analysis of unactivated and activated T-cell and whole blood cytokine expression using flow cytometry and qRT-PCR, respectively, and at 0, 2, 4, 6, 8, and 10 h postdosing for measurement of cyclosporine concentrations. Flow cytometry and qRT-PCR both demonstrated significant marked reductions in IL-2 and IFN-γ levels at 0, 2, 4, and 8 h after dosing compared to pretreatment levels (P < 0.05) for activated samples, with less consistent effects observed for unactivated samples. Both flow cytometry and qRT-PCR are viable techniques for measuring cyclosporine pharmacodynamics in dogs, yielding comparable results with activated samples. Two hours postdrug administration is the preferred time for concurrent assessment of peak drug concentration and cytokine expression, and T-cell activation is needed for optimal results. PMID:26676223

  10. An Interleukin-6 Neutralizing Antibody Prevents Cyclosporine Induced Nephrotoxicity in Mice

    PubMed Central

    LaSpina, Mark; Tripathi, Sudipta; Gatto, Louis A.; Bruch, David; Maier, Kristopher G.; Kittur, Dilip S.

    2008-01-01

    Introduction Chronic use of cyclosporine A (CyA) induces nephrotoxicity primarily due to endothelial dysfunction. In our previous studies, potential mechanisms were identified in vitro and implicated NADPH oxidase and Interleukin-6 (IL-6) as key components in causing endothelial dysfunction. In this study, we tested the hypothesis that NADPH oxidase activity and IL-6 are key components in renal damage in an in vivo model. Methods Male mice C57B/6 mice from JAX Laboratories at 6–8 weeks were subjected to a low salt diet throughout the trial. After one week on a low salt diet, the mice were injected daily with treatments in 50µL vehicle composed of 75% cremaphor and Ethanol for five weeks. A vehicle alone group was also set aside. Mice were weighed and 25mg/kg/day cyclosporine was injected daily. Apocynin 20mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 Antibody at 2µg/day along with CyA. The kidneys were removed en bloc immediately and submitted in formalin for paraffin sections. Trichrome stains were performed. Slides were blinded and ten photographs of cortical areas per treatment group were taken, which covered an estimate of 10% surface area in random fashion. Areas of renal damage, which were determined by tubular necrosis, were identified and quantified by amount of necrosis per photograph. Each photograph was divided into ten blocks, and the number of blocks that contained necrotic tubules per photo was recorded. Results The two control mice (low salt only) had no damage. The four vehicle mice had trace amounts of tubular necrosis. CyA treatment group demonstrated the highest amount of damage (29/70; 41%). CyA with apocynin, a specific NADPH oxidase inhibitor, was found to have 36% (22/60) damage, whereas the CyA with IL-6 antibody only was observed to have 15% (6/40) damage. Comparing imaging analysis, there was no difference between mice treated with CyA alone and with CyA with apocynin. However