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Sample records for chronic cyclosporine nephrotoxicity

  1. Cyclosporin nephrotoxicity following cardiac transplantation.

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    Woolfson, R G; Neild, G H

    1997-10-01

    The greatest change in GFR in response to treatment with cyclosporin occurs in the first 3-6 months and the magnitude of the decrement in the first year (or perhaps the first few months) appears to be a vital indicator of future problems. However, the apparent stabilization of renal function, particularly when monitored only by plasma creatinine, can conceal progressive tubulointerstitial injury, and increasing proteinuria is an ominous sign. Although lower doses of cyclosporin and careful monitoring of renal function may be helpful, there is at present no pharmacological intervention to protect or reverse the reduction in GFR that occurs. We believe that the vascular lesion induced by cyclosporin is fundamental, with early and initially reversible cyclosporin-induced vasospasm leading to progressive vascular damage with activation of endothelial cells and increased platelet interactions. Amongst other determinants, the renal response to this vasculopathy will depend on the balance between the presence of vasoactive factors with the vasoconstrictors promoting interstitial fibrosis and the vasodilators inhibiting proliferation. It is likely that the kidneys of heart-transplant recipients are chronically ischaemic and as a consequence their renin-angiotensin systems massively activated, which may further sensitize their kidneys to cyclosporin. Overproduction of angiotensin II, associated with the DD ACE genotype, has already been associated with poor prognosis in diabetic and IgA nephropathy. It is interesting to speculate that this ACE genotype, which is associated with a poor outcome in non-ischaemic heart disease can influence renal sensitivity to cyclosporin and predict the development of morphological injury. Extension of these experimental findings into the clinical arena with a placebo-controlled trial of early introduction of ACE inhibitor therapy in recipients of cardiac transplants would be timely.

  2. Human adipose tissue derived mesenchymal stem cells aggravate chronic cyclosporin nephrotoxicity by the induction of oxidative stress.

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    Byung Ha Chung

    Full Text Available The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA-induced renal injury. CsA (7.5 mg/kg and hATMSCs (3×10(6/5 mL were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05. An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.

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

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    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. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Black grape and garlic extracts protect against cyclosporine a nephrotoxicity.

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    Durak, Ilker; Cetin, Recep; Candir, Ozden; Devrim, Erdinç; Kiliçoğlu, Bülent; Avci, Aslihan

    2007-01-01

    The aim of this study was to determine if the natural antioxidant foods, dried black grape and garlic, protect against cyclosporine nephrotoxicity. Forty-two Sprague-Dawley rats were given Cyclosporine A (CsA) orally for 10 days, with the antioxidant food supplementation begun 3 days before CsA treatment and continued during the study period (totaling 13 days). In each group (control, CsA alone, CsA plus black grape, CsA plus aqueous garlic extract, aqueous garlic extract alone and black grape alone), there were 7 animals. At the end of the study period, the animals were sacrificed; their kidneys were removed and prepared for biochemical and histopathological investigations. Oxidant (xanthine oxidase enzyme and malondialdehyde) and antioxidant (superoxide dismutase, glutathione peroxidase and catalase enzymes) parameters were measured in the kidney tissues of the groups. Histopathological examinations of the tissues were also performed. It has been found that CsA creates oxidant load to the kidneys through both xanthine oxidase activation and impaired antioxidant defense system, which accelerates oxidation reactions in the kidney tissue. Supplementation with either dried black grape or aqueous garlic extract led to reduced malondialdehyde level in the kidney tissue possibly, by preventing oxidant reactions. In conclusion, the results suggest that impaired oxidant/antioxidant balance may play part in the CsA-induced nephrotoxicity, and some foods with high antioxidant power may ameliorate this toxicity, in agreement with studies with antioxidant vitamins.

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

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    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

  6. Exposure to nerve growth factor worsens nephrotoxic effect induced by Cyclosporine A in HK-2 cells.

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    Donatella Vizza

    Full Text Available Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkA(NTR and p75(NTR. 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 p75(NTR 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.

  7. Predictive usefulness of urinary biomarkers for the identification of cyclosporine A-induced nephrotoxicity in a rat model.

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    Carla Patrícia Carlos

    Full Text Available The main side effect of cyclosporine A (CsA, a widely used immunosuppressive drug, is nephrotoxicity. Early detection of CsA-induced acute nephrotoxicity is essential for stop or minimize kidney injury, and timely detection of chronic nephrotoxicity is critical for halting the drug and preventing irreversible kidney injury. This study aimed to identify urinary biomarkers for the detection of CsA-induced nephrotoxicity. We allocated salt-depleted rats to receive CsA or vehicle for 7, 14 or 21 days and evaluated renal function and hemodynamics, microalbuminuria, renal macrophage infiltration, tubulointerstitial fibrosis and renal tissue and urinary biomarkers for kidney injury. Kidney injury molecule-1 (KIM-1, tumor necrosis factor-alpha (TNF-α, interleukin 6 (IL-6, fibronectin, neutrophil gelatinase-associated lipocalin (NGAL, TGF-β, osteopontin, and podocin were assessed in urine. TNF-α, IL-6, fibronectin, osteopontin, TGF-β, collagen IV, alpha smooth muscle actin (α -SMA and vimentin were assessed in renal tissue. CsA caused early functional renal dysfunction and microalbuminuria, followed by macrophage infiltration and late tubulointerstitial fibrosis. Urinary TNF-α, KIM-1 and fibronectin increased in the early phase, and urinary TGF-β and osteopontin increased in the late phase of CsA nephrotoxicity. Urinary biomarkers correlated consistently with renal tissue cytokine expression. In conclusion, early increases in urinary KIM-1, TNF-α, and fibronectin and elevated microalbuminuria indicate acute CsA nephrotoxicity. Late increases in urinary osteopontin and TGF-β indicate chronic CsA nephrotoxicity. These urinary kidney injury biomarkers correlated well with the renal tissue expression of injury markers and with the temporal development of CsA nephrotoxicity.

  8. Effect of reduced form of coenzyme Q10 on cyclosporine nephrotoxicity.

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    Sato, Toshikazu; Ishikawa, Akira; Homma, Yukio

    2013-02-01

    Cyclosporine, a potent immunosuppressant, has nephrotoxic adverse effects that may be mediated by oxidative stress. The reduced form of coenzyme Q10 has antioxidant effects. The aim of the present study was to evaluate the effect of the reduced form of coenzyme Q10 on cyclosporine nephrotoxicity. Six-week-old male Wistar rats were divided into 3 groups (10 animals each). Group 1 (control) received olive oil only. Group 2 received cyclosporine (30 mg/kg/d, which is an experimentally nephrotoxic dose). Group 3 received cyclosporine (30 mg/kg/d) and the reduced form of coenzyme Q10 (600 mg/kg/d). The cyclosporine and the reduced form of coenzyme Q10 were given orally for 4 weeks. Daily urinary albumin excretion, serum creatinine level, and urinary 8-hydroxydeoxyguanosine level were measured, and renal tissue was evaluated by immunohistochemistry. In rats treated with cyclosporine and the reduced form of coenzyme Q10 (group 3), there were significantly less abnormalities in mean urinary albumin excretion (group 1: 2.8 ± 0.5; group 2: 41 ± 7; group 3: 21 ± 4 μg/d), serum creatinine (group 1: 1.0 ± 0.2; group 2: 1.8 ± 0.4; group 3: 1.4 ± 0.3 mg/dL), and urine 8-hydroxydeoxyguanosine levels (group 1: 7 ± 3; group 2: 10 ± 3; group 3: 7 ± 1 mg/mL creatinine) than rats treated with cyclosporine alone (group 2). There were 8-hydroxydeoxyguanosine deposits seen in the proximal tubular cells of group 2 that were not present in rats treated with the reduced form of coenzyme Q10 (group 3). The reduced form of coenzyme Q10 may prevent or minimize cyclosporine nephrotoxicity by an antioxidant effect.

  9. Nephrotoxicity of cyclosporin A in patients with newly diagnosed type 1 diabetes mellitus

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    Feldt-Rasmussen, B; Jensen, T; Dieperink, H

    1990-01-01

    Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12...... corrected for differences in blood glucose control it appeared that in three out of nine patients glomerular filtration rate had not completely returned to the reference range of the placebo group. We conclude that the nephrotoxic side-effects of cyclosporin A treatment for 1 year are reversible. There are...... to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance...

  10. Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

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    Nielsen, Finn Thomsen; Jensen, Boye L; Marcussen, Niels

    2008-01-01

    BACKGROUND: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. METHODS...

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

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    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

  12. Beneficial effect of ubiquinol, the reduced form of coenzyme Q10, on cyclosporine nephrotoxicity

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    Akira Ishikawa

    2012-04-01

    Full Text Available BACKGROUND: Cyclosporine (CyA nephrotoxicity is partly due to some oxidative stress. Ubiquinol, the reduced form of coenzyme Q10 (rCoQ10, has recently gained attention for its anti-oxidative potential. The aim of this study is to evaluate the effect of rCoQ10 on a CyA nephrotoxic rat model. MATERIALS AND METHODS: Six-week-old male Wistar rats were divided into three groups (five animals each. Group 1 received a medium only. Group 2 received 30 mg/kg/day of CyA only. Group 3 received both the same dose of CyA and 600 mg/kg/day of rCoQ10. CyA and rCoQ10 were both given orally for four weeks. Systolic blood pressure (BP, daily urinary albumin secretion (u-Alb, serum creatinine (s-Cr level, and super-oxide anion (SO level in the renal tissue were measured and compared among those three groups. Immunohistochemistry using an antibody for the transforming growth factor-beta (TGF-beta was also examined. RESULTS: BPs, u-Albs, s-Crs, and SO levels of groups 1, 2, and 3 were 114 ± 3, 132 ± 4, and 129 ± 5 mmHg, 2.6 ± 0.5, 42.1 ± 7.2, and 22.8 ± 3.4 micro-g/day, 1.1 ± 0.2, 1.7 ± 0.2, and 1.3 ± 0.2 mg/dl, and 224 ± 84, 1251 ± 138, and 512 ± 109 RLU/g kidney respectively. U-Albs, s-Crs, and SO levels were significantly ameliorated by rCoQ10. Micro-vacuolar changes and TGF-beta positive deposits in the proximal renal tubular cells of CyA group rats disappeared in those of CyA and rCoQ10 group rats. CONCLUSION: RCoQ10, an antioxidants, may have potential for preventing CyA nephrotoxicity.

  13. Anti-transforming growth factor antibody at low but not high doses limits cyclosporine-mediated nephrotoxicity without altering rat cardiac allograft survival: potential of therapeutic applications.

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    Khanna, Ashwani K; Plummer, Matthew S; Hilton, Gail; Pieper, Galen M; Ledbetter, Steven

    2004-12-21

    Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-beta (TGF-beta) is one of the most potent mediators of the fibrogenic effects of cyclosporine. With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-beta in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-beta antibody to determine whether anti-TGF-beta antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-beta, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-beta protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-beta protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-beta antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. These results provide credence to the pivotal role of TGF-beta in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-beta antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

  14. Preliminary experience with mycophenolate mofetil for preservation of renal function in cardiac transplant patients with documented cyclosporine nephrotoxicity.

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    Al-Aly, Ziyad; Sachdeva, Ashutosh; Philoctete Ashley, Jennifer M; Bastani, Bahar

    2006-04-01

    Cyclosporine (CyA) has positively impacted on the outcome of cardiac transplantation; however, the nephrotoxicity associated with CyA has been a major drawback. In an effort to reduce exposure to CyA and possibly alleviate its nephrotoxic effects, we undertook a therapeutic strategy to switch cardiac transplant patients with biopsy-proven CyA nephrotoxicity from azathioprine (AZA) to mycophenolate mofetil (MMF) with subsequent CyA dose reduction or elimination. MMF was substituted for AZA in five cardiac transplant patients (four males; mean age, 60 +/- 6 years old; average time from transplant was 7 +/- 3 years) who had biopsy proven evidence of CyA nephrotoxicity, and in whom CyA dose was reduced (3/5) or discontinued (2/5). At the time of the therapeutic intervention, four patients had an average serum creatinine of 230 +/- 62 micromol/L and one patient had just been started on haemodialysis (HD). During an average follow-up period of 42 months, the slope of the inverse serum creatinine significantly improved in three patients and continued to deteriorate in one patient. The patient on HD could be transiently taken off HD. However, he developed a severe episode of cardiac rejection requiring antirejection therapy and increase in the dose of CyA. The patient was subsequently returned back on HD. In this preliminary report, we show that AZA to MMF switch with subsequent CyA dose reduction or discontinuation may slow down the progression of kidney disease in some patients. However, the patients should be followed closely for evidence of cardiac rejection.

  15. Clinical efficiency of cyclosporine in chronic idiopathic urticaria in adults

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    V.I. Petrov

    2010-06-01

    Full Text Available The purpose of the research is to evaluate the clinical effectiveness of cyclosporine and other antihistamines in patients with chronic forms of urticaria resistant to basic first-line therapy. Open randomized controlled study has been performed in parallel groups. 53 patients with chronic idiopathic urticaria ages 18-50 years have been examined. In case of ineffectiveness of previous therapy, patients have been randomized into 2 groups: group I receiving cyclosporine (Sandimmune Neoral ® 2,5 mg/kg/day, group II receiving cetirizine (Zyrtec ® 10 mg/day and ranitidine (Zantac ® 300 mg/day orally. It has been found that the administration of cyclosporine in patients with severe chronic idiopathic urticaria provides a more rapid achievement of clinical effect than the therapy with H1/H2 histamine antagonists. It is confirmed by a significant decrease of total index of severity of illness and major symptoms of skin lesions. This tendency towards normalization of quality of life of patients taking cyclosporine remains during 8 weeks after the medication. Thus administration of cyclosporine can be considered as therapy of choice in patients with chronic idio-pathic urticaria with a severe course and ineffective long-term therapy with antihistamines / systemic corticosteroids

  16. Treatment of chronic urticaria in children with antihistamines and cyclosporine.

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    Neverman, Lisa; Weinberger, Miles

    2014-01-01

    Chronic idiopathic urticaria, daily hives that last >6 weeks, can be resistant to antihistamines, even when higher than conventional doses are used. Other pharmacologic agents have been associated with inconsistent benefit. We examined the relationship of clinical characteristics and the presence of autoimmune antibodies to antihistamine resistance in children. We further examined the efficacy and safety of cyclosporine in children whose urticaria was resistant to antihistamine. Patients referred to the pediatric allergy and pulmonary specialty clinic at the University of Iowa Children's Hospital and diagnosed as having chronic idiopathic urticaria were identified during the period from August 2008 to July 2013. A retrospective examination of treatment and outcome was performed. Forty-six patients, 26 female patients and 20 male patients, with chronic idiopathic urticaria were identified. The ages of 16 patients who were antihistamine resistant ranged from 9 to 18 years (median, 12.5 years). Those patients who were antihistamine responsive had a median age of 6 years, significantly lower than those who were antihistamine resistant (P = .0001). There was no significant association between autoimmune antibodies and antihistamine resistance. All the patients who were antihistamine resistant were treated with cyclosporine; all experienced complete resolution of urticaria at times that ranged from 2 days to 3 months (median, 7 days). Relapses responsive to repeated cyclosporine occurred in 5 of the patients after 1 week to 15 months (median, 6 months). Adverse effects were not seen in these patients. Our data were consistent with efficacy and safety of cyclosporine for chronic urticaria in children when even high doses of antihistamines are ineffective. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. The Usefulness of Determining Neutrophil Gelatinase-Associated Lipocalin Concentration Excreted in the Urine in the Evaluation of Cyclosporine A Nephrotoxicity in Children with Nephrotic Syndrome

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    Ewa Gacka

    2016-01-01

    Full Text Available Introduction. The use of cyclosporine (CsA in the treatment of nephrotic syndrome (NS contributed to a significant reduction in the amount of corticosteroids used in therapy and its cumulative side effects. One of the major drawbacks of CsA therapy is its nephrotoxicity. Prolonged CsA treatment protocols require sensitive, easily available, and simple to measure biomarkers of nephrotoxicity. NGAL is an antibacterial peptide, excreted by cells of renal tubules in response to their toxic or inflammatory damage. Aim of the Study. The aim of this study was to assess the suitability of the NGAL concentration in the urine as a potential biomarker of the CsA nephrotoxicity. Material and Methods. The study was performed on a group of 31 children with NS treated with CsA. The control group consisted of 23 children diagnosed with monosyptomatic enuresis. The relationship between NGAL excreted in urine and the time of CsA treatment, concentration of CsA in blood serum, and other biochemical parameters was assessed. Results. The study showed a statistically significant positive correlation between urine NGAL concentration and serum triglycerides concentration and no correlation between C0 CsA concentration and other observed parameters of NS. The duration of treatment had a statistically significant influence on the NGAL to creatinine ratio. Conclusions. NGAL cannot be used alone as a simple CsA nephrotoxicity marker during NS therapy. Statistically significant correlation between NGAL urine concentration and the time of CsA therapy indicates potential benefits of using this biomarker in the monitoring of nephrotoxicity in case of prolonged CsA therapy.

  18. Treatment of chronic dry eye: focus on cyclosporine

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    George D Kymionis

    2008-08-01

    Full Text Available George D Kymionis, Dimitrios I Bouzoukis, Vassilios F Diakonis, Charalambos SiganosDepartment of Ophthalmology, Vardinoyannion Eye Institute of Crete, University of Crete, GreeceAbstract: 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.Keywords: dry eye, cyclosporine A, inflammation, immunomodulator agents

  19. Arteriosclerosis in zero-time biopsy is a risk factor for tacrolimus-induced chronic nephrotoxicity.

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    Yagisawa, Takafumi; Omoto, Kazuya; Shimizu, Tomokazu; Ishida, Hideki; Tanabe, Kazunari

    2015-07-01

    Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens. Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score. Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity. © 2015 Asian Pacific Society of Nephrology.

  20. Successful reversal of acute vascular rejection and cyclosporine-associated nephrotoxicity in renal allograft with combined sirolimus and mycophenolate mofetil as immunotherapy.

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    Ołdakowska-Jedynak, U; Paczek, L; Mucha, K; Foroncewicz, B; Perkowska-Ptasińska, A

    2006-01-01

    Cyclosporine (CsA) has substantially improved patient and graft survival rates in solid organ transplantation. In clinical studies, sirolimus has been shown to be as effective as CsA to maintain survival of renal and cardiac allografts without causing nephrotoxicity. Herein we describe a patient with biopsy-proven CsA-associated nephrotoxicity and refractory renal allograft rejection who was converted from steroids, CsA, and azathioprine to steroids, sirolimus (RAPA), and low-dose mycophenolate mofetil (MMF). The follow-up period was 60 months. We observed substantial improvement, even normalization in renal function. Our patient did not give consent to repeat biopsy after conversion. We also observed a beneficial effect of CsA withdrawal on blood pressure control. The spectrum of adverse events induced by sirolimus seemed to be mild relative to the potency of the immunosuppressive effect. The excellent response to combined RAPA and MMF in this patient was probably due to "concerted actions" of these agents on both B- and T-cell functions. The combination enhanced therapeutic efficacy while minimizing the toxicity of individual drugs used in the regimen. These findings suggest that sirolimus, when used as a base therapy in combination with low-dose MMF in a renal allograft recipient, may be an alternative to CsA-based therapy, providing potent immunosuppression of a renal allograft. Sirolimus administration facilitated steroids dose reduction.

  1. Low-dose cyclosporin A therapy in treating chronic, noninfectious uveitis.

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    Vitale, A T; Rodriguez, A; Foster, C S

    1996-03-01

    To describe the authors' approach to the management of patients with recalcitrant, chronic, endogenous uveitis using low-dose Cyclosporin A (CSA) alone or in combination with other immunosuppressive agents with attention to the anti-inflammatory efficacy, visual outcome, and side effects of therapy. The authors reviewed the records of 50 patients (92 eyes) with uveitis of various etiologies who had been treated with low-dose CSA (2.5-5.0 mg/kg daily) alone or in combination with prednisone and/or azathioprine (1.5-2.0 mg/kg daily). The median follow-up on low-dose CSA was 16 months (range, 6-64 months). Inflammatory control was achieved in 68 (73.9%) eyes, while persistent inflammatory activity was observed in 14 (15.2%). Thirty-eight (41%) eyes improved two Snellen lines or more, 43 (47.0%) stabilized, and 11 (12.0%) lost two lines or more. The CSA was discontinued because of nephrotoxicity in three patients and in each of two with systemic hypertension and constitutional intolerance to the drug, respectively. Thirteen patients enjoy inflammatory remission with this regimen. Low-dose CSA used alone or in combination with other immunosuppressive agents is effective in achieving inflammatory control with a favorable visual outcome and provides a useful steroid-sparing strategy in the management of chronic endogenous uveitis. The CSA-associated toxicity may be reduced by initiating therapy at very low initial doses, with incremental dosage escalation to the desired target range.

  2. Cyclosporine arteriolopathy: effects of drug withdrawal.

    Science.gov (United States)

    Franceschini, N; Alpers, C E; Bennett, W M; Andoh, T F

    1998-08-01

    Renal arteriolopathy in chronic cyclosporine-induced nephrotoxicity is characterized by an eosinophilic granular transformation of vascular smooth muscle cells of afferent glomerular arterioles that is thought to eventually progress to necrosis of individual muscle cells and hyalinization of the vessel wall. Although the lesion is highly specific for cyclosporine-induced injury in humans, it has been difficult to reproduce in normotensive animals. To study the natural history of the cyclosporine arteriolopathy, we conducted sequential studies in salt-depleted Sprague-Dawley rats using cyclosporin A (15 mg/kg subcutaneously) treatment for 35 days, 49 days, 35 days plus 14 or 56 days of drug washout, or placebo (olive oil). Cyclosporin A produced a progressive decrease in renal function that significantly improved after discontinuation of the drug. The arteriolopathy, scored semiquantitatively, was present by day 35 and did not improve with cyclosporine withdrawal within 2 weeks but did dramatically regress after 56 days. However, tubulointerstitial changes did not regress with drug discontinuation and were present despite improvement in renal function. We conclude that cyclosporine-induced arteriolopathy may be reversible and associated with improving renal function. Thus, the morphological evidence of arteriolopathy is dissociable from the progressive tubulointerstitial scarring.

  3. Conversion to sirolimus from cyclosporine may induce nephrotic proteinuria and progressive deterioration of renal function in chronic allograft nephropathy patients.

    Science.gov (United States)

    Boratyńska, M; Banasik, M; Watorek, E; Falkiewicz, K; Patrzałek, D; Szyber, P; Klinger, M

    2006-01-01

    Antiproliferative and non-nephrotoxic properties of sirolimus have been exploited for treatment of patients with chronic graft dysfunction. In this paper we point to the possible association of nephrotic syndrome and renal impairment with rapid conversion from cyclosporine (CsA) to sirolimus in patients with chronic nephropathy. Five male patients, ages 34 to 56 years, with chronic renal failure in the course of glomerulonephritis, were transplanted between 1997 and 1999. For the first 49 to 65 months, the immunosuppressive regimen consisted of CsA, azathioprine (AZA), and prednisone. Thereafter, due to chronic nephropathy evidenced by biopsy, conversion to sirolimus was performed with sharp withdrawal of CsA. The serum creatinine level prior to conversion was 1.9 +/- 0.3 mg/dL. Trace to 86 mg/dL proteinuria was found in 3 patients, while 2 patients had about 200 mg/dL. After 2 to 4 months of sirolimus treatment the proteinuria progressed (558 +/- 183 mg/dL); edema, hypoproteinemia, hypoalbuminemia, and hyperlipidemia developed; and the serum creatinine increased to 3.5 +/- 0.8 mg/dL. Biopsies performed in three patients revealed new pathologic changes. After 4 to 5 months, we performed reconversion to calcineurin inhibitor. Proteinuria decreased to 0 to 150 mg/dL; nevertheless the serum creatinine was continuously rising. Six to 15 months after the conversion, 3 patients returned to dialysis. The fourth patient, who was earlier reconverted, has a serum creatinine level of 2.0 mg/dL after 15 months. In conclusion, conversion from CsA to sirolimus may induce nephrotic syndrome with progressive deterioration of renal function. Converted patients require careful monitoring of proteinuria and renal function. Early reconversion to calcineurin inhibitor may prevent progressive deterioration of graft function.

  4. Rosiglitazone suppresses cyclosporin-induced chronic transplant dysfunction and prolongs survival of rat cardiac allografts.

    Science.gov (United States)

    Chen, Yan; Liu, Yan; Yuan, Zhengwei; Tian, Lina; Dallman, Margaret J; Thompson, Paul W; Tam, Paul K H; Lamb, Jonathan R

    2007-06-27

    The lack of effective treatment for chronic transplant dysfunction restricts the long-term survival of solid organ allografts. Peroxisome proliferator-activated receptor ligands can suppress vascular inflammation. The aim of this study was to analyze the effects of rosiglitazone on chronic transplant dysfunction in a rat cardiac transplant model. Inbred male Fisher 344 (F344, RT1lvl) and Lewis (LEW, RT1(1)) rats were subjected to heterotopic abdominal heart transplantation according to standard procedures. Cyclosporine A was administered intraperitoneally to cover acute rejection, and rosiglitazone was administered orally by gavage daily from 3 days before the operation to the end of experiments. Rosiglitazone significantly prolonged the survival of cardiac allografts in rats (F344 to LEW) that had received a 10-day course of cyclosporin A compared to treatment with immunosuppressant alone. Analysis of allografts at 120 days posttransplantation showed that rosiglitazone reduced the inflammatory cell infiltrate in both the vessels and graft parenchyma as were neointimal formation, vascular occlusion, and fibrosis. Expression of transforming growth factor-beta and related proteins was less abundant after cyclosporin A/rosiglitazone treatment. The findings reported here demonstrate that rosiglitazone given under the cover of short-term treatment with cyclosporin A prolongs cardiac allograft survival and reduces the severity of chronic transplant dysfunction. This may be mediated in part through the downregulation of transforming growth factor-beta and related proteins. The combined effects of rosiglitazone and immunosuppressive drugs are potentially beneficial to patients receiving organ transplants.

  5. Acute and chronic nephrotoxicity of platinum nanoparticles in mice

    Science.gov (United States)

    Yamagishi, Yoshiaki; Watari, Akihiro; Hayata, Yuya; Li, Xiangru; Kondoh, Masuo; Yoshioka, Yasuo; Tsutsumi, Yasuo; Yagi, Kiyohito

    2013-09-01

    Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size.

  6. Infliximab Salvage Therapy after Cyclosporine in an Acute Flare of Chronic Ulcerative Colitis

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    ECS Lam

    2003-01-01

    Full Text Available Although infliximab (Remicade, Schering Canada Inc, Quebec therapy has been well studied in steroid refractory Crohn’s disease, its use remains controversial in chronic ulcerative colitis. A 24-year-old woman with a 14-year history of well controlled left sided ulcerative colitis presented with an acute flare. Clinical, endoscopic and biopsy evidence of an acute flare of ulcerative pancolitis were present. There was no response to intravenous steroids but improvement was seen after receiving 14 days of intravenous cyclosporine (4 mg/kg/day continuous infusion. The patient was discharged from hospital with azathioprine (2.5 mg/kg/day and low dose oral cyclosporine (4 mg/kg/day. She presented with worsening symptoms seven days after discharge. Because of the patient’s unwillingness for surgery, she instead received two injections of infliximab 5 mg/kg at week 0 and week 2. An initial response occurred, but her clinical improvement was not durable. Colectomy was performed four weeks later. This is the first report of infliximab as a salvage therapy in an acute flare of chronic ulcerative colitis following failure of cyclosporine.

  7. Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

    Science.gov (United States)

    Rehman, Hasibur; Krishnasamy, Yasodha; Haque, Khujista; Thurman, Ronald G; Lemasters, John J; Schnellmann, Rick G; Zhong, Zhi

    2014-01-01

    Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate Cs

  8. Green Tea Polyphenols Stimulate Mitochondrial Biogenesis and Improve Renal Function after Chronic Cyclosporin A Treatment in Rats

    Science.gov (United States)

    Rehman, Hasibur; Krishnasamy, Yasodha; Haque, Khujista; Lemasters, John J.; Schnellmann, Rick G.; Zhong, Zhi

    2013-01-01

    Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate Cs

  9. Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

    Directory of Open Access Journals (Sweden)

    Hasibur Rehman

    Full Text Available Our previous studies showed that an extract from Camellia sinenesis (green tea, which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA. Since polyphenols are stimulators of mitochondrial biogenesis (MB, this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1% starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks. CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS protein ATP synthase-β (AS-β by 42%, mitochondrial DNA (mtDNA-encoded OXPHOS protein NADH dehydrogenase-3 (ND3 by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV, an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam, the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate Cs

  10. Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study.

    Science.gov (United States)

    Fuchs, U; Zittermann, A; Hakim-Meibodi, K; Börgermann, J; Schulz, U; Gummert, J F

    2011-06-01

    The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m(2) in the ECN subgroup but decreased by 2.4 mL/min/1.73 m(2) and 9.0 mL/min/1.73 m(2) in the EDS subgroup and the CSA group, respectively (P cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka

    Energy Technology Data Exchange (ETDEWEB)

    Rango, Tewodros, E-mail: tg67@duke.edu [Division of Earth and Ocean Sciences, Nicholas School of the Environment, Duke University, Durham, NC (United States); Jeuland, Marc [Sanford School of Public Policy and Duke Global Health Institute, Duke University, Durham, NC (United States); Institute of Water Policy, National University of Singapore (Singapore); Manthrithilake, Herath; McCornick, Peter [International Water Management Institute, Colombo (Sri Lanka)

    2015-06-15

    Chronic kidney disease of unknown (“u”) cause (CKDu) is a growing public health concern in Sri Lanka. Prior research has hypothesized a link with drinking water quality, but rigorous studies are lacking. This study assesses the relationship between nephrotoxic elements (namely arsenic (As), cadmium (Cd), lead (Pb), and uranium (U)) in drinking water, and urine samples collected from individuals with and/or without CKDu in endemic areas, and from individuals without CKDu in nonendemic areas. All water samples – from a variety of source types (i.e. shallow and deep wells, springs, piped and surface water) – contained extremely low concentrations of nephrotoxic elements, and all were well below drinking water guideline values. Concentrations in individual urine samples were higher than, and uncorrelated with, those measured in drinking water, suggesting potential exposure from other sources. Mean urinary concentrations of these elements for individuals with clinically diagnosed CKDu were consistently lower than individuals without CKDu both in endemic and nonendemic areas. This likely stems from the inability of the kidney to excrete these toxic elements via urine in CKDu patients. Urinary concentrations of individuals were also found to be within the range of reference values measured in urine of healthy unexposed individuals from international biomonitoring studies, though these reference levels may not be safe for the Sri Lankan population. The results suggest that CKDu cannot be clearly linked with the presence of these contaminants in drinking water. There remains a need to investigate potential interactions of low doses of these elements (particularly Cd and As) with other risk factors that appear linked to CKDu, prior to developing public health strategies to address this illness. - Highlights: • Drinking water in rural Sri Lanka contains low levels of inorganic nephrotoxicants • Urinary nephrotoxicants are consistent with reference levels from

  12. Topical cyclosporine a 1% for the treatment of chronic ocular surface inflammation.

    Science.gov (United States)

    Ragam, Ashwinee; Kolomeyer, Anton M; Kim, Jason S; Nayak, Natasha V; Fang, Christina; Kim, Eliott; Chu, David S

    2014-09-01

    To evaluate the use of topical cyclosporine A (CsA) 1% emulsion in the treatment of chronic ocular surface inflammation (OSI). We conducted a retrospective chart review of patients with various forms of OSI treated with topical CsA 1% from 2001 to 2012. Twenty-nine patients (52 eyes) with various forms of OSI, including epidemic keratoconjunctivitis (n=14), chronic follicular conjunctivitis (n=12), Thygeson superficial punctate keratopathy (n=2), and vernal keratoconjunctivitis (n=1), were included. Twenty-seven patients had inflammation refractory to prior therapies. Twenty-four patients received concurrent medications with CsA 1%. Twenty-three of 24 patients on concurrent corticosteroids (CS) were able to taper their use while receiving CsA 1%. Thirteen patients experienced ocular discomfort with CsA 1%; one patient discontinued therapy all together as a result of these side effects; another switched to CsA 0.5% with improvement of adverse symptoms. Inflammation was controlled in 22 (92%) of the 24 patients who received CsA 1% for at least 2 months in duration. Topical CsA 1% helps to control inflammation and spares CS use in patients with chronic OSI.

  13. Intravitreal implantation of the biodegradable cyclosporin A drug delivery system for experimental chronic uveitis.

    Science.gov (United States)

    Dong, Xiaoguang; Shi, Weiyun; Yuan, Gongqiang; Xie, Lixin; Wang, Shenguo; Lin, Ping

    2006-04-01

    The purpose was to evaluate the efficacy of the intravitreal implantation of the biodegradable cyclosporin A (CsA) drug delivery system (DDS) for experimental chronic uveitis. The DDS was prepared by formulating CsA into glycolide-co-lactide-co-caprolactone copolymer (PGLC). Right eyes of 30 New Zealand white rabbits were used to establish a model of uveitis and randomized into control, intravitreal non-medicated DDS, oral CsA (15 mg/kg daily), and intravitreal CsA-PGLC DDS (each containing 2 mg CsA) groups. The progress of ocular inflammation, results of electroretinography, and histopathological examination of ocular, renal, and hepatic functions were recorded. Intravitreal CsA levels were measured in another 13 rabbits receiving an implant of the CsA-PGLC DDS. Chronic uveitis was successfully induced in all 30 eyes. The inflammation in the eyes with no treatment, non-medicated implant, and oral CsA was more severe than those with the CsA-PGLC DDS at each timepoint. The electroretinography b-wave was depressed much less in the CsA-PGLC DDS group than in the other three groups (ptoxicity was detected. Intravitreal implantation of the biodegradable CsA-PGLC DDS may effectively reduce the intraocular inflammation in rabbits with no toxicity, which provides a potentially safe and convenient approach for the treatment of chronic uveitis.

  14. N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity.

    Directory of Open Access Journals (Sweden)

    Leonardo Victor Barbosa Pereira

    Full Text Available The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC. Male Wistar rats were submitted to 5/6 nephrectomy (Nx to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine was administrated (1.5 mM/KgBW, intravenously 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (n = 7; 2--Nx+NAC (n = 6; 3--Nx+Gd (n = 7; 4--Nx+NAC+Gd (4.8 g/L in drinking water, initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6. This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW, proteinuria (mg/24 hs, serum iron (µg/dL; serum ferritin (ng/mL; transferrin saturation (%, TIBC (µg/dL and TBARS (nmles/ml. Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.

  15. Conversion to generic cyclosporine A in stable chronic patients after heart transplantation

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    Kraeuter M

    2013-11-01

    Full Text Available Maximilian Kraeuter,1 Matthias Helmschrott,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Bastian Schmack,2 Arjang Ruhparwar,2 Philipp Ehlermann,1 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, 2Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany Background: Cyclosporine A (CSA is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated. Methods: Twenty adult stable chronic (>24 months post heart transplant recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral® according to the patients’ preference during the clinical routine. Dose-normalized trough levels (DNL and trough levels (C0 at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared. Results: The mean DNL (adapted to the daily CSA dose in mg was 0.71±0.26 (ng/mL/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL/mg, (P=0.38. In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13. No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99. Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant. No adverse events after the conversion were observed. Conclusion: This study

  16. Tenofovir Nephrotoxicity: 2011 Update

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    Beatriz Fernandez-Fernandez

    2011-01-01

    Full Text Available Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.

  17. Cytokine array after cyclosporine treatment in rats.

    Science.gov (United States)

    Jin, K B; Choi, H J; Kim, H T; Hwang, E A; Han, S Y; Park, S B; Kim, H C; Ha, E Y; Kim, Y H; Suh, S I; Mun, K C

    2008-10-01

    Long-term treatment with cyclosporine (CsA) results in chronic nephrotoxicity, which is known to be mediated by several cytokines including transforming growth factor-betal. Cytokines are known to play an important role in innate immunity, apoptosis, angiogenesis, cell growth, and differentiation. They are known to be involved in most disease processes, including cancer, cardiac disease, and nephrotoxicity. To evaluate changes of cytokines in a rat model of CsA-induced chronic nephrotoxicity, we performed a cytokine array. Experiments were performed on two groups of rats; normal control group and CsA-treated group. Cytokine array in rat serum was performed using Cytokine Antibody Array I kit from RayBiotech. Serum creatinine, urine creatinine, and creatinine clearance increased in the CsA-treated group. Among the several cytokines, the expressions of the lipopolysaccharide-induced CXC chemokine (LIX), monocyte chemoattractant protein 1 (MCP-1), nerve growth factor (beta-NGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CsA-treated group were increased above that of cytokines in the control group. The density of the LIX in controls was 0.62, and in the CsA-treated group was 1.24. The density of the MCP-1 in controls was 0.68, and in CsA-treated, 1.43. The density of the beta-NGF in controls was 0.62, and that in CsA-treated, 1.24. The density of the TIMP-1 in controls 1.13, and in CsA-treated, 1.40. Our data suggested that among several cytokines elevated levels of the LIX, MCP-1, beta-NGF, and TIMP-1 are the contributing factors to CsA-induced nephropathy.

  18. Effect of cyclosporine therapy in transplanted patients-diagnostic values of tubular markers

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    Todor Gruev

    2003-09-01

    Full Text Available The introduction of cyclosporine A (CsA into the clinical practice has resulted in a major improvement in the short-term outcomes of solid organ transplantation and treatment of autoimune diseases. Chronic ScA nephrotoxicity has been described in kidneys of recepients of renal and other organ allografts. However, the exact mechanism underlying the development of fibrosis in chronic CsA nephrotoxicity has remained poorly understood. Evaluation with the validation data set showed that noninvasive urine protein differentiation might be a useful diagnostic strategy in nephrology. Over the past decade numerous studies in patients after transplantation have demonstrated that renal tubular cell injury after a toxic insult, results in sloughing of tubular debris and cell into the tubular lumen with eventual obstruction of tubular flow, increased intratubular pressure and backleak of glomerular filtrate out of the tubule. Urinary enzymes and low molecular proteins have been recommended as useful markers for the detection of changes in the kidney tissue in cases after renal transplantation. The aim of our study was to monitor the concentration and eventual nephrotoxic effect of Cyclosporine A using the concentration of low molecular proteins α-1-microglobulin and β−2-microglobulin, serum Cystatin C, as well as the concentration of isoform of GST-α and π.

  19. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression.

    Science.gov (United States)

    Goldstein, D J; Zuech, N; Sehgal, V; Weinberg, A D; Drusin, R; Cohen, D

    1997-03-15

    The salutary immunosuppressive effects of cyclosporine in extending cardiac allograft survival may be curtailed by its nephrotoxic effects. We reviewed our first 9 years of experience with cyclosporine after cardiac transplantation, to evaluate the incidence and progression of cyclosporine-associated end-stage renal failure necessitating chronic hemodialysis. Retrospective computer-based file review and personal interview when possible. The population at risk was comprised of all adult cardiac recipients surviving at least 3 years (n=293). Of these, 19 (6.5%) developed end-stage renal failure requiring chronic hemodialysis. There were 17 men and 2 women (mean age of 45 +/- 11 years). The mean creatinine clearance for the study group decreased by 38% (Ptransplant) by 6 months after transplantation and by 48% by 3 years postoperatively (Ptransplant). The mean serum creatinine rose by 80% (Ptransplant) by 6 months after transplantation and by 125% by 3 years postoperatively (Ptransplant). Time elapsed from transplantation to hemodialysis ranged from 3.7 to 9.5 years (mean 6.4 +/- 2). Actuarial 1- year survival after onset of hemodialysis was 75%. Although cyclosporine remains the central immunosuppressive agent for cardiac allograft recipients, its use leads to a greater than one-third decrease in creatinine clearance by 6 months after transplantation and progression to end-stage renal failure, requiring hemodialysis in 6.5% of cardiac transplant recipients. Moreover, these patients are at increased risk of death compared with other cardiac allograft recipients. This data warrants the search of alternative or adjunctive agents that would allow decreased dosing or reduced nephrotoxicity of cyclosporine, while maintaining equivalent survival.

  20. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Lundgren, Jens D; Ross, Michael

    2016-01-01

    BACKGROUND: Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of ...... nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored. FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee....

  1. Cyclosporine in thoracic organ transplantation.

    Science.gov (United States)

    Banner, N R; Yacoub, M H

    2004-03-01

    The discovery of cyclosporine proved to be a breakthrough that helped transform the status of both heart and lung transplantation from experimental to established therapeutic procedures. Cyclosporine inhibits the early phase of T-cell activation and thus of the alloimmune response. It proved to be highly effective in prophylaxis against acute rejection but its use has been limited by dose-related renal toxicity. Consequently, it has generally been used in regimens that combine it with other immunosuppressive agents with the aim of preventing acute rejection while minimising toxicity. For many years 'triple therapy' using cyclosporine, azathioprine and corticosteroids was the most commonly used regimen for both heart and lung transplantation. Other agents have now become available that provide more effective prophylaxis against acute rejection than azathioprine; these include, mycophenolate and the TOR inhibitors sirolimus and everolimus. Everolimus has also been shown to inhibit the early phase of cardiac allograft vasculopathy. Unfortunately, the TOR inhibitors also potentiate the nephrotoxicity of cyclosporine. Both mycophenolate and the TOR inhibitors are subject to pharmacokinetic interactions with cyclosporine. We are now entering a new phase of clinical immunosuppression where we need to learn how to best combine the agents that are currently available to provide the safest and most effective immunosuppression for patients undergoing heart or lung transplantation.

  2. Changing cyclosporin A formulation: an analysis in paediatric cardiac transplant recipients.

    Science.gov (United States)

    Gennery, A R; O'Sullivan, J J; Hasan, A; Hamilton, J R; Dark, J H

    1999-08-01

    Cyclosporin A is the primary immunosuppressive agent used in cardiac transplantation to maintain chronic immunosuppression. Absorption may be erratic and major side-effects include nephrotoxicity. A recently introduced formulation (Neoral) improves absorption in cystic fibrosis heart-lung transplant recipients, but episodes of rejection have been reported on conversion from the oil-based formulation. A retrospective analysis of 21 paediatric cardiac transplant recipients who had been converted from the oil-based formulation to the micro-emulsified formulation was performed. No clinical rejection episodes occurred following conversion. There was a significant reduction in dose following conversion (p cardiac transplant recipients despite conversion to the new formulation.

  3. Treatment with Dimethyl Fumarate attenuates calcineurin inhibitor-induced Nephrotoxicity

    OpenAIRE

    Takasu, Chie; Vaziri, Nosratola D.; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Liu, Shuman; Farzaneh, Seyed H.; Foster, Clarence E; Stamos, Michael J; Ichii, Hirohito

    2015-01-01

    Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Background. Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection after organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of dimethyl fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system. Methods. Male Sprague-Dawley rat...

  4. Cardiac transplant experience with cyclosporine.

    Science.gov (United States)

    Patel, J K; Kobashigawa, J A

    2004-03-01

    The advent of cyclosporine 20 years ago was a major advance in the field of solid organ transplantation. Its use enabled directed immunosuppression with a consequent decrease in the incidence of graft failure, acute rejection, and systemic infection. The early oil-based preparation, however, was difficult to administer and had limited bioavailability and unpredictable pharmacokinetics. The drug also has a fairly narrow therapeutic window with major long-term side effects, which include nephrotoxicity, malignancy, hyperlipidemia, and hypertension. The introduction of a microemulsion preparation (Neoral) with improved bioavailability has been associated with lower rates of rejection and comparable tolerability, therefore allowing the use of lower doses. Traditionally cyclosporine toxicity has been minimized by monitoring trough levels. Monitoring of levels 2 hours after dosing may provide a more accurate determination of cyclosporine exposure. The next phase in cardiac transplantation immunosuppression will most likely see a significantly diminished role for cyclosporine with the introduction of newer, more potent immunosuppressive agents with more favorable side-effect profiles. These agents, which include mycophenolate mofetil, sirolimus, and everolimus, also hold the promise of having a major impact on the development of transplant vasculopathy, which up to now has been an important determinant of limiting long-term allograft survival.

  5. Realgar, cinnabar and An-Gong-Niu-Huang Wan are much less chronically nephrotoxic than common arsenicals and mercurials.

    Science.gov (United States)

    Lu, Yuan-Fu; Wu, Qin; Yan, Jun-Wen; Shi, Jing-Zhen; Liu, Jie; Shi, Jing-Shan

    2011-02-01

    Realgar (As(4)S(4)) and cinnabar (HgS) are frequently included in traditional Chinese medicines and Indian Ayurvedic medicines. Both As and Hg are well known for toxic effects, and their safety is of concern. The aim of this study was to compare chronic nephrotoxicity of An-Gong-Niu-Huang Wan (AGNH), realgar and cinnabar with common arsenicals and mercurials. Mice were orally administrated with AGNH (3 g/kg, 6-fold of clinical dose), cinnabar (0.3 g/kg, amount in AGNH) and realgar (0.3 g/kg, amount in AGNH), HgCl(2) (0.118 mmol/kg, 1/10 of cinnabar), MeHg (0.012 mmol/kg, 1/100 of cinnabar), NaAsO(2) (As(3+) 0.028 mmol/kg, 1/100 of realgar) or Na(2)HAsO(4) (As(5+) 0.056 mmol/kg, 1/50 of realgar), daily for six weeks, and nephrotoxicity was examined. Animal body weights were decreased by MeHg and HgCl(2). Blood urea nitrogen and creatinine levels were elevated by MeHg. Renal pathology was severe in the MeHg and HgCl(2) groups, moderate in the arsenite, arsenate and realgar groups and mild in the cinnabar and AGNH groups. Renal Hg accumulation in the MeHg and HgCl(2) groups was 50-200 folds higher than the cinnabar group. Expressions of metallothionein-1 and heme oxygenase-1, biomarkers for metal toxicity, were increased 2-5 folds by arsenite, arsenate, MeHg and HgCl(2), but not by realgar, cinnabar and AGNH. The chemokine and glutathione-S transferase-α4, markers for inflammation, were also increased by MeHg and HgCl(2). Expressions of cell adhesion gene S100a9 and E-cadherin were altered by HgCl(2), arsenite and realgar. Taken together, chemical forms of mercury and arsenic are major determinants in their disposition and toxicity.

  6. Cyclosporine impairs vasodilation without increased sympathetic activity in humans.

    Science.gov (United States)

    Stein, C M; He, H; Pincus, T; Wood, A J

    1995-10-01

    Hypertension and nephrotoxicity frequently complicate treatment with cyclosporine; two suggested mechanisms are increased sympathetic activity and altered vascular reactivity. It is difficult to assess these mechanisms in patients receiving cyclosporine after transplantation because of the accompanying major physiological alterations. Therefore, we studied 12 patients with rheumatoid arthritis twice--while they were taking and not taking cyclosporine. We measured vascular response in the dorsal hand vein using the linear variable differential transformer technique. Cyclosporine treatment significantly attenuated vasodilation induced by 60 ng/min isoproterenol (no cyclosporine, 19.8 +/- 3.5% versus cyclosporine, 7.9 +/- 2.2%; P = .02) and prostaglandin E1 at 1000 pg/min (no cyclosporine, 72.6 +/- 10.2% versus cyclosporine 45.6 +/- 9.0%) and 2000 pg/min (no cyclosporine, 100.8 +/- 14.7% versus cyclosporine, 68.6 +/- 8.0%; F = 5.47, P = .047). However, neither vascular response to phenylephrine or nitroglycerin nor sympathetic activity assessed by measurement of norepinephrine spillover with a radioisotope dilution technique was affected by cyclosporine (no cyclosporine, 516.1 +/- 47.9 ng/min versus cyclosporine, 476.6 +/- 51.8 ng/min; P = .42). Cyclosporine impaired venodilation in response to two agonists that act through adenylate cyclase without altering alpha-agonist-induced venoconstriction or sympathetic activity. Therefore, in humans impaired vasodilation rather than sympathetic activation or enhanced vasoconstriction may be an important mechanism for the alterations of vascular tone that occur after long-term cyclosporine administration.

  7. Protective effects of puerarin on experimental chronic lead nephrotoxicity in immature female rats.

    Science.gov (United States)

    Wang, Lin; Lin, Shuqian; Li, Zifa; Yang, Dubao; Wang, Zhenyong

    2013-02-01

    Puerarin (PU), a natural flavonoid, has been reported to possess anti-oxidative and anti-inflammatory activities. In the present study, female Sprague-Dawley rats received lead (Pb) nitrate (300 mg/L, via drinking water) and/or PU (400 mg/kg/day, orally) to investigate the protective effects of PU on Pb-induced renal damage. Renal toxicity was evaluated by detecting urinary proteins excretion as well as levels of serum urea nitrogen and serum creatinine. Ultrastructural observations and real-time quantitative polymerase chain reaction analyses were performed on kidney cortex tissues to identify the mitochondrial damage and quantify gene expression levels of cytochrome oxidase submits (COX-I/II/III), respectively. Renal cell damage was assessed by light microscopic examination. Lipid peroxidation (LPO) levels and antioxidant status in kidney were also evaluated. Animals that received both Pb and PU showed a better renal function than those that received Pb alone, with minor pathological damage. Moreover, PU significantly reduced LPO and markedly restored the enzymatic and non-enzymatic antioxidants levels in kidney of Pb-treated rats, which may be related to its restoring mitochondrial function. Furthermore, PU administration significantly increased urinary Pb excretion and decreased its level in the serum and kidney. In conclusion, these results suggested that PU reduces renal damage induced by chronic Pb administration through its antioxidant properties and chelating ability.

  8. Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka?

    Science.gov (United States)

    Jayasumana, Channa; Gunatilake, Sarath; Senanayake, Priyantha

    2014-01-01

    The current chronic kidney disease epidemic, the major health issue in the rice paddy farming areas in Sri Lanka has been the subject of many scientific and political debates over the last decade. Although there is no agreement among scientists about the etiology of the disease, a majority of them has concluded that this is a toxic nephropathy. None of the hypotheses put forward so far could explain coherently the totality of clinical, biochemical, histopathological findings, and the unique geographical distribution of the disease and its appearance in the mid-1990s. A strong association between the consumption of hard water and the occurrence of this special kidney disease has been observed, but the relationship has not been explained consistently. Here, we have hypothesized the association of using glyphosate, the most widely used herbicide in the disease endemic area and its unique metal chelating properties. The possible role played by glyphosate-metal complexes in this epidemic has not been given any serious consideration by investigators for the last two decades. Furthermore, it may explain similar kidney disease epidemics observed in Andra Pradesh (India) and Central America. Although glyphosate alone does not cause an epidemic of chronic kidney disease, it seems to have acquired the ability to destroy the renal tissues of thousands of farmers when it forms complexes with a localized geo environmental factor (hardness) and nephrotoxic metals. PMID:24562182

  9. Renal vascular and thrombotic effects of cyclosporine.

    Science.gov (United States)

    Remuzzi, G; Bertani, T

    1989-04-01

    Cyclosporine A (CyA) given to prevent xenograft rejection induces renal function impairment. In the last few years many studies have been devoted to understanding the mechanism(s) of CyA-induced renal insufficiency. In humans, several specific findings--interstitial fibrosis, toxic tubulopathy, peritubular capillary congestion, arteriolopathy--have been associated with CyA administration. It is now recognized that CyA renal toxicity mainly manifests under three different syndromes: (1) acute reversible decrease in glomerular filtration rate (GFR), (2) acute microvascular disease with the pattern of thrombotic microangiopathy, and (3) chronic irreversible renal damage. This review analyzes the available evidence that the clinical syndromes of CyA nephrotoxicity are related to changes induced by CyA on renal vessels. Experimental studies have failed to document that the activation of renin-angiotensin axis or sympathetic nervous system plays a relevant role in the development of CyA-associated renal vasoconstriction, which is the main causal factor of acute reversible decrease in GFR, whereas it is possible that changes in arachidonic acid metabolites with vasoactive properties contribute to this CyA-induced phenomenon. In this context, findings of increased urinary TxB2 and protective effect of TxA2 receptor blocking are of particular interest. Since the introduction of CyA in clinical practice, a syndrome of thrombotic microangiopathy resembling hemolytic uremic syndrome/thrombotic thrombocytopenic purpura has been recognized in humans and reproduced in experimental animals. This is a rare form of vascular toxicity attributed to CyA which may have a poor prognosis and possibly results from a direct toxic effect of CyA on vascular endothelium. The syndrome of chronic progressive deterioration of renal function associated with CyA was first recognized in humans. Until recently the possibility of reproducing this syndrome in animals in order to better understand its

  10. Cyclosporine : A review article

    OpenAIRE

    Ask, Andreas; Eidet, Jon Roger

    2008-01-01

    Cyclosporine is a immunosuppressive agent used in solid organ and bone marrow transplantation worldwide. Its discovery in 1972 was revolutionary in transplant medicine because of the need to suppress the immune system without affecting other cells substantially. The biochemical effect of calcineurin inhibitors, including cyclosporine and tacrolimus, is the inhibition of T-cell activation through various mechanisms. Even though cyclosporine was considered less cytotoxic, some adverse effects w...

  11. C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A.

    Science.gov (United States)

    Jordan, J L; Hirsch, G M; Lee, T D G

    2008-07-01

    Immunosuppressive treatments are available to suppress acute cardiac rejection; however, no viable treatment exists for long-term cardiac graft failure. Moreover, extended use of calcineurin inhibitor immunosuppressants, the mainstay of the current therapeutic for cardiac transplantation, leads to significant associated pathologies such as nephrotoxicity and increased risk of cardiac disease. For the last ten years alternatives to calcineurin inhibitors, or adjuvant therapies designed to complement their activities, have been explored. In tandem with this development, there has been considerable interest in Traditional Chinese Medicines (TCM) as sources for novel therapeutics. Our study examines the ability of the TCM Cordyceps sinensis to reduce acute and chronic rejection associated with cardiac transplantation. The objectives of this study were to first determine if oral delivery of the extract could reduce acute rejection in a rat heterotopic heart model of transplantation. The second objective was to determine, in vitro, if a sterile, aqueous extract of C. sinensis could decrease CD8+ T cell activity. The third objective was to determine if oral delivery of the extract could ablate allograft vasculopathy in a mouse abdominal aortic transplant model. We found that oral delivery of the extract demonstrated a reduction in acute rejection when used in conjunction with a sub-therapeutic dose of Cyclosporine. Further, we found, using a mixed lymphocyte reaction, that the extract was able to significantly reduce CD8+ T cell activity. Finally, we demonstrate that oral delivery of the extract, used with a therapeutic dose of Cyclosporine to suppress acute rejection, ablates allograft vasculopathy.

  12. Suppression of acute and chronic cardiac allograft rejection in mice by inhibition of chemokine receptor 5 in combination with cyclosporine A.

    Science.gov (United States)

    Li, Jun; Xia, Jiahong; Zhang, Kailun; Xu, Lei

    2009-11-01

    Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is an effective antiviral therapy in patients with HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this study we examined the inhibition of CCR5 in combination with the treatment with cyclosporine A in acute and chronic rejection in cardiac transplantation. Eighty fully MHC-mismatched murine cardiac allograft models were randomized to four groups. Recipients in group A were treated with anti-CCR5 mAb and CsA, mice in group B were given anti-CCR5 mAb alone, animals in group C were administered only CsA, and group D were the control group with PBS. Acute and chronic rejection was investigated on day 7 and day 45 post-transplant, respectively. Allografts treated with anti-CCR5 mAb plus CsA showed significantly prolonged survival (44.73 +/- 0.258 d, P cardiac graft failure that has not been obviated by conventional immunosuppressive agents.

  13. Mechanisms of Cisplatin Nephrotoxicity

    Science.gov (United States)

    Miller, Ronald P.; Tadagavadi, Raghu K.; Ramesh, Ganesan; Reeves, William Brian

    2010-01-01

    Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention. PMID:22069563

  14. Does Mineralocorticoid Receptor Antagonism Prevent Calcineurin Inhibitor-Induced Nephrotoxicity?

    Directory of Open Access Journals (Sweden)

    Line Aas Mortensen

    2017-11-01

    Full Text Available Calcineurin inhibitors have markedly reduced acute rejection rates in renal transplantation, thus significantly improved short-term outcome. The beneficial effects are, however, tampered by acute and chronic nephrotoxicity leading to interstitial fibrosis and tubular atrophy, which impairs long-term allograft survival. The mineralocorticoid hormone aldosterone induces fibrosis in numerous organs, including the kidney. Evidence from animal models suggests a beneficial effect of aldosterone antagonism in reducing calcineurin inhibitor-induced nephrotoxicity. This review summarizes current evidence of mineralocorticoid receptor antagonism in animal models of calcineurin inhibitor-induced nephrotoxicity and the results from studies of mineralocorticoid antagonism in renal transplant patients.

  15. Renal effects of amino acids and dopamine in renal transplant recipients treated with or without cyclosporin A

    DEFF Research Database (Denmark)

    Hansen, J M; Olsen, Niels Vidiendal; Leyssac, P P

    1996-01-01

    1. The nephrotoxic effects of cyclosporin A may diminish the ability of the transplanted kidney to increase the glomerular filtration rate and effective renal plasma flow during infusion of dopamine or amino acids. 2. The present study included 16 renal transplant recipients transplanted for more...... and of dopamine in renal transplant recipients with a good graft function.......-creatinine, 89 +/- 6 mumol/l). The renal response to infusion of dopamine and of amino acids was investigated on two separate days. All clearance measurements were carried out at nadir cyclosporin A blood levels. 3. Effective renal plasma flow increased significantly in the non-cyclosporin A group...

  16. Renoprotective immunosuppression by pioglitazone with low-dose cyclosporine in rat heart transplantation.

    Science.gov (United States)

    Tanaka, Yosuke; Hasegawa, Tomomi; Chen, Zhi; Okita, Yutaka; Okada, Kenji

    2009-09-01

    kidneys, leading to improvement of graft survival with a minimal cyclosporine-induced nephrotoxicity.

  17. Mefenamic Acid Induced Nephrotoxicity: An Animal Model

    Directory of Open Access Journals (Sweden)

    Muhammad Nazrul Somchit

    2014-12-01

    Full Text Available Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. Methods: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day. Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN and creatinine activities were measured. Results: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. Conclusion: Results from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model.

  18. Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine.

    Science.gov (United States)

    Khanna, Ashwani K; Hosenpud, Jessica S; Plummer, Matthew S; Hosenpud, Jeffrey D

    2002-05-27

    Long-term treatment of heart transplantation recipients with cyclosporine (CsA) results in chronic nephrotoxic effects, which frequently lead to progressive renal failure. Transforming growth factor (TGF)-beta and other fibrogenic molecules are leading candidates for these effects, because CsA is known to induce TGF-beta. In this study we compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases, and tissue inhibitors of metalloproteinases in kidneys from recipients of heterotopic heart transplants treated with CsA for 30 and 180 days. Using a clinically relevant experimental rodent model (strain combination Wistar Furth [RT1u] into Lewis [RT1l]), heterotopic heart transplantation was performed, creating disparate cardiac allografts. The transplant study population was divided into three groups: controls and those receiving CsA immunosuppression therapy to maintain graft survival for 30-day and 180-day periods. Comparisons were made of intrarenal expression of TGF-beta, collagen, fibronectin, metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of MMP-2, using reverse transcriptase-polymerase chain reaction. Intrarenal expression of TGF-beta protein was also compared using immunochemical staining technique, and circulating levels of TGF-beta protein were quantified by ELISA. Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9, and tissue inhibitor of MMP-2 was significantly increased in rats treated with CsA for 180 days compared with untreated rats and those treated for 30 days. Circulating levels and intrarenal expression of TGF-beta were also significantly increased in rats treated for 180 days. Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.

  19. The effect of the carotenoid bixin and annatto seeds on hematological markers and nephrotoxicity in rats subjected to chronic treatment with cisplatin

    Directory of Open Access Journals (Sweden)

    Lucéia F. Souza

    Full Text Available ABSTRACT This study assessed the protective effect of the carotenoid bixin and annatto seeds against possible nephrotoxicity induced with a single peritoneal administration of pharmacological cisplatin in male Wistar rats. After 48 h, the blood cell differential count showed a significant reduction in neutrophil counts in rats that received a diet rich in bixin when compared to the group that received only cisplatin. The use of cisplatin led to an increase in kidney weight. The carotenoid bixin attenuated renal injury, characterized by increased polymorphonuclear infiltration. No protective effect was observed with respect to Annatto. These results demonstrate the role of toxic cisplatin and suggest that bixin affords a protective effect against cisplatin-induced nephrotoxicity in adult Wistar rats.

  20. Prevention of cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Hayati Fatemeh

    2016-01-01

    Full Text Available Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary.

  1. Solubilization of cyclosporin A

    OpenAIRE

    Ran, Yingqing; Zhao, Luwei; Xu, Qing; Yalkowsky, Samuel H.

    2001-01-01

    This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (α-cyclodextrin [(αCD)] and hydroxypropyl-β-cyclodextrin[(HP\\CD)] were used as...

  2. Pharmacodynamics of cyclosporine in heart and heart-lung transplant recipients. I: Blood cyclosporine concentrations and other risk factors for cardiac allograft rejection.

    Science.gov (United States)

    Best, N G; Trull, A K; Tan, K K; Spiegelhalter, D J; Cary, N; Wallwork, J

    1996-11-27

    We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (Pcyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.

  3. Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies.

    Science.gov (United States)

    Huang, Jiaguo; Wu, Huizi

    2017-11-08

    Overdosing of the drugs, drug-drug interaction or drug related adverse effects are the risk factors of drug-induced nephrotoxicity. Since the use of some nephrotoxic drugs is still unavoidable in clinic, to understand the pathogenic mechanisms of nephrotoxicity of these drugs is critical to decrease the incidence of kidney injury. Early detection of drug-induced nephrotoxicity and reduce the therapeutic side effects are still accessible approaches to avoid the end stage of renal failure. Therefore, the discovery or development of the early and accurate diagnostic biomarkers is an effective prevention strategy for drug-induced kidney impairment. In the present review, we summarized the mechanisms and prevention strategies for some common used drugs in clinic that induced acute and chronic kidney injury. We discussed the pros and cons of the biomarkers available nowadays. In addition, the in vitro and pre-clinical in vivo models to assess the nephrotoxicity during the drug development stages are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Comparative Analysis of Azathioprine versus Cyclosporine-based Therapy in Primary Haplo-identical Live-Donor Kidney Transplantation: A 20-Year Experience

    Directory of Open Access Journals (Sweden)

    Gheith Osama

    2008-01-01

    Full Text Available Chronic allograft nephropathy (CAN remains a major cause of graft failure over the long term, second only to patient mortality. The main adverse effects of cyclosporine A (CsA include nephrotoxicity, hypertension, symptomatic hyperuricemia, hirsutism, and gum hyperplasia. Available studies among live related donor renal transplants lack adequate information regarding the long-term efficacy and safety of primary CsA-based immunosuppressive regimens. This prospective randomized study is aimed at evaluating the long-term results of CsA-based immunosuppressive protocols in live-donor kidney transplantation. The follow-up data of 444 renal transplant recipients operated at the Urology and Nephrology Center, Mansoura University, prior to 1996 were reviewed. Primary immuno-suppressive protocols included: steroids and azathioprine (group I, 130 cases; steroids and CsA (group II, 75 cases; and steroids, CsA, and azathioprine (group III, 239 cases. Only adult primary renal transplant recipients with age ranging between 18 and 60 years and one haplotype HLA mismatch with the donor were included. All patients received kidneys from living related donors with previous donor non-specific blood transfusions. The percentage of cases with chronic rejection was significantly higher in group III. Living cases with graft failure were significantly higher in group III, whereas mortality was significantly higher in group I. Diabetic patients and those with serious bacterial infections were significantly more prevalent in group II. Hypertensive patients were significantly more common in groups I and II. Liver disease was more prevalent among patients in group III. Our study suggests that the long-term results of treatment with steroids and azathioprine are satisfactory in live related donor kidney transplant recipients. Chronic rejection was significantly higher in patients in group III, possibly due to the risk of CsA nephrotoxicity. Groups with CsA-based protocols

  5. Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

    Directory of Open Access Journals (Sweden)

    Séin O'Connell

    2012-01-01

    Full Text Available End Stage Renal Disease (ESRD is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed nephrotoxicity induced by the immunosuppressive agents’ cyclosporine A (CsA and sirolimus (SRL. Nephrotoxicity is the major limiting factor in long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and means to prevent ESRD induced by therapeutic drugs. Using ELISA, Western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of CsA and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9. Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.

  6. Treatment of psoriasis with cyclosporin

    African Journals Online (AJOL)

    Treatment of psoriasis with cyclosporin. Experience at Johannesburg Hospital. R. J. Nevin, E. J. Schulz. Ten patients with moderate to severe plaque psoriasis were treated with cyclosporin A (CyA) for 2 - 19 months. (mean 12 months). Initial dosages were 2,5 mg/kg/d in 6 patients and 5,0 mg/kg/d in 4. At 3 months the ...

  7. Treatment With Dimethyl Fumarate Attenuates Calcineurin Inhibitor-induced Nephrotoxicity.

    Science.gov (United States)

    Takasu, Chie; Vaziri, Nosratola D; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Liu, Shuman; Farzaneh, Seyed H; Foster, Clarence E; Stamos, Michael J; Ichii, Hirohito

    2015-06-01

    Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection after organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of dimethyl fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system. Male Sprague-Dawley rats were treated with CsA (n = 8, 20 mg/kg per day intraperitoneally) or CsA + DMF (n = 7, 50 mg/kg per day orally) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase levels, and antioxidant enzyme expression were determined. The DMF cotreatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 ± 0.02 mg/dL vs CsA + DMF 0.62 ± 0.04 mg/dL, P = 0.001) and urea (CsA 66.9 ± 0.4 mg/dL vs CsA + DMF 53.3 ± 2.6 mg/dl, P fumarate also significantly decreased serum MDA and renal tissue MDA and myeloperoxidase contents. The protein expression of NAD(P)H quinone oxidoreductase-1, a major cellular antioxidant and detoxifying enzyme, was significantly enhanced by DMF administration in kidney. Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity.

  8. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study.

    Science.gov (United States)

    Mocroft, Amanda; Lundgren, Jens D; Ross, Michael; Fux, Christoph A; Reiss, Peter; Moranne, Olivier; Morlat, Philippe; Monforte, Antonella d'Arminio; Kirk, Ole; Ryom, Lene

    2016-01-01

    (adjusted incidence rate ratio 1·14 [95% CI 1·10-1·19], p<0·0001), ritonavir-boosted atazanavir (1·20 [1·13-1·26], p<0·0001), and ritonavir-boosted lopinavir (1·11 [1·06-1·16], p<0·0001), but not other ritonavir-boosted protease inhibitors or abacavir. In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored. The Highly Active Antiretroviral Therapy Oversight Committee. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

    Science.gov (United States)

    Kim, Han Sung; Choi, Seung-Il; Jeung, Eui-Bae; Yoo, Yeong-Min

    2014-01-01

    Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

  10. Cyclosporine Neoral: A Local Experience

    Directory of Open Access Journals (Sweden)

    Nampoory Mangalathillam

    1999-01-01

    Full Text Available Cyclosporine (CsA is an effective immunosuppressant drug. Recently a new oral formulation, Sandimune Neoral (SIM-NOF has been developed to overcome the problems of poor bioavailability, unpredictable blood levels and variable gastro-intestinal absorption seen with the use of traditional Cyclosporine, Sandimune (SIM. We conducted a prospective, open label crossover tolerability, efficacy and safety of SIM-NOF and (2 to compare SIM-NOF with SIM for their bioavailability, absorption pattern and consistence of 12-hour trough levels. Fourteen renal transplant recipients, with stable renal function (serum creatinine stable for more than six immediate previous months and SIM dosages, were randomly selected for the study. Their age mean ± SD 38.2± 11.1 years, ad had completed 3.8± 2.2 years after transplantation. All patients were on triple drug immunosuppression with prednisone, azathioprine and SIM. The study consisted of an initial 12-week period, where SIM was used and cyclosporine 12-hour trough levels were monitored t least every four weeks. This was followed by a run-in period of two weeks, where a 12-hour cyclosporine profiling was done while patients were on SIM. This was followed by a 12-week period, Where SIM-NOF replaced SIM on a 1:1 dose conversion ratio. During this latter period, 12-hour trough levels (at 1,2,3,8 and 12 weeks were measured. The doses of the SIM-NOF were adjusted to maintain blood cyclosporine trough levels at 50-180 μg/ml. On cyclosporine profiling, SIN-NOF showed a predictable and constant absorption profile peaking at two hours in all instances with steady declining levels through the following ten hours. With SIM the levels were unpredictable and erratic. The Tmax for SIM-NOF was 2.0± 0 hours and for SIM 3.7± 1.7 hours (p< 0.0001. The Cmax for SIM- NOF was 2149 and for SIM 1942 (p=0.008. The 12-hour trough studies for SIM-NOF is a superior preparation to SIM in clinical practice. No specific adverse effects were

  11. Concomitant gentamicin-induced nephrotoxicity and bilateral ...

    African Journals Online (AJOL)

    2015-11-20

    Nov 20, 2015 ... ototoxicity, and, more rarely, neuromuscular blockade. Gentamicin‑induced nephrotoxicity ranges between ... corrected with oral potassium chloride. She received a total of 4 sessions of hemodialysis with ... disease, and multiple dosing of gentamicin. Gentamicin nephrotoxicity presents commonly as.

  12. Caffeic Acid Phenethyl Ester as a Protective Agent against Nephrotoxicity and/or Oxidative Kidney Damage: A Detailed Systematic Review

    Directory of Open Access Journals (Sweden)

    Sumeyya Akyol

    2014-01-01

    Full Text Available Caffeic acid phenethyl ester (CAPE, an active component of propolis, has been attracting the attention of different medical and pharmaceutical disciplines in recent years because of its antioxidant, anti-inflammatory, antiproliferative, cytotoxic, antiviral, antifungal, and antineoplastic properties. One of the most studied organs for the effects of CAPE is the kidney, particularly in the capacity of this ester to decrease the nephrotoxicity induced by several drugs and the oxidative injury after ischemia/reperfusion (I/R. In this review, we summarized and critically evaluated the current knowledge regarding the protective effect of CAPE in nephrotoxicity induced by several special medicines such as cisplatin, doxorubicin, cyclosporine, gentamycin, methotrexate, and other causes leading to oxidative renal injury, namely, I/R models and senility.

  13. Cyclosporin versus tacrolimus for liver transplanted patients

    DEFF Research Database (Denmark)

    Haddad, E M; McAlister, V C; Renouf, E

    2006-01-01

    Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies....... Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior....

  14. Successful whole blood exchange by apheresis in a patient with acute cyclosporine intoxication without long-term sequelae.

    Science.gov (United States)

    Kwon, Sung Uk; Lim, Seong-Hoon; Rhee, Il; Kim, Seon-Woon; Kim, Jong-kyu; Kim, Dae-Won; Jeon, Eun-Seok

    2006-04-01

    Acute cyclosporine A (CsA) intoxication after organ transplantation may occur during the changeover from one form of drug to another, or from miscalculation of dosage. Sometimes, it may cause severe hepatotoxicity, nephrotoxicity and neurotoxicity. However, the therapeutic plasma exchange for the CsA intoxication was not established. Here, we present a case of very severe CsA intoxication after cardiac transplantation who recovered from intoxication without long-term sequelae via whole blood exchange; therapeutic erythrocytapheresis followed by total plasma exchange.

  15. Cyclosporine and Herbal Supplement Interactions

    OpenAIRE

    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 bloo...

  16. Decreased oxidized glutathione with aerosolized cyclosporine delivery.

    Science.gov (United States)

    Katz, A; Coran, A G; Oldham, K T; Guice, K S

    1993-06-01

    Cyclosporine immunosuppression remains vital for successful lung transplantation. Cyclosporine also functions as a membrane active biological response modifier and has been noted to have a variable effect on ischemia-reperfusion (I/R) injury in various tissues. Glutathione plays an important role in the endogenous antioxidant defense system; plasma oxidized glutathione (GSSG) levels are useful as a sensitive indicator of in vivo oxidant stress and I/R injury. Lung transplantation results in ischemia, followed by a period of reperfusion, potentially producing functional injury. This study was designed to evaluate the effect of cyclosporine on oxygen radical generation in a model of single-lung transplantation. Single-lung transplantation was performed in 12 mongrel puppies, with animals assigned to receive either intravenous or aerosolized cyclosporine. Arterial blood and bronchoalveolar lavage fluid (BALF) samples were obtained to determine GSSG levels via a spectrophotometric technique. Samples were obtained both prior to and following the revascularization of the transplanted lung. Whole blood and tissue cyclosporine levels were determined via an high-performance liquid chromatography technique 3 hr following the completion of the transplant. Aerosolized cyclosporine administration resulted in greatly decreased arterial plasma and BALF GSSG levels, whole blood cyclosporine levels, and equivalent tissue cyclosporine levels when compared to intravenous cyclosporine delivery. These findings support the hypothesis that the transplanted lung is a source of GSSG production and release into plasma. Additionally, these findings suggest that cyclosporine may have a direct antioxidant effect on pulmonary tissue, with this activity occurring at the epithelial surface, an area susceptible to oxidant injury.

  17. Allicin ameliorates kidney function and urinary bladder sensitivity in cyclosporine A-treated rats.

    Science.gov (United States)

    El-Kashef, D H; El-Kenawi, A E; Suddek, G M; Salem, H A

    2017-07-01

    Cyclosporine-A (CsA) is an immunosuppressive drug which has been used to prevent rejection after organ transplantation and to treat certain autoimmune diseases. However, its therapeutic use is limited by nephrotoxicity. In this study, the modulator effect of allicin on the oxidative nephrotoxicity of CsA in rats was investigated. Furthermore, the effect of allicin on CsA-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was estimated. Rats were divided into three groups, control, CsA (15 mg/kg, subcutaneously), and CsA/allicin (50 mg/kg, orally). At the end of the study, all rats were killed and then blood, urine samples, and kidneys were taken. CsA administration caused a severe nephrotoxicity which was evidenced by elevated kidney/body weight ratio, serum creatinine (Cr), blood urea nitrogen, lactate dehydrogenase, and urinary protein with a concomitant reduction in serum albumin and Cr clearance as compared with control. A significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione, superoxide dismutase activities, and nitric oxide (NOx) content was detected upon CsA administration. Exposure to CsA increased the sensitivity of isolated urinary bladder rings to ACh. Histological analysis revealed that CsA caused tubular necrosis and moderate diffuse tubular atrophy. Allicin protected kidney tissue against the oxidative damage and the nephrotoxic effect of CsA and significantly reduced the responses of isolated bladder rings to ACh. Our study indicates that allicin administration has the potential to protect against CsA-induced renal injury by reducing oxidative stress and inflammation and restoring NOx level.

  18. Cyclosporine

    Science.gov (United States)

    ... 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 ...

  19. The use of cyclosporine in dermatology.

    Science.gov (United States)

    Dehesa, Luis; Abuchar, Adriana; Nuno-Gonzalez, Almudena; Vitiello, Magalys; Kerdel, Francisco A

    2012-08-01

    Cyclosporine is an immunosuppressive drug that acts selectively on T-cells by inhibiting calcineurin phosphorylase. It has been used in dermatology since its approval for US Food and Drug Administration in 1997 for the use in psoriasis. While indicated only for the treatment of moderate to severe psoriasis, cyclosporine has also been used as an off-label drug for the treatment of various inflammatory skin conditions, including atopic dermatitis, blistering disorders, and connective tissue diseases. In this article, we review the use of cyclosporine in dermatology.

  20. No association between single nucleotide polymorphisms and the development of nephrotoxicity after orthotopic heart transplantation.

    Science.gov (United States)

    Klauke, Bärbel; Wirth, Andreas; Zittermann, Armin; Bohms, Birte; Tenderich, Gero; Körfer, Reiner; Milting, Hendrik

    2008-07-01

    Survival for heart transplantation (HTx) patients is limited by nephrotoxicity of the calcineurin inhibitors cyclosporine and tacrolimus. To determine whether genetic factors are involved in the development of renal dysfunction under immunosuppressive therapy, we screened various genes for sequence variations. In a case-control study we analyzed in parallel polymorphisms within the transforming growth factor-beta1 gene (TGF-beta1; L10P, R25P), the multidrug resistance gene MDR 1 (A893T/S) and the CYP3A5 gene (CYP3A5*1/*3 allele). In total, we included 53 cardiac allograft recipients with renal insufficiency (serum creatinine >or=1.8 mg/dl and glomerular filtration rate 0.05) relationship was found between the polymorphisms investigated and the susceptibility of renal insufficiency under immunosuppressive therapy. Our data do not justify genotyping of the investigated single nucleotide polymorphisms (SNPs) to assess the development of renal dysfunction post-HTx.

  1. Topical cyclosporine for atopic keratoconjunctivitis.

    Science.gov (United States)

    González-López, Julio J; López-Alcalde, Jesús; Morcillo Laiz, Rafael; Fernández Buenaga, Roberto; Rebolleda Fernández, Gema

    2012-09-12

    Atopic keratoconjunctivitis (AKC) is a chronic ocular surface non-infectious inflammatory condition that atopic dermatitis patients may suffer at any time point in the course of their dermatologic disease and is independent of its degree of severity. AKC is usually not self resolving and it poses a higher risk of corneal injuries and severe sequelae. Management of AKC should prevent or treat corneal damage. Although topical corticosteroids remain the standard treatment for patients with AKC, prolonged use may lead to complications. Topical cyclosporine A (CsA) may improve AKC signs and symptoms, and be used as a corticosteroid sparing agent. To determine the efficacy and gather evidence on safety from randomised controlled trials (RCTs) of topical CsA in patients with AKC. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to July 2012), EMBASE (January 1980 to July 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to July 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en), the IFPMA Clinical Trials Portal (http://clinicaltrials.ifpma.org/no_cache/en/myportal/index.htm) and Web of Science Conference Proceedings Citation Index- Science (CPCI-S). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 9 July 2012. We also handsearched the following conference proceedings: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, International Council of Opthalmology and Societas

  2. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

    Directory of Open Access Journals (Sweden)

    Han Sung Kim

    Full Text Available Cyclosporine A (CsA is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2, indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA, but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

  3. Potentiation of cadmium nephrotoxicity by acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Bernard, A.M.; Russis, R. de; Ouled Amor, A.; Lauwerys, R.R.

    1988-10-01

    The possible interactions between acetaminophen and cadmium (Cd) on the kidney were investigated in female Sprague-Dawley rats. Acetaminophen was administered in the food at an average dose of 900 mg/kg and Cd in drinking water at the concentration of 200 ppm. The treatment with acetaminophen and Cd lasted 2 and 10 months, respectively. No interaction between Cd and acetaminophen was observed during the period of their concomitant administration: the increase in albuminuria caused by Cd and acetaminophen was additive, while the tubular impairment caused by acetaminophen (increased ..beta../sub 2/-microglobulinuria and decreased kidney concentrating ability) was not exacerbated by Cd. None of these treatments affected the glomerular filtration rate. Four months after the end of acetaminophen treatment, the renal changes had almost completely disappeared in the rats which had received the analgesic alone. Those continously exposed to Cd had developed slight tubular damage, as evidenced by an increased urinary excretion of ..beta../sub 2/-microglobulin and ..beta..-N-acetylglucosaminidase. By contrast, rats pretreated with acetaminophen for 2 months and exposed to Cd showed a marked increase in urinary excretion of albumin and ..beta../sub 2/-microglobulin, suggesting an interaction between both treatments. At the end of the study, only the interaction with ..beta../sub 2/-microglobulin excretion was still evident; that with the urinary excretion of ..beta..-N-acetylglucosaminidase and albumin having been masked by the chronic progessive nephrosis affecting most animals at that stage. As acetaminophen had no effect on the renal accumulation of Cd, it may be concluded that pretreatment with this analygesic at a dose causing slight tubular dysfunction renders rat kidney more sensitive to the nephrotoxic action of Cd. This observation may be of clinical relevance for population groups occupationally or environmentally exposed to Cd.

  4. Compound list: cyclosporine A [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available cyclosporine A CSA 00142 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/cyclosporine..._A.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/cyclosporine...iencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/cyclosporine_A.Rat.in_vivo.Liver.Repeat.zip... ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/cyclosporine_A.Rat.in_vivo....Kidney.Single.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Repeat/cyclosporine_A.Rat.in_vivo.Kidney.Repeat.zip ...

  5. Cyclosporine and Herbal Supplement Interactions

    Directory of Open Access Journals (Sweden)

    D. Colombo

    2014-01-01

    Full Text Available 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.

  6. Cyclosporine and Herbal Supplement Interactions

    Science.gov (United States)

    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

  7. A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats.

    Science.gov (United States)

    Othman, Rgia A; Suh, Miyoung; Fischer, Gabor; Azordegan, Nazila; Riediger, Natalie; Le, Khuong; Jassal, Davinder S; Moghadasian, Mohammed H

    2008-03-01

    Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.

  8. Oral cyclosporine therapy for refractory severe vernal keratoconjunctivitis

    Directory of Open Access Journals (Sweden)

    Nikhil S Gokhale

    2012-01-01

    Full Text Available We report the success of oral cyclosporine therapy in a patient with severe vision-threatening vernal keratoconjunctivitis. A child presented with severe allergy which was not controlled with topical steroids, cyclosporine and mast cell stabilizers. Oral steroids were required repeatedly to suppress inflammation. Child showed a dramatic improvement and stabilization with oral cyclosporine therapy. Oral cyclosporine therapy can be tried in severe vision-threatening allergy refractory to conventional therapy.

  9. Oral cyclosporine therapy for refractory severe vernal keratoconjunctivitis

    Science.gov (United States)

    Gokhale, Nikhil S; Samant, Rohini; Sharma, Vishnu

    2012-01-01

    We report the success of oral cyclosporine therapy in a patient with severe vision-threatening vernal keratoconjunctivitis. A child presented with severe allergy which was not controlled with topical steroids, cyclosporine and mast cell stabilizers. Oral steroids were required repeatedly to suppress inflammation. Child showed a dramatic improvement and stabilization with oral cyclosporine therapy. Oral cyclosporine therapy can be tried in severe vision-threatening allergy refractory to conventional therapy. PMID:22569387

  10. Protective Effects of Vitamin E and/or Quercetin Co-Supplementation on the Morphology of Kidney in Cyclosporine A-Treated Rats

    OpenAIRE

    Zohreh Mostafavi Pour; Mahmood Vessal; Fatemeh Zal; Zahra Khoshdel; Simin Torabinejad

    2009-01-01

    Background: Cyclosporine A (CsA) is a nephrotoxic immunosuppressivedrug. Antioxidants might attenuate its toxicity. Inthe present study, the effects of vitamin E and quercetin on themorphology of kidney in CsA-treated rats were investigated.Methods: Six groups of rats were used in this gavage feedingstudy either for 4 or 8 weeks. Groups 1 and 2 received eitherolive oil or 25% ethanol in olive oil per day. Group 3 receivedCsA (25 mg/kg/day) in olive oil. All other groups received CsAplus the f...

  11. Cyclosporine and lactation: when the mother is willing to breastfeed.

    Science.gov (United States)

    Osadchy, Alla; Koren, Gideon

    2011-04-01

    We describe a woman treated with cyclosporine after renal transplantation who commenced breastfeeding of her newborn infant. The child had no apparent clinical adverse effects to cyclosporine. To confirm the safety of breastfeeding and guide the patient and her clinician, cyclosporine concentrations in maternal blood, breast milk, and infant blood were measured. Maternal cyclosporine concentration (1-hour postdose) was 49 μg/L, and the breast milk cyclosporine concentration (2-hour postdose) was 46 μg/L. Infant cyclosporine blood concentration shortly after breastfeeding was undetectable (<10 μg/L). Analysis revealed that the estimated infant exposure to cyclosporine via breast milk was minimal and provided reassurance to continue breastfeeding in this case.

  12. Cyclosporine enhances theophylline neurotoxicity in rats.

    Science.gov (United States)

    Hoffman, A; Pinto, E; Afargan, M; Schattner, A

    1994-04-01

    Treatment with cyclosporine may be associated with adverse central nervous system (CNS) effects as well as with the potentiation of effects of certain other drugs. In particular, theophylline-induced seizures, which are often fatal and occur unpredictably over a wide range of serum theophylline concentrations, may be precipitated. To study this interaction, adult rats that were injected with cyclosporine or placebo (50 mg/kg in a single dose or on each of four consecutive days) received a constant infusion of theophylline (2 mg/min iv) until the onset of maximal seizures. At that time, blood, cerebrospinal fluid (CSF), and brain tissue samples were obtained for theophylline concentration determinations by HPLC, as well as for measurement of several biochemical parameters in the serum. Consecutive cyclosporine administration (but not a single dose) reduced serum protein levels. There was a small increase in theophylline sensitivity after a single dose of cyclosporine. The CSF theophylline concentrations at the onset of seizures were 215 +/- 10 vs 202 +/- 5 mg/L (P theophylline concentrations required to produce convulsions (231 +/- 8 vs 191 +/- 10, P theophylline toxicity and increase the risk for generalized seizures.

  13. Cyclosporine treatment of severe Hidradenitis suppurativa

    DEFF Research Database (Denmark)

    Anderson, Marianne D; Zauli, Stefania; Bettoli, Vincenzo

    2016-01-01

    Background: Hidradenitis suppurativa (HS) is an overlooked but common disease severely affecting both genders. HS is generally perceived as difficult to treat and although a number of treatments are available, the need for more effective treatment is apparent. Objectives: Cyclosporine A (CsA) has...

  14. Adefovir nephrotoxicity in a renal allograft recipient

    Directory of Open Access Journals (Sweden)

    N George

    2015-01-01

    Full Text Available Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.

  15. Prevention of nephrotoxicity of ochratoxin A, a food contaminant.

    Science.gov (United States)

    Creppy, E E; Baudrimont, I; Betbeder, A M

    1995-12-01

    Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicilium verrucosum. It was found all over the world in feed and human food and blood as well as in animal blood and tissues. The most threatening effects of OTA are its nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all animal species studied so far and is increasingly involved in the Balkan endemic nephropathy (BEN), a human chronic interstitial nephropathy which is most of the time associated to urinary tract tumours. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, detoxification and detoxication for OTA are needed. To reduce or abolish the OTA-induced toxic effects, several mechanisms were investigated. The results of these investigations showed that some of the potential antidotes were efficient in preventing the main OTA toxic effects whereas some others were not. Promising compounds are structural analogues of OTA, and/or compounds having a high binding affinity for plasma proteins such as piroxicam, a non-steroidal anti-inflammatory drug (NSAID). Some enzymes such as superoxide dismutase (SOD) and catalase, radical scavengers, vitamins, prostaglandin (PG) synthesis inhibitors, (such as piroxicam), pH modificators, adsorbant resin such as cholestyramine etc. are efficient in vivo. Some of the results obtained in vivo were already confirmed in vitro and gave useful information on how to safely use these antidotes. The most generally acting compound seems to be A19 (Aspartame), a structural analogue of OTA and phenylalanine. When given to rats A19 (25 mg/kg/48 h) combined to OTA (289 micrograms/kg/48 h) for several weeks largely prevented OTA nephrotoxicity and genotoxicity. When given after intoxication of animals with OTA it washes out the toxin efficiently from the body. In vitro, A19 (10 micrograms/ml) prevents OTA (20-500 micrograms/ml) binding to plasma proteins. Its general

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Augusto Afonso Guerra Júnior

    2015-01-01

    Full Text Available 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.

  18. Risk Factors for Chronic Renal Insufficiency Following Cardiac Transplantation.

    Science.gov (United States)

    Lachance, Kim; White, Michel; de Denus, Simon

    2015-09-29

    Although previous publications have discussed kidney disease in nonrenal solid-organ transplantation, none has reviewed thoroughly the potential predictors of long-term renal impairment in cardiac recipients. Thus, the purpose of this review article is to summarize the current state of knowledge on risk factors of chronic renal insufficiency in heart transplant patients. An English language Medline literature search (1946-April 2014) was conducted using the search terms renal insufficiency, kidney failure, kidney diseases, nephrotoxi$ ($ for truncation), creatinine, glomerular filtration rate, heart transplantation and organ transplantation. Additional references were identified from a review of literature citations. A total of 74 articles discussing key risk factors were included in the manuscript.         The existing literature reveals that several recipient characteristics (age, female sex, pretransplant/early post-transplant kidney impairment, diabetes, and hypertension) increase the risk of renal insufficiency after transplantation. Current data also indicate that, while cyclosporine and tacrolimus are most likely major determinants of post-transplant kidney failure, the effects of calcineurin inhibitor doses and concentrations remain unclear. A small number of studies suggest that tacrolimus could possibly induce less nephrotoxicity than cyclosporine, but meta-analyses of randomized controlled trials show the opposite with comparable incidences of dialysis after cardiac transplantation. Finally, the role of genetic variations has only been explored to a limited extent in heart transplant patients. This growing body of evidence should ultimately lead to a better risk prediction regarding chronic renal insufficiency following cardiac transplantation and a more personalized tailoring of immunosuppressive regimens.

  19. Cyclosporine dosage can be reduced when used in combination with an anti-intercellular adhesion molecule-1 monoclonal antibody in rats undergoing heterotopic heart transplantation.

    Science.gov (United States)

    Harrison, P C; Mainolfi, E; Madwed, J B

    1998-02-01

    of cyclosporine necessary for immune suppression. Such a reduction could lead to a lowering of the incidence of nephrotoxicity and other side effects associated with long-term cyclosporine administration.

  20. Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury.

    Science.gov (United States)

    Badalzadeh, Reza; Azimi, Ako; Alihemmati, Alireza; Yousefi, Bahman

    2017-02-01

    It has been shown that diabetes modifies the myocardial responses to ischemia/reperfusion (I/R) and to cardioprotective agents. In this study, we aimed to investigate the effects of combined treatment with ischemic postconditioning (IPostC) and cyclosporine A (CsA) on inflammation and apoptosis of the diabetic myocardium injured by I/R. Eight weeks after induction of diabetes in Wistar rats, hearts were mounted on a Langendorff apparatus and were subsequently subjected to a 30-min regional ischemia followed by 45-min reperfusion. IPostC was induced at the onset of reperfusion, by 3 cycles of 30-s reperfusion/ischemia (R/I). The concentration of creatine kinase (CK), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined; the levels of total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β) and B-cell lymphoma 2 (Bcl-2) were quantified by western blotting, and the rate of apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Administration of either IPostC or CsA alone in nondiabetic animals significantly reduced CK, TNF-α, IL-1β, and IL-6 concentrations, increased the p-GSK3β and Bcl-2, and decreased the level of apoptosis (P < 0.05) but had no effect on diabetic hearts. However, in diabetic animals, after administration of CsA, the cardioprotective effects of IPostC in increasing the p-GSK3β and Bcl-2 and decreasing apoptosis and inflammation were restored in comparison with nonpostconditioned diabetic hearts. IPostC or CsA failed to affect apoptosis and inflammation and failed to protect the diabetic myocardium against I/R injury. However, combined administration of IPostC and CsA at reperfusion can protect the diabetic myocardium by decreasing the inflammatory response and apoptosis.

  1. Treatment of ocular rosacea:comparative study of topical cyclosporine and oral doxycycline

    Directory of Open Access Journals (Sweden)

    Aysegul Arman

    2015-06-01

    Full Text Available AIM:To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS:One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups:nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline.RESULTS:Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes (P<0.001. Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs (P=0.01. There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group (P<0.05.CONCLUSION:Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.

  2. Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity.

  3. The Aging Kidney: Increased Susceptibility to Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Xinhui Wang

    2014-09-01

    Full Text Available Three decades have passed since a series of studies indicated that the aging kidney was characterized by increased susceptibility to nephrotoxic injury. Data from these experimental models is strengthened by clinical data demonstrating that the aging population has an increased incidence and severity of acute kidney injury (AKI. Since then a number of studies have focused on age-dependent alterations in pathways that predispose the kidney to acute insult. This review will focus on the mechanisms that are altered by aging in the kidney that may increase susceptibility to injury, including hemodynamics, oxidative stress, apoptosis, autophagy, inflammation and decreased repair.

  4. Carvedilol Protects against Cyclosporine Nephropathy in Rats

    Directory of Open Access Journals (Sweden)

    H. Kotolová

    2006-01-01

    Full Text Available The aim of our experimental work was to study whether carvedilol is able to protect renal tissue from cyclosporine toxic effect in animal model of cyclosporine nephropathy. The study was performed on twenty Wistar rats divided in two experimental groups: control (treated with placebo and carvedilol (treated with p.o. dose 10mg/kg/day in 1 ml solution. Cyclosporine in oral dose of 15 mg/kg/day was administered to all animals during 15 days of experiment. Urine was collected daily for the assessment of diuresis, proteinuria, and determination of urea and creatinine levels. Serum collected at the end of the experiment (day 15 was used for the determination of urea and transferrin levels. The level of renal tissue damage was evaluated by the Jones method for basal membranes, glomeruli and tubuli impregnation, and by the Kossa method for calcium impregnation. For the determination of paranuclear inclusions presence we used chromanilinblue (CAB method. Statistically significant differences between total protein levels in urine on day 7 of the experiment and urea levels in serum at the end of the experiment in the control group and the carvedilol-treated group indicate a protective effect of carvedilol on renal tissue, which is supported also by the results of a histological examination of renal tissue. Significant increase in the serum transferrin level was registered in the carvedilol-treated group and no significant changes were noted in ceruloplasmin serum levels. In conclusion, our pilot study showed that carvedilol has the ability to protect renal tissue from cyclosporine induced nephropathy in rats.

  5. Contrast Media: Are There Differences in Nephrotoxicity among Contrast Media?

    Science.gov (United States)

    2014-01-01

    Iodinated contrast agents are usually classified based upon their osmolality—high, low, and isosmolar. Iodinated contrast agents are also nephrotoxic in some but not all patients resulting in loss of glomerular filtration rate. Over the past 30 years, nephrotoxicity has been linked to osmolality although the precise mechanism underlying such a link has been elusive. Improvements in our understanding of the pathogenesis of nephrotoxicity and prospective randomized clinical trials have attempted to further explore the relationship between osmolality and nephrotoxicity. In this review, the basis for our current understanding that there are little if any differences in nephrotoxic potential between low and isosmolar contrast media will be detailed using data from clinical studies. PMID:24587997

  6. Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers.

    Science.gov (United States)

    Teng, Renli; Kujacic, Mirjana; Hsia, Judith

    2014-08-01

    Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y(12) receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug-drug interaction between ticagrelor and cyclosporine. In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of ≥14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed. Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 2.83 (2.63-3.06), and the maximum plasma concentration (C(max)) was 2.30 (2.06-2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC(∞) (1.33 [1.23-1.42]) and decreased C(max) (0.85 [0.76-0.94]). Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80-1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated. Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine's effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.

  7. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study

    NARCIS (Netherlands)

    Mocroft, A.; Lundgren, J.D.; Ross, M.; Fux, C.A.; Reiss, P.; Moranne, O.; Morlat, P.; Monforte, A.; Kirk, O.; Ryom, L.; Burger, D.M.

    2016-01-01

    BACKGROUND: Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of

  8. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study

    NARCIS (Netherlands)

    Mocroft, Amanda; Lundgren, Jens D.; Ross, Michael; Fux, Christoph A.; Reiss, Peter; Moranne, Olivier; Morlat, Philippe; Monforte, Antonella d'Arminio; Kirk, Ole; Ryom, Lene; Steering, D.; Powderly, B.; Shortman, N.; Moecklinghoff, C.; Reilly, G.; Franquet, X.; Ryom, L.; Hatleberg, C. I.; Sabin, C. A.; Kamara, D.; Smith, C.; Phillips, A.; Mocroft, A.; Bojesen, A.; Grevsen, A. L.; Matthews, C.; Raben, D.; Lundgren, J. D.; Brandt, R. S.; Rickenbach, M.; Fanti, I.; Hillebreght, M.; Zaheri, S.; Gras, L.; Pernot, E.; Mourabi, J.; Sundström, A.; Delforge, M.; Fontas, E.; Torres, F.; McManus, H.; Wright, S.; Kristensen, D.; Sjøl, A.; Meidahl, P.; Helweg-Larsen, J.; Schmidt Iversen, J.; Kirk, O.; Smit, C.; Ross, M.; Fux, C. A.; Morlat, P.; Moranne, O.; Kamara, D. A.; Weber, R.; Pradier, C.; Friis-Møller, N.; Kowalska, J.; Sabin, C.; Law, M.; d'Arminio Monforte, A.; Dabis, F.; Bruyand, M.; Bonnet, F.; Bower, M.; Fätkenheuer, G.; Donald, A.; Grulich, A.; Prins, J. M.; Kuijpers, T. W.; Scherpbier, H. J.; van der Meer, J. T. M.; Wit, F. W. M. N.; Godfried, M. H.; van der Poll, T.; Nellen, F. J. B.; Geerlings, S. E.; van Vugt, M.; Pajkrt, D.; Bos, J. C.; Wiersinga, W. J.; van der Valk, M.; Goorhuis, A.; Hovius, J. W.; van Eden, J.; Henderiks, A.; van Hes, A. M. H.; Mutschelknauss, M.; Nobel, H. E.; Pijnappel, F. J. J.; Westerman, A. M.; Jurriaans, S.; Back, N. K. T.; Zaaijer, H. L.; Berkhout, B.; Cornelissen, M. T. E.; Schinkel, C. J.; Thomas, X. V.; de Ruyter Ziekenhuis, Admiraal; van den Berge, M.; Stegeman, A.; Baas, S.; de Looff, L. Hage; Versteeg, D.; Pronk, M. J. H.; Ammerlaan, H. S. M.; Korsten-Vorstermans, E. M. H. M.; de Munnik, E. S.; Jansz, A. R.; Tjhie, J.; Wegdam, M. C. A.; Deiman, B.; Scharnhorst, V.; Kinderziekenhuis, Emma; van der Plas, A.; Weijsenfeld, A. M.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; van Gorp, E. C. M.; Schurink, C. A. M.; Nouwen, J. L.; Verbon, A.; Rijnders, B. J. A.; Bax, H. I.; Hassing, R. J.; van der Feltz, M.; Bassant, N.; van Beek, J. E. A.; Vriesde, M.; van Zonneveld, L. M.; de Oude-Lubbers, A.; van den Berg-Cameron, H. J.; Bruinsma-Broekman, F. B.; de Groot, J.; de Man, de Zeeuw; Broekhoven-Kruijne, M. J.; Schutten, M.; Osterhaus, A. D. M. E.; Boucher, C. A. B.; Driessen, G. J. A.; van Rossum, A. M. C.; van der Knaap, L. C.; Visser, E.; Branger, J.; Duijf-van de Ven, C. J. H. M.; Haag, Den; Schippers, E. F.; van Nieuwkoop, C.; Brimicombe, R. W.; van IJperen, M.; van der Hut, G.; Franck, P. F. H.; van Eeden, A.; Brokking, W.; Groot, M.; Damen, M.; Kwa, I. S.; Groeneveld, P. H. P.; Bouwhuis, J. W.; van den Berg, J. F.; van Hulzen, A. G. W.; van der Bliek, G. L.; Bor, P. C. J.; Bloembergen, P.; Wolfhagen, M. J. H. M.; Ruijs, G. J. H. M.; Gasthuis, Kennemer; van Lelyveld, S. F. L.; Soetekouw, R.; Hulshoff, N.; van der Prijt, L. M. M.; Schoemaker, M.; Bermon, N.; van der Reijden, W. A.; Jansen, R.; Herpers, B. L.; Veenendaal, D.; Kroon, F. P.; Arend, S. M.; de Boer, M. G. J.; Bauer, M. P.; Jolink, H.; Vollaard, A. M.; Dorama, W.; Moons, C.; Claas, E. C. J.; Kroes, A. C. M.; den Hollander, J. G.; Pogany, K.; Kastelijns, M.; Smit, J. V.; Smit, E.; Bezemer, M.; van Niekerk, T.; Pontesilli, O.; Lowe, S. H.; Oude Lashof, A.; Posthouwer, D.; Ackens, R. P.; Schippers, J.; Vergoossen, R.; Weijenberg Maes, B.; Savelkoul, P. H. M.; Loo, I. H.; Zuiderzee, M. C.; Weijer, S.; el Moussaoui, R.; Heitmuller, M.; Kortmann, W.; van Twillert, G.; Cohen Stuart, J. W. T.; Diederen, B. M. W.; Pronk, D.; van Truijen-Oud, F. A.; Leyten, E. M. S.; Gelinck, L. B. S.; van Hartingsveld, A.; Meerkerk, C.; Wildenbeest, G. S.; Mutsaers, J. A. E. M.; Jansen, C. L.; van Vonderen, M. G. A.; van Houte, D. P. F.; Dijkstra, K.; Faber, S.; Weel, J.; Kootstra, G. J.; Delsing, C. E.; van der Burgvan de Plas, M.; Heins, H.; Lucas, E.; Brinkman, K.; Frissen, P. H. J.; Blok, W. L.; Schouten, W. E. M.; Bosma, A. S.; Brouwer, C. J.; Geerders, G. F.; Hoeksema, K.; Kleene, M. J.; van der Meché, I. B.; Toonen, A. J. M.; Wijnands, S.; van Ogtrop, M. L.; Koopmans, P. P.; Keuter, M.; van der Ven, A. J. A. M.; ter Hofstede, H. J. M.; Dofferhoff, A. S. M.; van Crevel, R.; Albers, M.; Bosch, M. E. W.; Grintjes-Huisman, K. J. T.; Zomer, B. J.; Stelma, F. F.; Burger, D.; Richter, C.; van der Berg, J. P.; Gisolf, E. H.; Beest, G. Ter; van Bentum, P. H. M.; Langebeek, N.; Tiemessen, R.; Swanink, C. M. A.; Veenstra, J.; Lettinga, K. D.; Spelbrink, M.; Sulman, H.; Witte, E.; Peerbooms, P. G. H.; Mulder, J. W.; Vrouenraets, S. M. E.; Lauw, F. N.; van Broekhuizen, M. C.; Paap, H.; Vlasblom, D. J.; Oudmaijer Sanders, E.; Smits, P. H. M.; Rosingh, A. W.; Verhagen, D. W. M.; Geilings, J.; van Kasteren, M. E. E.; Brouwer, A. E.; de Kruijf-van de Wiel, B. A. F. M.; Kuipers, M.; Santegoets, R. M. W. J.; van der Ven, B.; Marcelis, J. H.; Buiting, A. G. M.; Kabel, P. J.; Bierman, W. F. W.; Sprenger, H. G.; Scholvinck, E. H.; van Assen, S.; Wilting, K. R.; Stienstra, Y.; de Groot-de Jonge, H.; van der Meulen, P. A.; de Weerd, D. A.; Niesters, H. G. M.; Riezebos-Brilman, A.; van Leer-Buter, C. C.; Hoepelman, A. I. M.; Schneider, M. M. E.; Mudrikova, T.; Ellerbroek, P. M.; Oosterheert, J. J.; Arends, J. E.; Barth, R. E.; Wassenberg, M. W. M.; van Elst-Laurijssen, D. H. M.; Laan, L. M.; van Oers-Hazelzet, E. E. B.; Patist, J.; Vervoort, S.; Nieuwenhuis, H. E.; Frauenfelder, R.; Schuurman, R.; Verduyn-Lunel, F.; Wensing, A. M. J.; Peters, E. J. G.; van Agtmael, M. A.; Perenboom, R. M.; Bomers, M.; de Vocht, J.; Elsenburg, L. J. M.; Pettersson, A. M.; Vandenbroucke-Grauls, C. M. J. E.; Ang, C. W.; Geelen, S. P. M.; Wolfs, T. F. W.; Bont, L. J.; Nauta, N.; Bezemer, D. O.; van Sighem, A. I.; Hillebregt, M.; Kimmel, V.; Tong, Y.; Lascaris, B.; van den Boogaard, R.; Hoekstra, P.; de Lang, A.; Berkhout, M.; Grivell, S.; Jansen, A.; de Groot, L.; van den Akker, M.; Bergsma, D.; Lodewijk, C.; Meijering, R.; Peeck, B.; Raethke, M.; Ree, C.; Regtop, R.; Ruijs, Y.; Schoorl, M.; Tuijn, E.; Veenenberg, L.; Woudstra, T.; Bakker, Y.; de Jong, A.; Broekhoven, M.; Claessen, E.; Rademaker, M. J.; Munjishvili, L.; Kruijne, E.; Tuk, B.; Bouchet, S.; Breilh, D.; Chêne, G.; Dupon, M.; Fleury, H.; Gaborieau, V.; Lacoste, D.; Malvy, D.; Mercié, P.; Neau, D.; Pellegrin, I.; Pellegrin, J. L.; Tchamgoué, S.; Fagard, C.; Lawson-Ayayi, S.; Richert, L.; Thiébaut, R.; Wittkop, L.; André, K.; Bernard, N.; Caunègre, L.; Cazanave, C.; Ceccaldi, J.; Chossat, I.; Courtault, C.; Dauchy, F. A.; de Witte, S.; Dondia, D.; Dupont, A.; Duffau, P.; Dutronc, H.; Farbos, S.; Faure, I.; Gerard, Y.; Greib, C.; Hessamfar-Joseph, M.; Imbert, Y.; Lataste, P.; Lazaro, E.; Marie, J.; Mechain, M.; Meraud, J. P.; Monlun, E.; Ochoa, A.; Pillot-Debelleix, M.; Pistone, T.; Raymond, I.; Receveur, M. C.; Rispal, P.; Sorin, L.; Valette, C.; Vandenhende, M. A.; Vareil, M. O.; Viallard, J. F.; Wille, H.; Wirth, G.; Moreau, J. F.; Lafon, M. E.; Reigadas, S.; Trimoulet, P.; Haramburu, F.; Miremont-Salamé, G.; Blaizeau, M. J.; Crespel, I.; Decoin, M.; Delveaux, S.; Diarra, F.; D'Ivernois, C.; Hanappier, C.; Leleux, O.; Le Marec, F.; Lenaud, E.; Mourali, J.; Pougetoux, A.; Uwamaliya-Nziyumvira, B.; Tsaranazy, A.; Valdes, A.; Conte, V.; Louis, I.; Palmer, G.; Sapparrart, V.; Touchard, D.; Petoumenos, K.; Bendall, C.; Moore, R.; Edwards, S.; Hoy, J.; Watson, K.; Roth, N.; Nicholson, J.; Bloch, M.; Franic, T.; Baker, D.; Vale, R.; Carr, A.; Cooper, D.; Chuah, J.; Ngieng, M.; Nolan, D.; Skett, J.; Calvo, G.; Mateu, S.; Domingo, P.; Sambeat, M. A.; Gatell, J.; del Cacho, E.; Cadafalch, J.; Fuster, M.; Codina, C.; Sirera, G.; Vaqué, A.; de Wit, S.; Clumeck, N.; Necsoi, C.; Gennotte, A. F.; Gerard, M.; Kabeya, K.; Konopnicki, D.; Libois, A.; Martin, C.; Payen, M. C.; Semaille, P.; van, Y.; Neaton, J.; Bartsch, G.; El-Sadr, W. M.; Krum, E.; Thompson, G.; Wentworth, D.; Luskin-Hawk, R.; Telzak, E.; Abrams, D. I.; Cohn, D.; Markowitz, N.; Arduino, R.; Mushatt, D.; Friedland, G.; Perez, G.; Tedaldi, E.; Fisher, E.; Gordin, F.; Crane, L. R.; Sampson, J.; Baxter, J.; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Pedersen, C.; Møller, N. F.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Aho, I.; Katlama, C.; Viard, J.-P.; Girard, P.-M.; Cotte, L.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Chkhartishvili, N.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Lourida, P.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Sthoeger, Z. M.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; D'Offizi, G.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Parczewski, M.; Pynka, M.; Maciejewska, K.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Rakhmanova, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Shunnar, A.; Staneková, D.; Tomazic, J.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miró, J. M.; Gutierrez, M.; Mateo, G.; Laporte, J. M.; Blaxhult, A.; Flamholc, L.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Ledergerber, B.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Elzi, L.; Schmid, P.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Baskakov, I.; Servitskiy, S.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Johnson, M. A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Lundgren, J.; Grarup, J.; Cozzi-Lepri, A.; Thiebaut, R.; Peters, L.; Fischer, A. H.; Grønborg Laut, K.; Larsen, J. F.; Podlekareva, D.; Grint, D.; Shepherd, L.; Schultze, A.; Morfeldt, L.; Thulin, G.; Åkerlund, B.; Koppel, K.; Karlsson, A.; Håkangård, C.; Moroni, M.; Angarano, G.; Armignacco, O.; Castelli, F.; Cauda, R.; Di Perri, G.; Iardino, R.; Ippolito, G.; Perno, C. F.; von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Puoti, M.; Andreoni, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, R.; Cingolani, A.; Cinque, P.; de Luca, A.; Di Biagio, A.; Gori, A.; Guaraldi, G.; Lapadula, G.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Cicconi, P.; Formenti, T.; Galli, L.; Lorenzini, P.; Giacometti, A.; Costantini, A.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Cassola, G.; Viscoli, G.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Onofrio, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; d'Avino, A.; Gallo, L.; Nicastri, E.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Pellizzer, G.; Manfrin, V.; Dollet, K.; Caissotti, C.; Dellamonica, P.; Bernard, E.; Cua, E.; de Salvador-Guillouet, F.; Durant, J.; Ferrando, S.; Dunais, B.; Mondain-Miton, V.; Naqvi, A.; Perbost, I.; Prouvost-Keller, B.; Pillet, S.; Pugliese, P.; Risso, K.; Roger, P. M.; Aubert, V.; Bernasconi, E.; Böni, J.; Bucher, H. C.; Burton-Jeangros, C.; Dollenmaier, G.; Egger, M.; Fehr, J.; Fellay, J.; Gorgievski, M.; Günthard, H.; Haerry, D.; Hasse, B.; Hirsch, H. H.; Hoffmann, M.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kouyos, R.; Kovari, H.; Martinetti, G.; Martinez de Tejada, B.; Metzner, K.; Müller, N.; Nadal, D.; Nicca, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rudin, C.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Yerly, S.

    2016-01-01

    Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to

  9. Long-term cyclosporine A treatment of steroid-resistant and steroid-dependent nephrotic syndrome.

    Science.gov (United States)

    Melocoton, T L; Kamil, E S; Cohen, A H; Fine, R N

    1991-11-01

    Eighteen patients with steroid-resistant nephrotic syndrome (SRNS) and steroid-dependent nephrotic syndrome (SDNS) were treated with cyclosporine A (CyA) (6 mg/kg/d) for 2 to 29 months. CyA levels were monitored monthly and plasma levels by Abbott TDX (Therapeutic Drug Analyzer System) fluorescence polarization immunoassay were maintained at 100 to 150 ng/mL. The corticosteroid dosage administered at the time CyA therapy was initiated was variable and was continued following CyA therapy. Six of these patients (all with SDNS and minimal change nephrotic syndrome [MCNS]) had been treated with one or more courses of cytotoxic drug therapy, and all had clinical evidence of corticosteroid toxicity after receiving corticosteroid therapy for 26 to 120 months. The corticosteroid dosage was reduced by slow tapering and was ultimately discontinued in six patients. These patients were maintained on CyA monotherapy for 7 to 21 months at a dose of 3.2 to 6.7 mg/kg/d. Following 11 to 29 months of CyA therapy, seven patients underwent an elective renal biopsy, which showed nephrotoxicity in all seven. This led to discontinuation of CyA in four patients. Following discontinuation of CyA monotherapy, all four patients relapsed within 2 to 4 months. CyA therapy did not achieve a remission in 10 patients with SRNS regardless of the presence of focal segmental glomerulosclerosis (FSGS) or MCNS on renal biopsy. In conclusion, CyA has limited effectiveness in patients with SDNS who manifest corticosteroid toxicity; however, CyA should be used cautiously because of the potential for CyA nephrotoxicity and the failure to obtain a sustained remission following discontinuation of CyA monotherapy. CyA dependence is substituted for corticosteroid dependence.

  10. Tacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis.

    Science.gov (United States)

    Kilmartin, D J; Forrester, J V; Dick, A D

    1998-06-01

    Tacrolimus (FK506) is effective in Japanese endogenous posterior uveitis (EPU), but there is limited data on its role in refractory EPU where cyclosporin A (CsA) toxicity/resistance develops. This open prospective clinical study aimed to assess the efficacy and adverse effects of low-dose FK506 therapy in western patients with refractory EPU where CsA resistance or toxicity has developed. Patients with CsA resistant/toxic EPU were started on low-dose (efficacy was assessed by visual acuity, binocular indirect ophthalmoscopy (BIO) scores, and change in clinical features. Adverse effects were assessed by routine biochemical tests (including serum creatinine) and symptoms. Seven patients (13 eyes), aged (mean +/- SD) 37.5 +/- 14.8 years, were recruited with previous CsA nephrotoxicity as the main indication and prior duration of EPU of (mean +/- SD) 13.1 +/- 7.3 years. Behçet's disease was the commonest diagnosis. FK506 therapy was maintained at 0.06 +/- 0.02 mg/kg/day, trough level of 8.7 +/- 1.8 ng/ml, in combination with low-dose prednisolone (0.11 +/- 0.04 mg/kg/day) in all patients for a mean duration of 8.7 months (range 1.0-17.7). From baseline (for 11 eyes with meaningful follow-up), visual acuity was maintained in nine eyes and BIO score improved in nine eyes. No major adverse effects developed, with only a 7.5 +/- 6.5% maximum increase in serum creatinine in patients with previous CsA-induced nephrotoxicity. Minor adverse effects (especially mild hyperglycaemia and neurological symptoms) were common and usually well tolerated, except for two patients in whom drug withdrawal was necessary, thus producing therapeutic failure. Low-dose FK506 is effective in refractory EPU as CsA-rescue therapy, and should be considered earlier in the evolution of refractory EPU.

  11. Treatment of ligneous conjunctivitis with amniotic membrane transplantation and topical cyclosporine

    Directory of Open Access Journals (Sweden)

    Ozlem Yalcin Tok

    2012-01-01

    Full Text Available Ligneous conjunctivitis (LC is a rare form of bilateral chronic recurrent disease in which thick membranes form on the palpebral conjunctiva and other mucosal sites. We report the clinical features and describe the management of two cases. Case 1 was an 8-month-old patient with bilateral membranous conjunctivitis. Case 2 was a 5-year-old patient with unilateral membranous conjunctivitis, esotropia, mechanical ptosis and complicated cataract, and had been treated with a number of medications. Histological investigation of the membrane in both cases showed LC. Treatments with amniotic membrane transplantation and institution of topical cyclosporine have shown good response. There has been complete resolution of the membranes with no recurrence at the end of 40- and 28-month follow-ups, respectively. No treatment related side effects were seen. Thus, it appears that amniotic membrane transplantation and topical cyclosporine are effective alternatives for the treatment of LC.

  12. Treatment of ligneous conjunctivitis with amniotic membrane transplantation and topical cyclosporine.

    Science.gov (United States)

    Tok, Ozlem Yalcin; Kocaoglu, Fatma Akbas; Tok, Levent; Burcu, Ayse; Ornek, Firdevs

    2012-01-01

    Ligneous conjunctivitis (LC) is a rare form of bilateral chronic recurrent disease in which thick membranes form on the palpebral conjunctiva and other mucosal sites. We report the clinical features and describe the management of two cases. Case 1 was an 8-month-old patient with bilateral membranous conjunctivitis. Case 2 was a 5-year-old patient with unilateral membranous conjunctivitis, esotropia, mechanical ptosis and complicated cataract, and had been treated with a number of medications. Histological investigation of the membrane in both cases showed LC. Treatments with amniotic membrane transplantation and institution of topical cyclosporine have shown good response. There has been complete resolution of the membranes with no recurrence at the end of 40- and 28-month follow-ups, respectively. No treatment related side effects were seen. Thus, it appears that amniotic membrane transplantation and topical cyclosporine are effective alternatives for the treatment of LC.

  13. Treatment of ligneous conjunctivitis with amniotic membrane transplantation and topical cyclosporine

    Science.gov (United States)

    Tok, Ozlem Yalcin; Kocaoglu, Fatma Akbas; Tok, Levent; Burcu, Ayse; Ornek, Firdevs

    2012-01-01

    Ligneous conjunctivitis (LC) is a rare form of bilateral chronic recurrent disease in which thick membranes form on the palpebral conjunctiva and other mucosal sites. We report the clinical features and describe the management of two cases. Case 1 was an 8-month-old patient with bilateral membranous conjunctivitis. Case 2 was a 5-year-old patient with unilateral membranous conjunctivitis, esotropia, mechanical ptosis and complicated cataract, and had been treated with a number of medications. Histological investigation of the membrane in both cases showed LC. Treatments with amniotic membrane transplantation and institution of topical cyclosporine have shown good response. There has been complete resolution of the membranes with no recurrence at the end of 40- and 28-month follow-ups, respectively. No treatment related side effects were seen. Thus, it appears that amniotic membrane transplantation and topical cyclosporine are effective alternatives for the treatment of LC. PMID:23202401

  14. Improvement of impaired renal function in heart transplant recipients treated with mycophenolate mofetil and low-dose cyclosporine.

    Science.gov (United States)

    Aleksic, I; Baryalei, M; Busch, T; Pieske, B; Schorn, B; Strauch, J; Sîrbu, H; Dalichau, H

    2000-04-27

    Cyclosporine (CsA) nephrotoxicity is a common problem after cardiac transplantation. We have studied the impact of CsA dose reduction in association with mycophenolate mofetil (MMF) treatment on renal function in heart transplant recipients with suspected CsA nephrotoxicity (serum creatinine level >2 mg/dl). Twelve heart transplant recipients (11 men, 1 woman; 111 to 1813 days after transplantation) with CsA-based immunosuppression (plus azathioprine and/or steroids) and a serum creatinine level >2.0 mg/dl were started on a daily dose of 2000 mg of MMF. Dilated cardiomyopathy was the underlying disease in nine patients, ischemic cardiomyopathy in three patients. Mean patient age was 57 years (range 44-69 years). Azathioprine was discontinued and CsA slowly tapered. Creatinine clearance, serum creatinine level, urea nitrogen, and uric acid were monitored. CsA levels were measured, and CsA dose was adjusted for whole blood levels of 70-120 microg/L. Ten patients still had endomyocardial biopsies, whereas one had echocardiographic controls only. One grade 1B rejection episode according to ISHLT (International Society for Heart and Lung Transplantation) was observed until 1 year after the switch to MMF. One patient was excluded due to gastrointestinal side effects. Conversion from azathioprine to MMF with consecutive reduction of CsA in heart transplant recipients with CsA-impaired renal function improves renal function as evidenced by lower serum creatinine, urea nitrogen, uric acid, and higher creatinine clearance.

  15. Chronic Renal Allograft Dysfunction: Risk Factors, Immunology and ...

    African Journals Online (AJOL)

    mediated rejection. Non immunological factors include brain death in the donor, increasing donor age, ischemia-reperfusion injury, calcineurin inhibitor nephrotoxicity, hypertension, diabetes mellitus, hyperlipidemia, chronic obstruction and chronic ...

  16. CYCLOSPORIN A IN THERAPY FOR JUVENILE ARTHRITIS

    Directory of Open Access Journals (Sweden)

    E S Fedorov

    2010-01-01

    Full Text Available The paper describes approaches to using cyclosporin A (CsA in juvenile arthritis (JA. It shows the benefits of combination basic therapy with CsA and methotrexate included into a treatment regimen mainly for systemic JA and JA involving the eye (uveitis versus monotherapy with the above drugs. Attention is drawn to that the oral dose of glucocorticoids may be decreased when CsA is incorporated into the treatment regimen. CsA is shown to be of value as the drug of choice for the therapy of such a menacing complication of systemic JA as the macrophage activation syndrome

  17. Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year-old man.

    Science.gov (United States)

    van Sloten, Thomas T; de Klaver, Paul A G; van den Wall Bake, A Warmold L

    2018-01-01

    A drug interaction leading to higher exposure to cyclosporine. Cyclosporine and ticagrelor. A 49-year-old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pectoris. The timeline was consistent with the appearance of an interaction, the interaction was confirmed by an increase in trough concentration of cyclosporine, and there were no alternative causes that by themselves could have caused the increase in cyclosporine exposure. Cessation of ticagrelor. Inhibition of CYP3A4 and P-glycoprotein by ticagrelor. Clinicians should be aware of this potential interaction as ticagrelor is frequently prescribed in individuals using cyclosporine. Close monitoring of cyclosporine serum concentrations is warranted to avoid overdosing of cyclosporine. A pharmacokinetic study is needed to further examine the probable interaction between cyclosporine and ticagrelor. © 2017 The British Pharmacological Society.

  18. Attenuation of cisplatin-induced nephrotoxicity in rats using ...

    African Journals Online (AJOL)

    USER

    2010-07-28

    Jul 28, 2010 ... quantitative data. Our study revealed that zerumbone reduced kidney damage and preserved renal functions as proved by microscopic observations and lesion scoring. ... Key words: Zerumbone, cisplatin, nephrotoxicity, oxidative stress, antioxidant glutathione. ..... monohydrated complex in the guinea pig.

  19. Conversion from cyclosporine to tacrolimus improves renal function and lipid profile after cardiac transplantation.

    Science.gov (United States)

    Garlicki, Mirosław; Czub, Paweł; Labuś, Krzysztof; Ehrlich, Marek P; Rdzanek, Hanna

    2006-01-01

    Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. The impact on renal function after conversion from cyclosporine (CsA) to tacrolimus (TAC) is reported. Fifteen patients (men age 42 +/- 11 years) after cardiac transplantation (HTX) were switched from CsA to TAC (mean time after HTX 21 +/- 6 months). There were 13 male and 2 female patients. Mean cholesterol and LDL level at the time of conversion were 217 +/- 65 ml/dl and and 136 +/- 51 mg/100 ml respectively. Indication for HTX was ischemic cardiomyopathy (CMP) in 8, congenital in 3 and dilatative CMP in the remaining 4 patients. Mean tacrolimus level (microg/dl) at 1, 3, 6 and 12 months were 8.6 +/- 3.3, 8.6 +/- 1.4, 9.2 +/- 2.8 and 9.8 +/- 2.5 respectively. There was a statistically significant improvement in creatinine levels at 1, 3, 6 and 12 months after conversion from baseline 1.9 +/- 0.7 mg/dl to 1.4 +/- 0.5 mg/dl, 1.4 +/- 0.4 mg/dl, 1.3 +/- 0.4 mg/dl and 1.2 +/- 0.4 mg/dl, respectively (p transplantation improves renal function.

  20. The protective effect of curcumin against lithium-induced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Mohammad Shaterpour

    2017-08-01

    Full Text Available Lithium is an element which has been used as salts of chloride or carbonate for many years in the treatment of some psychological disorders such as mania, bipolar or schizophrenic diseases. Chronic application of lithium may induce some serious nephropathies such as natriuresis, renal tubular acidosis, tubulointerstitial nephritis progression to progressive chronic kidney disease and hypercalcemia and, most commonly, nephrogenic diabetes insipidus. Curcumin is an antioxidant derived from Curcuma longa (turmeric or curcuma which has the ability to react directly with reactive species and up-regulation of many cytoprotective and antioxidant proteins. The preventive roles of curcumin in nephropathies were reported, but there was little information on the protective effect of curcumin against lithium-induced nephrotoxicity. In this study, male Wistar rats divided into five groups of six each and were treated as follows: group1; animals were received lithium chloride as 2 mmol/kg, group 2; animals were received normal saline (0, 5%, group 3; animals were received curcumin (200 mg/kg, group 4 animals were received curcumin plus lithium and group 5; animals were received solvent intraperitoneally for three weeks. Then the animals were killed and biochemical parameters of blood were assayed and histopathological assessment was performed. The results have shown that curcumin significantly improved the biochemicals (BUN, creatinine, malondialdehyde. Curcumin prevented significantly the histological parameters that were changed by lithium administration in rats. Our results provide new insights into beneficial usages of curcumin in chronic nephrotoxicity induced by lithium salts.

  1. Extended cyclosporine delivery by silicone-hydrogel contact lenses.

    Science.gov (United States)

    Peng, Cheng-Chun; Chauhan, Anuj

    2011-09-25

    Cyclosporine A (CyA) is effective in treating chronic dry eyes and contact lens mediated dry eyes. CyA is delivered through eye drops of an oil-in-water emulsion, which has a small residence time in the eyes, leading to low bioavailability. Here we explore delivery of CyA from contact lenses to provide controlled and extended drug delivery with an increased bioavailability due to enhanced ocular residence time. Loading and release profiles of CyA from commercial contact lenses are presented to show that 1-DAY ACUVUE® releases CyA for about a day and extended wear silicone hydrogel (SiH) lenses release CyA for about 2-weeks. The longer duration from SiH lenses compared to the 1-DAY ACUVUE®lens is due to larger partition coefficients in the gel. A novel approach is presented for increasing release duration from the SiH lenses to the desired 1-month through incorporation of Vitamin E. The results show that Vitamin E loaded lenses can provide CyA release within the therapeutic window for a period of about a month. This pilot study demonstrates the promising potential of delivering CyA from contact lens for treatment of chromic dry eyes and contact lens mediated dry eyes. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Effects of powdered whole grapefruit and metoclopramide on the pharmacokinetics of cyclosporine in dogs.

    Science.gov (United States)

    Radwanski, Noel E; Cerundolo, Rosario; Shofer, Frances S; Hanley, Michael J; Court, Michael H

    2011-05-01

    To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. 8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective.

  3. Urine proteomic profiling of uranium nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Malard, V.; Gaillard, J.C.; Sage, N. [CEA, DSV, IBEB, SBTN, Laboratoire de Biochimie des Systemes Perturbes (LBSP), Bagnols-sur-Ceze, F-30207 (France); Berenguer, F. [CEA, DSV, IBEB, SBTN, Laboratoire d' Etude des Proteines Cibles (LEPC), Bagnols-sur-Ceze, F-30207 (France); Quemeneur, E. [CEA, DSV, IBEB, SBTN, Bagnols-sur-Ceze, F-30207 (France)

    2009-07-01

    Uranium is used in many chemical forms in civilian and military industries and is a known nephro-toxicant. A key issue in monitoring occupational exposure is to be able to evaluate the potential damage to the body, particularly the kidney. In this study we used innovative proteomic techniques to analyse urinary protein modulation associated with acute uranium exposure in rats. Given that the rat urinary proteome has rarely been studied, we first identified 102 different proteins in normal urine, expanding the current proteome data set for this central animal in toxicology. Rats were exposed intravenously to uranyl nitrate at 2.5 and 5 mg/kg and samples were collected 24 h later. Using two complementary proteomic methods, a classic 2-DE approach and semi-quantitative SDS-PAGE-LC-MS/MS, 14 modulated proteins (7 with increased levels and 7 with decreased levels) were identified in urine after uranium exposure. Modulation of three of them was confirmed by western blot. Some of the modulated proteins corresponded to proteins already described in case of nephrotoxicity, and indicated a loss of glomerular permeability (albumin, alpha-1-anti-proteinase, sero-transferrin). Others revealed tubular damage, such as EGF and vitamin D-binding protein. A third category included proteins never described in urine as being associated with metal stress, such as ceruloplasmin. Urinary proteomics is thus a valuable tool to profile uranium toxicity non-invasively and could be very useful in follow-up in case of accidental exposure to uranium. (authors)

  4. Movement disorders secondary to long-term treatment with cyclosporine A

    OpenAIRE

    Munhoz,Renato P.; Teive,Helio A.G.; Germiniani,Francisco M.B.; Gerytch Jr,Júlio C.; Sá,Daniel S.; Bittencourt,Marco A.; Pasquini,Ricardo; Camargo,Carlos H.F.; Werneck,Lineu César

    2005-01-01

    OBJECTIVE: To analyze the prevalence, severity and functional interference of movement disorders (MD) secondary to chronic use of cyclosporine A (CsA). METHOD: We conducted a cross-sectional study of 60 patients (58.3% male) with mean age 23.1 (3-75) years, followed at the Bone Marrow Transplantation Service of the Hospital de Clínicas of the Federal University of Paraná, Brazil, taking CsA for at least six months. Our protocol included clinical data, assessment of functional interference of ...

  5. An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects.

    Science.gov (United States)

    Bifano, Marc; Adamczyk, Robert; Hwang, Carey; Kandoussi, Hamza; Marion, Alan; Bertz, Richard J

    2015-05-01

    Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug-drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir-a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)-and cyclosporine or tacrolimus in healthy subjects. Healthy fasted subjects (aged 18-49 years; body mass index 18-32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4-11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8-19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC-MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC-MS/MS methods. Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration-time curve of daclatasvir but did not affect its maximum observed concentration. On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.

  6. Pituitary transplantation: cyclosporine enables transplantation across a minor histocompatibility barrier.

    Science.gov (United States)

    Tulipan, N B; Huang, S; Allen, G S

    1986-03-01

    Pituitary glands from neonatal donors were transplanted to the median eminence of hypophysectomized adult rats. Rats with transplants were then treated for 2 weeks with the immunosuppressive drug cyclosporine. For 5 weeks thereafter, blood was drawn at regular intervals for determination of serum thyroxine, prolactin, and luteinizing hormone. Cyclosporine-treated recipients of grafts with minor histocompatibility differences had normal levels of thyroxine and prolactin, whereas untreated animals did not. In addition, the treated animals responded to oophorectomy with a marked elevation in serum luteinizing hormone. This evidence indicates that cyclosporine enables successful transplantation across a minor histocompatibility barrier. It also suggests that these grafts interact with the hypothalamus. Transplantation across a major histocompatibility barrier was unsuccessful even in the presence of cyclosporine.

  7. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation

    DEFF Research Database (Denmark)

    McAlister, V C; Haddad, E; Renouf, E

    2006-01-01

    A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were...

  8. Population pharmacokinetics of cyclosporine in chinese cardiac transplant recipients.

    Science.gov (United States)

    Yin, Ophelia Q P; Lau, So-Kei; Chow, Moses S S

    2006-06-01

    To characterize the population pharmacokinetics of cyclosporine in Chinese patients undergoing cardiac transplantation and to identify the demographic and clinical covariates affecting cyclosporine clearance. Population pharmacokinetic analysis using data from a retrospective chart review. Specialty hospital in Hong Kong for treatment of cardiac and pulmonary diseases. Thirty-eight Chinese adult patients (mean age 46 yrs) who had undergone routine cyclosporine therapeutic drug monitoring after cardiac transplantation between January 1, 1991, and December 31, 2003. Data regarding dosing, demographics, clinical laboratory values, and concurrent drugs were collected retrospectively. Data were included if patients had blood cyclosporine concentrations determined for at least 12 weeks after transplantation; an average of 18 blood samples/patient were collected. Population modeling was performed using a one-compartment linear model with first-order absorption and elimination. Various demographic and clinical covariates were tested for their significant effects on the apparent oral clearance (Cl/F) of cyclosporine. The stability of the final population model was evaluated by using the bootstrap resampling method. Statistically significant associations were observed between Cl/F and each of the following covariates: body weight (BW), use of diltiazem (DIL), and hematocrit value (HCT). The final model was Cl/F=5.00*(1-DIL)+365/HCT+(0.144*BW). The interindividual variabilities of Cl/F and apparent volume of distribution were 14.5% and 40.2%, respectively. The mean parameter estimates obtained from bootstrap analyses were highly consistent with those obtained with the original data set. The estimated Cl/F values of cyclosporine in our Chinese cardiac transplant recipients appeared to be similar to those reported for Caucasian cardiac transplant recipients. Thus, our data provide support that a cyclosporine dosage regimen similar to that in Caucasian patients may be needed in

  9. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference

    Directory of Open Access Journals (Sweden)

    Zohreh Zamani

    2016-01-01

    Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.

  10. Telmisartan attenuates chronic ciclosporin A nephrotoxicity in a pig model

    DEFF Research Database (Denmark)

    Cibulskyte, Donata; pedersen, michael; Hørlyck, Arne

    2007-01-01

    BACKGROUND: We have previously demonstrated renal enlargement in pigs treated with ciclosporin A (CsA) 10 mg/kg/day orally for 6 months. The aim of the study was to investigate the effect of oral CsA (10 mg/kg/day) for 12 months on kidney structure and function and the potential renoprotective ro...

  11. A comparison of cyclosporine A and cyclosporine G in a rabbit heterotopic cardiac transplant model: graft outcome and histological findings

    OpenAIRE

    Fryer, J.P.; Pascoe, E.A.; Yatscoff, R W; Thliveris, J A

    1996-01-01

    Cervical heterotopic heart transplants were performed on 20 male New Zealand white rabbits comprising 4 treatment groups. Animals in each group were injected daily via the marginal ear vein and received one of the following regimes: Cyclosporine A, 10 mglkglday; Cyclosporine G, 15 mglkglday; cremophor-El, 3mllday; or normal saline. Measurement of 24 hour trough blood concentrations revealed no significant differences between the average concentrations of Cy...

  12. High-dose intravenous vancomycin therapy and the risk of nephrotoxicity.

    Science.gov (United States)

    Rostas, Sara E; Kubiak, David W; Calderwood, Michael S

    2014-07-01

    National guidelines recommend higher serum trough concentrations when using vancomycin to treat certain clinical conditions, but there is concern that higher-dose vancomycin therapy causes nephrotoxicity. We evaluated risk factors associated with nephrotoxicity in patients receiving high-dose intravenous vancomycin. This retrospective cohort study evaluated the clinical outcome of 80 hospitalized adult patients with normal baseline renal function who received ≥4 g/d of intravenous vancomycin for ≥48 hours between January 1, 2011, and December 31, 2011. After abstracting clinical risk factors, we used an analysis by methods of best clinical subsets to develop a multivariable model predicting nephrotoxicity in patients receiving high-dose vancomycin. The overall rate of nephrotoxicity in the study population was 6%. Trough concentrations >20 mg/L were identified in a similar proportion of patients who did and did not develop nephrotoxicity. Patients who developed nephrotoxicity trended toward having a lower body mass index, higher daily dose, longer duration of therapy, and greater exposure to intravenous contrast and nephrotoxic medications. In a multivariable model, the combination of intravenous contrast and nephrotoxic medications was a significant predictor of nephrotoxicity, and duration of high-dose vancomycin was a significant confounder. Administration of high-dose intravenous vancomycin may have less associated nephrotoxicity than previously reported, although duration of vancomycin therapy may play a role. Concomitant exposure to intravenous contrast and other nephrotoxic medications is a more significant predictor of developing nephrotoxicity than vancomycin dose or trough. Published by EM Inc USA.

  13. Megalin Contributes to Kidney Accumulation and Nephrotoxicity of Colistin

    Science.gov (United States)

    Suzuki, Takahiro; Yamaguchi, Hiroaki; Ogura, Jiro; Kobayashi, Masaki; Yamada, Takehiro

    2013-01-01

    Interest has recently been shown again in colistin because of the increased prevalence of infections caused by multidrug-resistant Gram-negative bacteria. Although the potential for nephrotoxicity is a major dose-limiting factor in colistin use, little is known about the mechanisms that underlie colistin-induced nephrotoxicity. In this study, we focused on an endocytosis receptor, megalin, that is expressed in renal proximal tubules, with the aim of clarifying the role of megalin in the kidney accumulation and nephrotoxicity of colistin. We examined the binding of colistin to megalin by using a vesicle assay. The kidney accumulation, urinary excretion, and concentrations in plasma of colistin in megalin-shedding rats were also evaluated. Furthermore, we examined the effect of megalin ligands and a microtubule-depolymerizing agent on colistin-induced nephrotoxicity. We found that cytochrome c, a typical megalin ligand, inhibited the binding of colistin to megalin competitively. In megalin-shedding rats, renal proximal tubule colistin accumulation was decreased (13.5 ± 1.6 and 21.3 ± 2.6 μg in megalin-shedding and control rats, respectively). Coadministration of colistin and cytochrome c or albumin fragments resulted in a significant decrease in urinary N-acetyl-β-d-glucosaminidase (NAG) excretion, a marker of renal tubular damage (717.1 ± 183.9 mU/day for colistin alone, 500.8 ± 102.4 mU/day for cytochrome c with colistin, and 406.7 ± 156.7 mU/day for albumin fragments with colistin). Moreover, coadministration of colistin and colchicine, a microtubule-depolymerizing agent, resulted in a significant decrease in urinary NAG excretion. In conclusion, our results indicate that colistin acts as a megalin ligand and that megalin plays a key role in the accumulation in the kidney and nephrotoxicity of colistin. Megalin ligands may be new targets for the prevention of colistin-induced nephrotoxicity. PMID:24100504

  14. Nefrotoxicidade por lítio Lithium nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Jobson Lopes de Oliveira

    2010-01-01

    Full Text Available O lítio é amplamente empregado na terapia do transtorno bipolar. Sua toxicidade renal inclui distúrbio na capacidade de concentração urinária e natriurese, acidose tubular renal, nefrite túbulo-intersticial evoluindo para doença renal crônica e hipercalcemia. O efeito adverso mais comum é o diabetes insipidus nefrogênico, que acomete de 20%-40% dos pacientes semanas após o início do tratamento. A nefropatia crônica correlaciona-se com a duração do uso de lítio. A detecção precoce de disfunção renal deve ser feita através de monitoração rigorosa dos pacientes e colaboração entre o psiquiatra e o nefrologista. Recentes trabalhos experimentais e clínicos começam a esclarecer os mecanismos pelos quais o lítio induz alteração da função renal. No presente trabalho, objetivamos revisar a patogênese, a apresentação clínica, os aspectos histopatológicos e o tratamento da nefrotoxicidade induzida pelo lítio.Lithium is widely used in the therapy of bipolar disorder. Its toxicity includes urinary concentration deficit and natriuresis, renal tubular acidosis, tubulointerstitial nephritis which complicates with chronic kidney disease and hypercalcemia. The most common adverse effect is diabetes insipidus, which occurs in 20-40% of patients some weeks after initiation of treatment. Such chronic nephropathy correlates with duration of lithium use. Early detection of renal dysfunction should be achieved by rigorous monitoring of patients and collaboration between the psychiatrist and nephrologist. Recent experimental and clinical studies are now clarifying the mechanisms by which lithium induces renal abnormalities. The aim of this work is to review the pathogenesis, clinical presentation, histopathologic aspects and treatment of lithium nephrotoxicity.

  15. Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution.

    Science.gov (United States)

    Glezerman, I; Kris, M G; Miller, V; Seshan, S; Flombaum, C D

    2009-02-01

    Gemcitabine is used in a variety of advanced malignancies. Hemolytic uremic syndrome has been reported as a side effect. we reviewed medical records of 29 patients with gemcitabine nephrotoxicity. The median cumulative dose of gemcitabine was 22 g/m2 (4 - 81) given over 7.5 months (2 - 34). Prior chemotherapy with mitomycin had been given to 9 patients, and in 4 the hemolytic uremic syndrome was particularly severe and appeared shortly after gemcitabine initiation. All patients had renal insufficiency. Microhematuria and proteinuria were present in 27 patients and red blood cell casts were seen in 8. Renal biopsies in 4 patients showed thrombotic microangiopathy. Worsening or new-onset hypertension was seen in 26 patients. Edema, shortness of breath and congestive heart failure were present in 21, 15 and 7 patients, respectively. All had anemia, thrombocytopenia and elevated serum lactate dehydrogenase. Haptoglobin was low in 23 of the 26 patients who had it measured. Schistocytes were present in 21 of the 24 patients who had blood smear reviewed. Gemcitabine was discontinued once hemolytic uremic syndrome was recognized. Full or partial recovery of renal function occurred in 19 patients. 7 patients progressed to end-stage renal disease and 3 patients developed chronic renal failure. Gemcitabine nephrotoxicity presents as new-onset renal disease with associated hypertension, thrombocytopenia and microangiopathic hemolytic anemia. Prior chemotherapy with mitomycin, especially when given in close proximity, may be synergistic. A high index of suspicion is essential to make an early diagnosis. Stopping gemcitabine improves the outcome.

  16. Cyclosporine for the treatment of HLTV-1-induced HAM/TSP: an experience from a case report.

    Science.gov (United States)

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

    2015-01-01

    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.

  17. Prevalence of acute and chronic viral seropositivity and characteristics of disease in patients with psoriatic arthritis treated with cyclosporine: a post hoc analysis from a sex point of view on the observational study of infectious events in psoriasis complicated by active psoriatic arthritis.

    Science.gov (United States)

    Colombo, Delia; Chimenti, Sergio; Grossi, Paolo Antonio; Marchesoni, Antonio; Bardazzi, Federico; Ayala, Fabio; Simoni, Lucia; Vassellatti, Donatella; Bellia, Gilberto

    2016-01-01

    Sex medicine studies have shown that there are sex differences with regard to disease characteristics in immune-mediated inflammatory diseases, including psoriasis, in immune response and susceptibility to viral infections. We performed a post hoc analysis of the Observational Study of infectious events in psoriasis complicated by active psoriatic arthritis (SYNERGY) study in patients with psoriatic arthritis (PsA) treated with immunosuppressive regimens including cyclosporine, in order to evaluate potential between-sex differences in severity of disease and prevalence of viral infections. SYNERGY was an observational study conducted in 24 Italian dermatology clinics, which included 238 consecutively enrolled patients with PsA, under treatment with immunosuppressant regimens including cyclosporin A. In this post hoc analysis, patients' demographical data and clinical characteristics of psoriasis, severity and activity of PsA, prevalence of seropositivity for at least one viral infection, and treatments administered for PsA and infections were compared between sexes. A total of 225 patients were evaluated in this post hoc analysis, and 121 (54%) were males. Demographic characteristics and concomitant diseases were comparable between sexes. Statistically significant sex differences were observed at baseline in Psoriasis Area and Severity Index score (higher in males), mean number of painful joints, Bath Ankylosing Spondylitis Disease Activity Index, and the global activity of disease assessed by patients (all higher in females). The percentage of patients with at least one seropositivity detected at baseline, indicative of concomitant or former viral infection, was significantly higher among women than among men. No between-sex differences were detected in other measures, at other time points, and in treatments. Patients developed no hepatitis B virus or hepatitis C virus reactivation during cyclosporine treatment. Our post hoc sex analysis suggests that women with

  18. TREATMENT OF STEROID DEPENDENT ASTHMATICS WITH LOW DOSES OF CYCLOSPORINE

    Directory of Open Access Journals (Sweden)

    Stanislav Šuškovič

    2004-01-01

    Full Text Available Background. Asthmatics with glucocorticoid dependent asthma should be treated with systemic steroids. Cyclosporine is in many ways a potent anti-inflammatory drug. Cyclosporine is sometimes very effective in treating asthmatics and could allow us to lower the dose of oral steroid. In some randomized, double blind studies steroid dependent asthmatics were treated 12–36 weeks with cyclosporine in dose 5 mg/kg/day. We tried cyclosporine in steroid dependent asthmatics in shorter course and in lower dose.Methods. 13 steroid dependent asthmatics were in the first four weeks of the study treated by their own drugs (phase 1. Then they were for the next four weeks (phase 2 randomly and in double blind fashion treated with either cyclosporine (mean 1.7 mg/kg/day, SD 0.5, 6 patients – group 1 or by identical placebo (7 patients – group 2. To the patients in the group 2 serum concentration of cyclosporine was measured on the eight day of the study.Results. Morning peak expiratory flow (PEF raised significantly in group 1 (200 L/sec to 247 L/sec or for 23%. Patients in group1 had significantly less episodes of nocturnal asthma (2.2 episodes/night to 1.5 episodes/night or for 32%. In group 2 were not found any changes between first phase and second phase of the study. Steroid consumption did not change in any group. Mean serum concentration of cyclosporine in patients of group1 was 35.7 µg/L. We did not find any adverse effects of cyclosporine or placebo.Conclusions. Cyclosporine could have dangerous side effects, which are dependent on its serum concentration. So it should be administered in the lowest possible dose and for the most possible short period. In our study it was found that it is possible to successfully treat steroid dependent asthmatics with lower daily dose and for shorter time, than was found in other similar studies.

  19. Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.

    Directory of Open Access Journals (Sweden)

    Rahul Bohra

    Full Text Available Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL and sirolimus (SRL alone, and in combination with cyclosporine (CsA, on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination. After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1H-magnetic resonance spectroscopy (MRS and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.

  20. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    The present study was conducted to evaluate the hepatotoxic and nephrotoxic effects of petroleum fumes on male and female petrol attendants. Investigations had been carried out on thirty (30) adult petrol attendants from different filling stations in Ibadan metropolis of Nigeria with ten (10) healthy adults as control. All the ...

  1. The role of lipid peroxidation in the nephrotoxicity of cisplatin

    NARCIS (Netherlands)

    Vermeulen, N P; Baldew, G S

    1992-01-01

    The possible role of lipid peroxidation in the nephrotoxicity of the antitumour drug cisplatin was studied in vitro. In contrast to Adriamycin, cisplatin did not induce lipid peroxidation in rat kidney microsomes containing a NADPH-generating system. Pretreatment of rat kidney microsomes with

  2. Nebivolol Ameliorates Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Morsy, Mohamed A; Heeba, Gehan H

    2016-06-01

    Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with Nω -nitro-L-arginine methyl ester, the non-specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin-induced nephrotoxicity that is most likely through its antioxidant, anti-inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  3. Amelioration of Cisplatin-Induced Nephrotoxicity in Rats by ...

    African Journals Online (AJOL)

    Purpose: To investigate the possible protective role of curcumin and α-tocopherol against cisplatininduced nephrotoxicity in rat. Methods: Male Wistar rats were divided into five groups. Groups 1 and 2 were intraperitoneally (i.p.) injected with normal saline and cisplatin (20 mg/kg), respectively. Groups 3, 4 and 5 were ...

  4. Ginger Essential Oil Ameliorates Cisplatin-Induced Nephrotoxicity in ...

    African Journals Online (AJOL)

    HP

    poessess potential benefits to renal patients. However, further investigations are essential to elucidate the mechanism by which GEO treatment ameliorates the nephrotoxicity. ACKNOWLEDGMENT. This study was supported by grants from the. Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, Capes, and ...

  5. PERSIST: Physician's Evaluation of Restasis® Satisfaction in Second Trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review

    Directory of Open Access Journals (Sweden)

    Mah F

    2012-11-01

    Full Text Available Francis Mah,1 Mark Milner,2 Samuel Yiu,3 Eric Donnenfeld,4 Taryn M Conway,5 David A Hollander51University of Pittsburgh, Pittsburgh, PA, 2The Eye Center, Hamden, CT, 3University of Southern California, Los Angeles, CA, 4Ophthalmic Consultants of Long Island and Connecticut, Rockville Centre, New York, NY, 5Allergan Inc, Irvine, CA, USABackground: Chronic dry eye disease often requires long-term therapy. Tear film alterations in the setting of dry eye may include reduced tear volume as well as an increase in inflammatory cytokines and osmolarity. Topical cyclosporine ophthalmic emulsion 0.05% (Restasis®; Allergan Inc, Irvine, CA is indicated to increase tear production in patients with dry eye and reduced tear production presumed to be due to ocular inflammation. This study was designed to evaluate the efficacy of a second trial of topical cyclosporine in patients with dry eye who were previously considered treatment failures.Materials and methods: This multicenter (three cornea practices retrospective chart review evaluated clinical outcomes in patients with dry eye who received a second trial of cyclosporine after a prior treatment failure, defined as prior discontinuation of topical cyclosporine after less than 12 weeks.Results: Thirty-five patients, most of whom were female (71.4% and Caucasian (62.9%, were identified. Prior discontinuation was most commonly due to burning/stinging (60%. The median duration of second treatment was 10 months (range 1 week to 45 months. Physician education was provided in the second trial in 97.1% of cases. At initiation of the second trial of cyclosporine, 10 (28.6% patients received courses of topical corticosteroids. Physicians reported on a questionnaire that 80% of patients achieved clinical benefit with a second trial of cyclosporine.Conclusion: A repeat trial with topical cyclosporine can achieve clinical success. Direct patient education via the physician and staff may be key to success. Proper patient

  6. Cyclosporin drug-interaction-induced rhabdomyolysis. A report of two cases in lung transplant recipients.

    Science.gov (United States)

    Cohen, E; Kramer, M R; Maoz, C; Ben-Dayan, D; Garty, M

    2000-07-15

    In rare cases the use of cyclosporin in transplant patients can cause myopathic changes. We describe two patients, the recipients of lung transplants, who developed severe reversible rhabdomyolysis associated with cyclosporin drug-drug interaction.

  7. The Effects of Cyclosporine and Aspirin on Platelet Function in Normal Dogs

    OpenAIRE

    Thomason, J.; Archer, T.; Wills, R.; Press, S.; Mackin, A.

    2016-01-01

    Background Cyclosporine increases thromboxane synthesis in dogs, potentially increasing the thrombogenic properties of platelets. Hypothesis/Objectives Our hypothesis was that the concurrent administration of low?dose aspirin and cyclosporine would inhibit cyclosporine?associated thromboxane synthesis without altering the antiplatelet effects of aspirin. The objective was to determine the effects of cyclosporine and aspirin on primary hemostasis. Animals Seven healthy dogs. Methods A randomiz...

  8. Prevalence of acute and chronic viral seropositivity and characteristics of disease in patients with psoriatic arthritis treated with cyclosporine: a post hoc analysis from a sex point of view on the observational study of infectious events in psoriasis complicated by active psoriatic arthritis

    Directory of Open Access Journals (Sweden)

    Colombo D

    2015-12-01

    Full Text Available Delia Colombo,1 Sergio Chimenti,2 Paolo Antonio Grossi,3 Antonio Marchesoni,4 Federico Bardazzi,5 Fabio Ayala,6 Lucia Simoni,7 Donatella Vassellatti,1 Gilberto Bellia1 On behalf of SYNERGY Study Group 1Novartis Farma Italia, Origgio (VA, 2Tor Vergata Polyclinic Rome, 3Macchi Hospital and Foundation, Varese, 4Orthopaedic Institute Pini, Milan, 5S Orsola-Malpighi Polyclinic, Bologna, 6University Federico II Naples, 7MediData srl, Modena, Italy Background: Sex medicine studies have shown that there are sex differences with regard to disease characteristics in immune-mediated inflammatory diseases, including psoriasis, in immune response and susceptibility to viral infections. We performed a post hoc analysis of the Observational Study of infectious events in psoriasis complicated by active psoriatic arthritis (SYNERGY study in patients with psoriatic arthritis (PsA treated with immunosuppressive regimens including cyclosporine, in order to evaluate potential between-sex differences in severity of disease and prevalence of viral infections.Methods: SYNERGY was an observational study conducted in 24 Italian dermatology clinics, which included 238 consecutively enrolled patients with PsA, under treatment with immunosuppressant regimens including cyclosporin A. In this post hoc analysis, patients' demographical data and clinical characteristics of psoriasis, severity and activity of PsA, prevalence of seropositivity for at least one viral infection, and treatments administered for PsA and infections were compared between sexes.Results: A total of 225 patients were evaluated in this post hoc analysis, and 121 (54% were males. Demographic characteristics and concomitant diseases were comparable between sexes. Statistically significant sex differences were observed at baseline in Psoriasis Area and Severity Index score (higher in males, mean number of painful joints, Bath Ankylosing Spondylitis Disease Activity Index, and the global activity of disease

  9. Tacrolimus vs. cyclosporine eyedrops in severe cyclosporine-resistant vernal keratoconjunctivitis: A randomized, comparative, double-blind, crossover study.

    Science.gov (United States)

    Pucci, Neri; Caputo, Roberto; di Grande, Laura; de Libero, Cinzia; Mori, Francesca; Barni, Simona; di Simone, Lorena; Calvani, Annamaria; Rusconi, Franca; Novembre, Elio

    2015-05-01

    Vernal keratoconjunctivitis (VKC) is a chronic sight-threatening ocular disease. Topical cyclosporine A (Cyc) has been widely administered as a steroid-sparing drug, although in about 7-10% of cases, it has been ineffective. The purpose of this study was to evaluate the efficacy of 0.1% topical tacrolimus (Tcr) in patients with severe VKC who failed to respond to 1% Cyc eyedrops. Consecutive patients with severe, Cyc-resistant VKC were enrolled in a double-blind, comparative, crossover (DBCO) trial; all patients were treated with 1% Cyc in one eye and 0.1% Tcr in the other eye for 3 wk. After a washout period of 7 days, patients were instructed to cross over the medications for three additional weeks. Objective ocular score, subjective score, and quality-of-life questionnaires (QoLQ) were collected during the trial. Blood samples were drawn to assess several safety parameters. Thirty patients have been enrolled (mean age 9.05 ± 2.12 yr). In each of the two phases of the DBCO trial, a significant improvement in objective and subjective scores was observed in the eyes treated with 0.1% Tcr (p < 0.001). Likewise, the quality of life significantly improved despite only half the eyes being successfully treated. Serum creatinine and blood parameters were constantly within the normal range, and both blood Cyc and Tcr concentrations remained below the lowest detectable levels. Topical Tcr is very effective and safe in the short term for patients suffering from severe VKC resistant to topical Cyc. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Generalized pustular psoriasis of pregnancy successfully treated with cyclosporine

    Directory of Open Access Journals (Sweden)

    Hazarika Debeeka

    2009-01-01

    Full Text Available Two multigravidae aged 27 and 29 years, with previous uneventful pregnancies, second being psoriatic, reported at 24 and 28 weeks of pregnancies, with generalized pustular lesions. Laboratory findings, including serum calcium were normal. Ultrasonography showed normal fetal growth. Histopathology confirmed pustular psoriasis. Patients were put on cyclosporine 3 mg/ kg weight/ day after failure of an initial systemic steroid. Blood pressure, pulse, and fetal heart sounds were recorded every 12 hours, and ultrasonography and blood parameters, biweekly. Cyclosporine was tapered and stopped after delivery of two healthy babies at 38 weeks. We conclude that cyclosporine can be an option in the management of pustular psoriasis of pregnancy or psoriasis with pustulation in pregnancy.

  11. Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission.

    Science.gov (United States)

    de Arriba, Gabriel; Calvino, Miryam; Benito, Selma; Parra, Trinidad

    2013-03-27

    Cyclosporine A (CsA) nephrotoxicity has been linked to reactive oxygen species (ROS) production in renal cells. We have demonstrated that the antioxidant Vitamin E (Vit E) abolished renal toxicity in vivo and in vitro models. As one of the main sources of intracellular ROS are mitochondria, we studied the effects of CsA on several mitochondrial functions in LLC-PK1 cells. CsA induced ROS synthesis and decreased reduced glutathione (GSH). The drug decreased mitochondrial membrane potential (ΔΨm) and induced physiological modifications in both the inner (IMM) and the outer mitochondrial membranes (OMM). In the IMM, CsA provoked mitochondrial permeability transition pores (MPTP) and cytochrome c was liberated into the intermembrane space. CsA also induced pore formation in the OMM, allowing that intermembrane space contents can reach cytosol. Furthermore, CsA altered the mitochondrial dynamics, inducing an increase in mitochondrial fission; CsA increased the expression of dynamin related protein 1 (Drp1) that contributes to mitochondrial fission, and decreased the expression of mitofusin 2 (Mfn2) and optic atrophy protein 1 (Opa1), proteins involved in the fusion process. All these phenomena were related to apoptosis. These effects were inhibited when cells were treated with the antioxidant Vit E suggesting that they were mediated by the synthesis of ROS. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Retrospective Evaluation of Colistin Associated Nephrotoxicity at Oncology Hospital Intensive Care Unit

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    Menşure Kaya

    2014-08-01

    Full Text Available Objective: The aim of our study, is to determine the nephrotoxicity rates and risk factors for the development of nephrotoxicity by retrospective evaluation of patients who were given colistin therapy oncology hospital intensive care unit. Material and Method: Total of 33 adult patients were included in the study. Renal function tests and hemodialysis requirements were recorded. In addition, patients age, gender, concurrently used drugs with colistin therapy, duration of colistin therapy and total colistin doses were noted. RIFLE criteria (risk, injury, failure, loss, end-stage kidney disease were used for evaluation of nephrotoxicity. Results: Nephrotoxicity was observed in 69,7% of patients (23 patients. According to RIFLE criteria nephrotoxicity rates were; risk 36,36%, injury 15,15% and failure 18,18%. In patients who developed nephrotoxicity, creatinine and blood urea nitrogen values were observed to rise significantly on the 5th day of colistin treatment (p≤0,05. In patients with malignancy, nephrotoxicity rate was 5.4 times higher than those without the diagnosis of malignancy. Concurrent use of diuretic, aminoglycoside, vancomycin and carbapenem did not increase the risk of nephrotoxicity. Conclusion: In our study, the rate of nephrotoxicity was higher than those in the literature. We found that underlying malignant tumor diagnosis increases the rate of nephrotoxicity.

  13. [Cyclosporine A based therapy for myelodysplastic syndrome].

    Science.gov (United States)

    Li, Zhen-Ling; Gong, Ming; Xu, Shao-Hua; Huang, Fan-Zhou; Chen, Yan-Rong; Ma, Yi-Gai

    2005-10-01

    To determine the efficacy and tolerance to cyclosporine A (CsA) based therapy in patients with myelodysplastic syndrome (MDS), 16 patients with MDS consisting of 10 refractory anemia (RA) and 6 refractory anemia with accessory blasts less than 10% (RAEB-1) were analyzed. Five patients had hypocellular bone marrows and 11 patients had normocellular or hypercellular marrows. The dose of CsA was 2.5-5.5 mg/(kg.d) for 2 weeks to 2 years (mean 8 months). Two out of 16 patients were treated with CsA alone, 14 patients were treated with CsA, recombinant human erythropoietin, androgens, 1, 25 dihydroxy vitamin D(3) or two or three of them combination with CsA. Treatment responses were classified according to the International Working Group (IWG) criteria as complete remission (CR), partial remission (PR), hematological improvement (HI) and no response (NR). Patients who obtained CR, PR or HI were defined as responders. The results showed that HI was observed in 12 patients, PR in 2 patients and NR in 2 patients. Total response rate was 87.5%. Response rates shown in neutrophil lineage, platelet and erythroid lineage were 83.3%, 66.7% and 60%, respectively; their shortest time required to obtain some hematologic improvement after initiation of CsA therapy was 2 weeks, 1 month and 1 month, respectively. Of 13 patients being transfusion-dependent before treatment, 3 patients did not need transfusion any more and 5 showed the reduced transfusion requirements after CsA therapy. In 10 patients with RA, 9 responded to CsA. Of 6 patients with RAEB, 1 patient had no response and died of RAEB-t and 5 patients had transient responses. One of the latter transformed to CMML and two relapsed. The total response rate decreased to 50% in the patients with CsA therapy lasting more than 3 months at the end of following-up. The adverse effects included hirsutism, hyperplastic gingiva, reversible hepatic and renal dysfunction. In conclusion, the usefulness of CsA based therapy for MDS-RA and

  14. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

    DEFF Research Database (Denmark)

    Penninga, Luit; Penninga, Ida Elisabeth Irene; Møller, Christian H

    2013-01-01

    Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without...

  15. Successful treatment of metastatic Crohn's disease with cyclosporine.

    Science.gov (United States)

    Carranza, Dafnis C; Young, Lorraine

    2008-08-01

    Metastatic Crohn's disease refers to cutaneous granulomatous lesions that are noncontiguous to the gastrointestinal tract. The treatment of cutaneous Crohn's disease is challenging. A patient with metastatic Crohn's disease whose lesions cleared after a 3-month course of cyclosporine is reported.

  16. 21 CFR 862.1235 - Cyclosporine test system.

    Science.gov (United States)

    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 § 862...

  17. Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

    Science.gov (United States)

    Renner, Brandon; Klawitter, Jelena; Goldberg, Ryan; McCullough, James W.; Ferreira, Viviana P.; Cooper, James E.; Christians, Uwe

    2013-01-01

    Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases. PMID:24092930

  18. Characterization of a cyclosporine solid dispersion for inhalation

    NARCIS (Netherlands)

    Zijlstra, Gerrit S; Rijkeboer, Michiel; van Drooge, Dirk; Sutter, Marc; Jiskoot, Wim; van de Weert, Marco; Hinrichs, Wouter L J; Frijlink, Henderik W

    2007-01-01

    For lung transplant patients, a respirable, inulin-based solid dispersion containing cyclosporine A (CsA) has been developed. The solid dispersions were prepared by spray freeze-drying. The solid dispersion was characterized by water vapor uptake, specific surface area analysis, and particle size

  19. Physicochemical properties of radiographic contrast media, potential nephrotoxicity and prophylaxis.

    Science.gov (United States)

    Hogstrom, Barry; Ikei, Nobuhiro

    2015-12-01

    Contrast induced nephropathy (CIN) remains a controversial topic. The clinical relevance of changes in laboratory parameters has been challenged; some authors have even suggested that CIN simply reflects natural fluctuations. Other areas of controversy include the pathophysiology of CIN, effectiveness of prophylactic approaches and differences in nephrotoxicity between individual contrast media (CM). The aim of this review is to summarize the current understanding of laboratory findings and explore its relationship to CM toxicity. © 2015 Wiley Publishing Asia Pty Ltd.

  20. Efficacy of safranal to cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  1. Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET{sub B} receptor cascade

    Energy Technology Data Exchange (ETDEWEB)

    El-Gowelli, Hanan M. [Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria (Egypt); Helmy, Maged W.; Ali, Rabab M. [Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria (Egypt); El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com [Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria (Egypt)

    2014-03-01

    Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET{sub B} receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β{sub 1}, TGF-β{sub 1}). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET{sub B} receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET{sub B} receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ET{sub B} receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET{sub B} receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. - Highlights: • Celecoxib abolishes nephrotoxic manifestations of CSA in rats. • Blockade of ETB receptors by BQ788 mimicked the nephrotoxic effects of CSA. • CSA or BQ788 reduces renal protein expression of COX-2 and endothelin ETB receptors. • Enhanced TGFβ1/IL-2/COX2/ETB

  2. Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity.

    Directory of Open Access Journals (Sweden)

    Ping Jia

    Full Text Available Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram-negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N2 balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia-inducible factor 2α (HIF-2α and its downstream effector vascular endothelial growth factor, but not HIF-1α. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain-containing protein-2 (PHD2, suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity.

  3. Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats▿

    Science.gov (United States)

    Yousef, Jumana M.; Chen, Gong; Hill, Prue A.; Nation, Roger L.; Li, Jian

    2011-01-01

    Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P colistin group on day 6. Significant histological abnormalities (P colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic. PMID:21709095

  4. Nephrotoxicity of halogenated alkenyl cysteine-S-conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Nagelkerke, J.F.; Boogaard, P.J. (Univ. of Leiden (Netherlands))

    1991-01-01

    In 1916 a relationship was postulated between the occurrence of aplastic anemia in cattle and the soy bean meal that they had been fed, which had been extracted with trichloroethylene. The toxic compound was later identified as S-(1,2-dichlorovinyl)-L-cysteine (DCV-Cys). In addition to effects on the hemopoietic system it also produced nephrotoxicity in calves. In rats only renal tubular necrosis was found. Further research demonstrated that other halogenated hydrocarbons produced similar nephrotoxicity. The haloalkenyl cysteine-S-conjugates (Cys-D-conjugates) have extensively been studied; this has provided new insight into the biochemical processes that lead to nephrotoxicity. It has been shown that a combination of transport processes and specific metabolic pathways, resulting in reactive intermediates that bind to cellular macromolecules, makes the kidney vulnerable to the noxious effects of the haloakenyl Cys-S-conjugates. The first part of this review gives a brief overview of the bioactivation of the haloalkenes; in the second part the present knowledge of the underlying mechanisms of cytotoxicity is outlined.

  5. Species Differences in Renal Development and Associated Developmental Nephrotoxicity.

    Science.gov (United States)

    Frazier, Kendall S

    2017-10-02

    The developing kidney is sensitive to both morphological and functional disturbances during the gestational and postnatal phases of growth and differentiation. Exposure to drugs or chemicals during these critical windows of renal development can result in aplasia, dysplasia, polycystic kidney disease, hydronephrosis, or other features characteristic of nephrotoxicity, including tubule dilation, necrosis, or mineralization. Functional effects can occur without associated morphological abnormalities. Differences in the timing of nephrogenesis and morphologic renal development among species help to explain specific phenotypes of various gestational and postnatal teratogens and nephrotoxins. Functional maturation follows anatomical maturation, but important differences in maximally achieved glomerular filtration rate, concentrating ability and acid-base equilibrium between species makes comparison of these timings critical for accurate and consistent translation of laboratory animal toxicity data to the human clinical experience. Species and age dependent differences in the maturation of kidney transporters, renal xenobiotic metabolism and renal blood flow can have a profound effect on the toxicity profiles of agents and marked differences in the tolerability based on age. Advances in the understanding of the genetics of inherited renal diseases and the underlying cellular and molecular pathogenesis of renal developmental anomalies has helped provide mechanistic understanding of many teratogenic and perinatal nephrotoxic agents. Investigative studies have provided important translational and mechanistic information for assessing human pediatric nephrotoxic potential. Birth Defects Research 109:1243-1256, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Nephroprotection of lacidipine against gentamycin-induced nephrotoxicity in albino rats

    OpenAIRE

    Shams, Sahar

    2010-01-01

    Sahar KamalPharmacology Department, Faculty of Medicine, Ain Shams University, Cairo Aim: Gentamycin, a widely-used aminoglycoside antibiotic, is recognized as possessing significant nephrotoxic potential in human beings. Gentamycin-induced nephrotoxicity is suggested to be mediated via reactive oxygen species. The present study investigated the possible antioxidant nephroprotective effect of lacidipine as a calcium-channel blocker in a gentamycin-induced nephrotoxicity model in albino rats.M...

  7. Comparison between swallowing and chewing of garlic on levels of serum lipids, cyclosporine, creatinine and lipid peroxidation in Renal Transplant Recipients

    Directory of Open Access Journals (Sweden)

    Ghorbanihaghjo Amir

    2005-05-01

    Full Text Available Abstract Abstract Hyperlipidemia and increased degree of oxidative stress are among the important risk factors for Atherosclerosis in renal transplant recipients (RTR. The Medical treatment of hyperlipidemia in RTR because of drugs side effects has been problematic, therefore alternative methods such as using of Garlic as an effective material in cholesterol lowering and inhibition of LDL Oxidation has been noted. For evaluation of garlic effect on RTR, 50 renal transplant patients with stable renal function were selected and divided into 2 groups. They took one clove of garlic (1 gr by chewing or swallowing for two months, after one month wash-out period, they took garlic by the other route. Results indicated that although lipid profile, BUN, Cr, serum levels of cyclosporine and diastolic blood pressure did not change, Systolic blood pressure decreased from138.2 to 132.8 mmHg (p=0.001 and Malondialdehyde (MDA decreased from 2.4 to1.7 nmol/ml (p=0.009 by swallowing route, Cholesterol decreased from 205.1 to 195.3 mg/dl (p=0.03, triglyceride decreased from 195.7 to 174.8 mg/dl (p=0.008, MDA decreased from 2.5 to 1.6 nmol/ml (p=0.001, systolic blood pressure decreased from 137.5 to 129.8 mmHg (p=0.001, diastolic blood pressure decreased from 84.6 to 77.6 mmHg (p=0.001 and Cr decreased from 1.51 to 1.44 mg/dl (p=0.03 by chewing route too. However HDL, LDL and cyclosporine serum levels had no significant differences by both of swallowing and chewing routes. We conclude that undamaged garlic (swallowed had no lowering effect on lipid level of serum. But Crushed garlic (chewed reduces cholesterol, triglyceride, MDA and blood pressure. Additionally creatinine reduced without notable decrease in cyclosporine serum levels may be due to cyclosporine nephrotoxicity ameliorating effect of garlic.

  8. Lack of nephrotoxicity and renal cell proliferation following subchronic dermal application of a hydroquinone cream.

    Science.gov (United States)

    David, R M; English, J C; Totman, L C; Moyer, C; O'Donoghue, J L

    1998-07-01

    Hydroquinone (HQ) is used in over-the-counter formulations of skin-lightening creams sold in the United States and European Union. HQ was introduced into these formulations to provide a safe and effective alternative to mercury and other less effective ingredients. Recent studies involving subchronic oral exposure of male F344 rats to HQ have shown nephrotoxicity and renal tubule cell proliferation (English et al., 1994), while chronic exposures of male F344 rats were reported to cause renal cell adenomas (NTP, 1989). Previous subchronic dermal toxicity studies (CTFA, 1986; NTP, 1989) with HQ failed to detect nephrotoxicity; however, these studies were not specifically designed to assess renal structure and function. More sensitive endpoints were used in the present subchronic study to address concerns over potential toxicity from repeated dermal exposure to HQ. Male and female F344 rats were given topical applications with 0, 2.0, 3.5, or 5.0% HQ in an oil-in-water emulsion cream for 13 wk (5 days/wk). Body weights, feed consumption and water consumption were monitored, and animals were observed for clinical signs of toxicity and dermal irritation. Blood taken at termination was analysed for haematological and clinical chemistry effects. Erythema, which abated when exposure stopped, was the only dermatological effect seen at the HQ-cream application sites. Cell proliferation in the kidneys was evaluated after 3, 6 and 13 wk of treatment using bromodeoxyuridine (BrdU) labelling, but no changes indicative of sustained cell proliferation were seen. The renal histopathological lesions noted after oral exposure to HQ were not present after dermal exposure. Thus, topical exposure to HQ does not result in the renal toxicity observed in previous studies with F344 rats given HQ orally.

  9. Amelioration of cyclosporine A-induced renal, hepatic and cardiac damages by ellagic acid in rats.

    Science.gov (United States)

    Yüce, Abdurrauf; Ateşşahin, Ahmet; Ceribaşi, Ali Osman

    2008-08-01

    Treatment with cyclosporine A has significantly improved long-term survival after organ transplantations. Cyclosporine A also causes a dose-related decrease in body functions in experimental animals and human beings. The generation of reactive oxygen species has been implicated in cyclosporine A-induced dysfunctions. The aim of this study was to determine the effects of ellagic acid on cyclosporine A-induced alterations in the kidney, liver and heart oxidant/antioxidant system. The control group was treated with placebo and subcutaneous injection of 0.5 ml isotonic saline + 0.5 ml slightly alkaline solution for 21 days. The cyclosporine A group received a subcutaneous injection of cyclosporine A (15 mg/kg) + 0.5 ml slightly alkaline solution for 21 days. The ellagic acid group was treated with a subcutaneous injection of 0.5 ml isotonic saline + ellagic acid (10 mg/kg) for 21 days. The cyclosporine A plus ellagic acid group received a subcutaneous injection of cyclosporine A + ellagic acid for 21 days. Ellagic acid and slightly alkaline solution were administered by gavage. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney, liver and heart tissues. While administration of cyclosporine A increased the MDA levels in kidney, liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. However, the simultaneously administration of ellagic acid markedly normalized the cyclosporine A-induced liver and heart MDA levels, liver CAT activities and GSH-Px activities of all samples. Cyclosporine A caused marked damages in the histopathological status of kidney, liver and heart tissues, which were partially ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cyclosporine A in transplantation treatment to improve the

  10. The Effects of Cyclosporine and Aspirin on Platelet Function in Normal Dogs.

    Science.gov (United States)

    Thomason, J; Archer, T; Wills, R; Press, S; Mackin, A

    2016-07-01

    Cyclosporine increases thromboxane synthesis in dogs, potentially increasing the thrombogenic properties of platelets. Our hypothesis was that the concurrent administration of low-dose aspirin and cyclosporine would inhibit cyclosporine-associated thromboxane synthesis without altering the antiplatelet effects of aspirin. The objective was to determine the effects of cyclosporine and aspirin on primary hemostasis. Seven healthy dogs. A randomized, crossover study utilized turbidimetric aggregometry and a platelet function analyzer to evaluate platelet function during the administration of low-dose aspirin (1 mg/kg PO q24h), high-dose aspirin (10 mg/kg PO q12h), cyclosporine (10 mg/kg PO q12h), and combined low-dose aspirin and cyclosporine. The urine 11-dehydro-thromboxane-B2 (11-dTXB2 )-to-creatinine ratio also was determined. On days 3 and 7 of administration, there was no difference in the aggregometry amplitude or the platelet function analyzer closure time between the low-dose aspirin group and the combined low-dose aspirin and cyclosporine group. On day 7, there was a significant difference in amplitude and closure time between the cyclosporine group and the combined low-dose aspirin and cyclosporine group. High-dose aspirin consistently inhibited platelet function. On both days, there was a significant difference in the urinary 11-dTXB2 -to-creatinine ratio between the cyclosporine group and the combined low-dose aspirin and cyclosporine group. There was no difference in the urinary 11-dTXB2 -to-creatinine ratio among the low-dose aspirin, high-dose aspirin, and combined low-dose aspirin and cyclosporine groups. Low-dose aspirin inhibits cyclosporine-induced thromboxane synthesis, and concurrent use of these medications does not alter the antiplatelet effects of aspirin. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  11. Risk factors for cisplatin-induced long-term nephrotoxicity in pediatric cancer survivors.

    Science.gov (United States)

    Arga, Mustafa; Oguz, Aynur; Pinarli, Faruk Guclu; Karadeniz, Ceyda; Citak, Elvan Caglar; Emeksiz, Hamdi Cihan; Duran, Esra Akdeniz; Soylemezoglu, Oguz

    2015-06-01

    The aim of this study was to compare the nephrotoxicity risk of cisplatin (CPL) and ifosfamide (IFO) combination treatment (CT) with that of CPL alone and to evaluate the prevalence of CPL-induced long-term nephrotoxicity in pediatric cancer survivors (CS). A total of 33 patients with pediatric solid tumors who have been cured of their disease were included in the study. They were divided into two groups based on the type of chemotherapeutics, either CPL (n = 21) or CT (n = 12), given during cancer treatment and were evaluated for glomerular and tubular function using the Skinner grading system. Nephrotoxicity was found in 15 CS (45.4%): seven (21.3%) of those had moderate, six (18.2%) had mild, and two (6.1%) had severe nephrotoxicity. Neither the rates of overall nephrotoxicity, glomerular toxicity and tubular toxicity, nor the mean overall, glomerular and tubular toxicity scores differed significantly among the CPL and CT groups (P > 0.05 for all parameters). Cumulative IFO dose and age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity (P = 0.025 and P = 0.036 for development of nephrotoxicity; P = 0.004 and P = 0.050 for severity of nephrotoxicity, respectively). Although CPL-induced long-term nephrotoxicity was found in half of the pediatric CS of solid tumors, clinically significant nephrotoxicity was detected only in a minority of them. Both higher cumulative IFO dose and younger age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity. © 2014 Japan Pediatric Society.

  12. Chronic urticaria and treatment options

    Directory of Open Access Journals (Sweden)

    Godse Kiran

    2009-01-01

    Full Text Available Chronic urticaria has a wide spectrum of clinical presentations and causes. Still, despite our best efforts no cause may be found in the majority of cases. The treatment options are: Primary prevention in the form of avoidance of aggravating factors; counseling; antihistamines; leukotriene receptor antagonists; prednisolone; sulfasalazine and a host of immunosuppressives like methotrexate, cyclosporine, omalizumab etc.

  13. Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries

    Science.gov (United States)

    Mohamed, Fahim; Endre, Zoltan H; Buckley, Nicholas A

    2015-01-01

    Acute kidney injury (AKI) has diverse causes and is associated with increased mortality and morbidity. In less developed countries (LDC), nephrotoxic AKI (ToxAKI) is common and mainly due to deliberate ingestion of nephrotoxic pesticides, toxic plants or to snake envenomation. ToxAKI shares some pathophysiological pathways with the much more intensively studied ischaemic AKI, but in contrast to ischaemic AKI, most victims are young, previously healthy adults. Diagnosis of AKI is currently based on a rise in serum creatinine. However this may delay diagnosis because of the kinetics of creatinine. Baseline creatinine values are also rarely available in LDC. Novel renal injury biomarkers offer a way forward because they usually increase more rapidly in AKI and are normally regarded as absent or very low in concentration, thereby reducing the need for a baseline estimate. This should increase sensitivity and speed of diagnosis. Specificity should also be increased for urine biomarkers since many originate from the renal tubular epithelium. Earlier diagnosis of ToxAKI should allow earlier initiation of appropriate therapy. However, translation of novel biomarkers of ToxAKI into clinical practice requires better understanding of non-renal factors in poisoning that alter biomarkers and the influence of dose of nephrotoxin on biomarker performance. Further issues are establishing LDC population-based normal ranges and assessing sampling and analytical parameters for low resource settings. The potential role of renal biomarkers in exploring ToxAKI aetiologies for chronic kidney disease of unknown origin (CKDu) is a high research priority in LDC. Therefore, developing more sensitive biomarkers for early diagnosis of nephrotoxicity is a critical step to making progress against AKI and CKDu in the developing world. PMID:26099916

  14. Cilostazol attenuates gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Abdelsameea, Ahmed A; Mohamed, Ahmed M; Amer, Mona G; Attia, Shahera M

    2016-04-01

    Gentamycin is a widely used antibiotic. The nephrotoxic adverse effects of the drug may limit its use. Cilostazol, a phosphodiesterase III inhibitor, was reported to protect from renal oxidative stress. This work aimed to investigate the possible protective effect of cilostazol on gentamicin-induced nephrotoxicity and the possible underlying mechanisms. 40 male albino rats were divided into 4 equal groups: (1) Control; (2) Cilostazol, 10mg/kg, p.o.; (3) Gentamicin, 80 mg/kg, i.p.; (4) Gentamicin 80 mg/kg, i.p. along with cilostazol 10mg/kg, p.o. All drugs were administered once daily for 8 days. On 9th day blood samples were collected for the estimation of creatinine, urea and uric acid in serum. Then the rats were sacrificed and kidneys were removed for light and electron microscope studies. Moreover, reduced glutathione (GSH) and malondialdehyde (MDA) levels as well as catalase (CAT) and superoxide dismutase (SOD) activities were determined in renal tissues. Gentamicin elevated the serum levels of creatinine, urea and uric acid as well as the MDA level in the renal tissue, while it decreased CAT, SOD activities and GSH levels as well as produced degenerative changes in glomeruli and tubules associated with increased expression of apoptotic markers and decreased expression of anti-apoptotic markers. Administration of cilostazol decreased urea, creatinine, uric acid and MDA levels while increased CAT and SOD activities and GSH levels as well as ameliorated the histopathological changes in relation to gentamicin group. Cilostazol protected rats from gentamicin-induced nephrotoxicity possibly, in part through its antioxidant and anti-apoptotic activity. Copyright © 2016 Elsevier GmbH. All rights reserved.

  15. Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients.

    Science.gov (United States)

    Lehmkuhl, Hans B; Arizon, José; Viganò, Mario; Almenar, Luis; Gerosa, Gino; Maccherini, Massimo; Varnous, Shaida; Musumeci, Francesco; Hexham, J Mark; Mange, Kevin C; Livi, Ugolino

    2009-07-15

    Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable. In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids+/-induction therapy. In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5+/-27.9 and 76.8+/-32.1 mL/min at baseline, 65.4+/-24.7 and 72.2+/-26.2 mL/min at month 6, and 68.7+/-27.7 and 71.8+/-29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01). Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.

  16. CYCLOSPORINE IN TREATMENT OF SEVERE ATOPIC DERMATITIS IN CHILDREN

    Directory of Open Access Journals (Sweden)

    A.A. Alekseeva

    2010-01-01

    Full Text Available Atopic dermatitis (AtD is one of the most widespread types of allergic lesions of skin in children. Increase of severe types of AtD with lesion of big parts of skin, high frequency of exacerbations, presence of concomitant atopic diseases, and inefficiency of standard therapeutic approaches, torpid clinical course and early development of disability, causes an anxiety. Present standard approaches can be ineffective in children with severe clinical course of AtD and they are not able to prevent progression of disease, development of severe exacerbations and child’s disability. One of therapeutic alternatives for these patients is treatment with immunosuppressive agents. The article describes questions of treatment with cyclosporine in systemic therapy of severe resistant forms of AtD in children. Author discusses effectiveness and safety of a drug, formulated rules of treatment of severe AtD with cyclosporine. Key words: children, atopic dermatitis, cyclosporine, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2010;9(5:117-120

  17. Multiple Eruptive Sebaceous Hyperplasia Secondary to Cyclosporin in a Patient with Bone Marrow Transplantation

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    Begonia Cortés

    2016-11-01

    Full Text Available Many cutaneous complications have been described in patients treated with cyclosporin. Alterations of the pilosebaceous unit such as hypertrichosis are particularly frequent. However, the occurrence of sebaceous hyperplasia is exceptional. These lesions seem to be specific to cyclosporin rather than secondary to immunosuppression. Here, we report an exceptional case of eruptive and disseminated sebaceous hyperplasia arising in a bone marrow transplant recipient only a few months after starting immunosuppressive treatment with cyclosporin.

  18. Low-dose cyclosporine treatment for sight-threatening uveitis: Efficacy, toxicity, and tolerance

    OpenAIRE

    Mathews D; Mathews John; Jones N

    2010-01-01

    Aim : To ascertain the effectiveness, tolerability, and safety of low-dose cyclosporine in the management of sight-threatening uveitis. Materials and Methods: This was a retrospective clinical case series of patients using oral low-dose cyclosporine for the management of sight-threatening uveitis in the uvea clinic (UC). Patients receiving cyclosporine were identified from the clinic database. Main outcome measures were degree of intraocular inflammation, visual acuity and dose reduction of...

  19. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China); Peng, Shuangqing [Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071 (China); Wang, Weidong, E-mail: wwdwyl@sina.com [Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Li, Rong, E-mail: yuhui_hao@126.com [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China)

    2015-09-15

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  20. Severity of gentamicin's nephrotoxic effect on patients with infective endocarditis: a prospective observational cohort study of 373 patients

    DEFF Research Database (Denmark)

    Buchholtz, Kristine; Larsen, Carsten T; Hassager, Christian

    2009-01-01

    BACKGROUND: Gentamicin is often used to treat infective endocarditis (IE). Gentamicin is highly effective, but its applicability is reduced by its nephrotoxic effect. The aim of this study was to quantify the nephrotoxic effect of gentamicin and the association between the nephrotoxic effect...

  1. Urinary metabolomics and biomarkers of aristolochic acid nephrotoxicity by UPLC-QTOF/HDMS.

    Science.gov (United States)

    Zhao, Ying-Yong; Tang, Dan-Dan; Chen, Hua; Mao, Jia-Rong; Bai, Xu; Cheng, Xiao-Hong; Xiao, Xin-Yue

    2015-01-01

    Drug-induced nephrotoxicity was one of the most important health problems, with increasing morbidity and mortality. Urinary metabolomics based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-definition mass spectrometry was applied to aristolochic acid (AA) nephrotoxicity rats to characterize the excretion pathways of endogenous metabolites. Compared with the control rats, serum creatinine, serum blood urea nitrogen and urine protein levels were significantly increased in AA nephrotoxicity rats. Metabolomics showed that metabolites including citrate, aconitate, fumarate, glucose, creatinine, p-cresyl sulfate, indoxyl sulfate, hippuric acid, phenylacetylglycine, kynurenic acid, indole-3-carboxylic acid, spermine, uric acid, allantoin, cholic acid and taurine were identified in AA nephrotoxicity rats. The identified metabolites suggested that AA nephrotoxicity rats occurred perturbations in Krebs cycle, gut microflora metabolism, amino acid metabolism, purine metabolism and bile acid biosynthesis.

  2. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarró, Eduard, E-mail: eduard.sarro@vhir.org [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Itarte, Emilio, E-mail: emili.itarte@uab.es [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Meseguer, Anna, E-mail: ana.meseguer@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain)

    2012-01-15

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  3. Correlations between calcineurin phosphatase inhibition and cyclosporine metabolites concentrations in kidney transplant recipients: implications for immunoassays

    DEFF Research Database (Denmark)

    Karamperis, N; Koefoed-Nielsen, PB; Brahe, P

    2006-01-01

    Cyclosporine exhibits a wide spectrum of metabolites that vary considerably in the extent to which they interfere with the various parent drug monitoring immunoassays. There is no consensus regarding the clinical significance of metabolites. Cyclosporine exerts its immunosuppressive action...... transplant patients were included in the study. Blood samples were drawn before, 1, 2, 3, 4, 6, 8, and 12 hr after oral intake of cyclosporine. Parent drug and metabolites were determined by liquid chromatography/tandem mass spectrometry (LC/MSMS). Additionally, cyclosporine concentration was determined...

  4. Proximal Tubular Injury in Medullary Rays Is an Early Sign of Acute Tacrolimus Nephrotoxicity

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    Diane Cosner

    2015-01-01

    Full Text Available Tacrolimus (FK506 is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1 is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.

  5. Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys.

    Science.gov (United States)

    Kelishadi, Shahrooz S; Azimzadeh, Agnes M; Zhang, Tianshu; Stoddard, Tiffany; Welty, Emily; Avon, Christopher; Higuchi, Mitch; Laaris, Amal; Cheng, Xiang-Fei; McMahon, Christine; Pierson, Richard N

    2010-04-01

    Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (alphaCD20) rituximab depleted CD20+ B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20+ B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with alphaCD20 or CsA alone. In animals treated with both alphaCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20+ B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic.

  6. Protective Effects of Vitamin E and/or Quercetin Co-Supplementation on the Morphology of Kidney in Cyclosporine A-Treated Rats

    Directory of Open Access Journals (Sweden)

    Zohreh Mostafavi Pour

    2009-12-01

    Full Text Available Background: Cyclosporine A (CsA is a nephrotoxic immunosuppressivedrug. Antioxidants might attenuate its toxicity. Inthe present study, the effects of vitamin E and quercetin on themorphology of kidney in CsA-treated rats were investigated.Methods: Six groups of rats were used in this gavage feedingstudy either for 4 or 8 weeks. Groups 1 and 2 received eitherolive oil or 25% ethanol in olive oil per day. Group 3 receivedCsA (25 mg/kg/day in olive oil. All other groups received CsAplus the following: group 4, vitamin E (100 mg/kg/day in oliveoil; group 5, quercetin (15 mg/kg/day in 25% ethanol in oliveoil; and group 6, vitamin E plus quercetin. In the final day of thestudy, the animals were sacrificed and kidney sections were preparedfor morphologic studies using light microscopy.Results: Acute morphologic alterations induced by CsA in thekidney tubules included isometric vacuolization, brush borderloss, microcalcification, and presence of inclusion bodies. Smoothmuscle degeneration and necrosis were developed in arterioles.Treatment with vitamin E plus quercetin prevented severe,moderate, and mild abnormalities of the tubules. However fibrosiswas the only microscopic change of the interstitium thatwas not present in animals treated with vitamin E plusquercetin after both periods.Some mild morphological changes of the blood vesselssuch as arteriolar medial smooth muscle degeneration and necrosis,arteriolar myocyte dropout and arteriolar wall hyalinizationcaused by CsA disappeared with administration of vitaminE, quercetin or vitamin E plus quercetin in both periods.Conclusion: Co-administration of vitamin E plus quercetinwith CsA in renal transplant patients may be beneficial inreducing the nephrotoxic effects of CsA.

  7. Therapeutic and toxicological evaluations of cyclosporine a microspheres as a treatment vehicle for uveitis in rabbits.

    Science.gov (United States)

    He, Yuan; Wang, Jian-Cheng; Liu, Yu-Ling; Ma, Zhi-Zhong; Zhu, Xiu-An; Zhang, Qiang

    2006-04-01

    This study was undertaken to investigate the therapeutic efficacy and the toxicity of the intravitreal biodegradable poly(dl-lactide-co-glycolide)co-polymer microspheres containing cyclosporin A (CsA-PLGA-MS) on experimental uveitis in rabbits. CsA-PLGA-MS that had been prepared by a solvent evaporation approach were characterized for morphology, particle size, entrapment efficiency, and in vitro release profile of CsA-PLGA-MS. Therapeutic efficacy of the CsA-PLGA-MS was evaluated by scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination, and histological examination in the experimental rabbits with artificial uveitis induced by the injection of lipopolysaccharide. The toxicity was investigated by slit-lamp examination, indirect ophthalmoscopy, and electroretinography (ERG) in the noninflamed rabbit eye. The CsA-PLGA-MS were spherical in shape, with an average particle size of nearly 50 microm and an entrapment efficiency of more than 80%. The compositions of the formulation that was most effective in the in vivo studies included CsA, PLGA, and 3% Pluronic F68. In vitro released cyclosporine A from the optimized microspheres was approximately 25% during the 60-day incubation at 37 degrees C. It was demonstrated that the intravitreal injection of the optimized CsA-PLGA-MS decreased significantly the severity of the inflammatory signs, cellular infiltrate, aqueous leukocyte counts, and protein levels in the eyes of experimental rabbits with uveitis, compared to other formulations. Also, the preparation did not cause obvious toxicity in the noninflamed eyes of rabbits, except that the ERG b-wave amplitude for the test eyes was reversibly depressed, compared to those of the control eyes at 2 weeks, which almost recovered at the end of 6 weeks. The CsA-PLGA-MS preparation might be useful in the treatment of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy.

  8. Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

    Science.gov (United States)

    Abdel Moneim, Ahmed E; Othman, Mohamed S; Aref, Ahmed M

    2014-01-01

    We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt) on cisplatin- (CP-) induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt) was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i) as histopathological damage of the renal tissue, (ii) as increases in serum uric acid, urea, and creatinine, (iii) as increases in malondialdehyde (MDA) and nitric oxide (NO), (iv) as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v) as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  9. Azadirachta indica Attenuates Cisplatin-Induced Nephrotoxicity and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Ahmed E. Abdel Moneim

    2014-01-01

    Full Text Available We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt on cisplatin- (CP- induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i as histopathological damage of the renal tissue, (ii as increases in serum uric acid, urea, and creatinine, (iii as increases in malondialdehyde (MDA and nitric oxide (NO, (iv as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  10. Prevention of chemotherapy-induced nephrotoxicity in children with cancer

    Directory of Open Access Journals (Sweden)

    Fatemeh Ghane Sharbaf

    2017-01-01

    Full Text Available Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL, ifosfamide (IFO, carboplatin, and methotrexate (MTX. Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI, tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS, and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.

  11. Effect of platelet activating factor antagonist treatment on gentamicin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Barbero

    1992-01-01

    Full Text Available To assess whether PAF could be involved in the gentamicin-induced nephrotoxicity, we have studied the effect of PAF antagonist BN-52021 on renal function in rats after gentamicin (GENTA treatment. Experiments were completed in 21 Wistar rats divided into three groups: group GENTA was injected with gentamicin 100 mg kg−1 body wt/day s.c. for 6 days. Group GENTA + BN received gentamicin and BN-52021 i.p. 5 mg kg−1 body wt/day. A third group served as control. Rats were placed in meta-bolic cages and plasma creatinine and creatinine clearance were measured daily. GENTA group showed a progressive increase in plasma creatinine, a drop in creatinine clearance and an increase in urinary excretion of N-acetyl-β-D-glucosaminidase and alkaline phosphatase. GENTA + BN group showed a lesser change in plasma creatinine and a creatinine clearance, but no difference with GENTA group in urinary excretion of NAG and AP were observed. Histological examination revealed a massive cortical tubular necrosis in rats treated with gentamicin, whereas in BN-52021 injected animals tubular damage was markedly attenuated. The present results suggest a role for PAF in the gentamicininduced nephro-toxicity.

  12. Luteolin ameliorates colistin-induced nephrotoxicity in the rat models.

    Science.gov (United States)

    Arslan, Birsen Yigit; Arslan, Ferhat; Erkalp, Kerem; Alagöl, Ayşin; Sevdi, Mehmet Salih; Yıldız, Güneş; Küçük, Suat Hayri; Altınay, Serdar

    2016-11-01

    To study the protective, preventive effect of luteolin from colistin-induced nephrotoxicity. Four different treatment options were tested on rats: colistin, luteolin, and a combination of colistin and luteolin, intraperitoneally as two doses a day, for seven days. Another group of rats were used as the control and treated with sterile saline. Serum creatinine levels were measured before and after treatment. Histological changes and colistin-induced apoptosis (Insitu BrdU-red DNA Fragmentation Assay Kit) of the renal tissues were examined after the scarification procedure. In the Colistin Group, post-treatment creatinine levels were statistically higher than the pretreatment levels (p = .001). In the remaining groups, no significant changes were observed. Cells that undergo apoptosis were counted and it was shown that all groups except the colistin-treated group had a similar number of apoptotic cells, whereas the colistin-treated group had statistically higher number of apoptotic cells compared to other groups (p = .0001). Renal histological damage was also measured and the score of the colistin treated group was higher as compared to other groups. The results obtained from this study demonstrated us that luteolin was capable of preventing colistin-induced nephrotoxicity and that this effect was significant at histopathological level.

  13. Cyclosporine mitigates graft coronary artery disease in murine cardiac allografts: description and validation of a novel fully allogeneic model.

    Science.gov (United States)

    Tanaka, Masashi; Mokhtari, Golnaz K; Balsam, Leora B; Cooke, David T; Kofidis, Theo; Zwierzchonievska, Monika; Robbins, Robert C

    2005-04-01

    The effect of cyclosporine (CsA) on the development of graft coronary artery disease (GCAD) is controversial. We developed a novel allogeneic mouse model of heart transplantation and investigated the effect of CsA on acute rejection and GCAD. Hearts of FVB mice (H-2(q)) were heterotopically transplanted into 60 C57BL/6 mice (H-2(b)). CsA was administered to recipients at 10, 20 or 30 mg/kg/day for 10 or 30 days after transplantation. Untreated recipients as well as isograft recipients served as controls. Viability of the grafts was assessed daily by palpation. Parenchymal rejection was scored in grafts surviving 30 days in the 30-day treatment groups. GCAD was evaluated by the percentage of luminal narrowing, intima/media ratio and percentage of diseased vessels. Blood CsA and creatinine levels were also evaluated. Results were evaluated statistically. All groups except the untreated control group and the allograft groups treated with 10 or 20 mg for 10 days showed significant graft survival (>/=33% survival for 30 days). An inverse correlation was observed between CsA treatment dose, parenchymal rejection score and degree of GCAD in the 30-day treatment groups. However, graft survival in the 20-mg/kg/day group was significantly better than that in the 30-mg/kg/day group. Serum creatine levels showed no nephrotoxicity. Relatively high-dose CsA mitigated parenchymal rejection and GCAD of the mouse cardiac allografts. In addition, a valuable mouse model mimicking the clinical course of GCAD was achieved with CsA treatment of 20 mg/kg/day for 30 days.

  14. Adult Heart Transplantation Under Tacrolimus (FK506) Immunosuppression: Histopathologic Observations and Comparison to a Cyclosporine-based Regimen with Lympholytic (ATG) Induction

    Science.gov (United States)

    Tsamandas, Athanassios C.; Pham, Si M.; Seaberg, Eric C.; Pappo, Orit; Kormos, Robert L.; Kawai, Akihiko; Griffith, Bartley P.; Zeevi, Adriana; Duquesnoy, Rene; Fung, John J.; Starzl, Thomas E.; Demetris, Anthony J.

    2011-01-01

    refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. Conclusions Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction. PMID:9257254

  15. [Treatment of patients with severe glucocorticoid-refractory ulcerative colitis: cyclosporine or infliximab?

    NARCIS (Netherlands)

    Lowenberg, M.; Boer, N.K. de; Dewint, P.; Hoentjen, F.

    2013-01-01

    - Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis.- A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe

  16. Skeletal muscle magnesium content during cyclosporin and azathioprine treatment in renal transplant recipients

    DEFF Research Database (Denmark)

    Frost, L; Danielsen, H; Dørup, I

    1993-01-01

    Cyclosporin treatment is often accompanied by hypomagnesaemia and renal magnesium wasting, but it is unknown whether cyclosporin induces tissue magnesium depletion. Magnesium status is best evaluated by measurement of skeletal muscle magnesium content. The purpose of the present study was to eval...

  17. Cyclosporine in the Treatment of a Case of Fulminant and Refractory Acute Disseminated Encephalomyelitis

    Science.gov (United States)

    Taghdiri, Mohammd-Mehdi; Amanati, Ali; Abdolkarimi, Babak

    2011-01-01

    Background Acute disseminated encephalomyelitis (ADEM) is a rare, monophasic, demyelinating disease of the CNS which sometimes could be refractory to traditional treatment. Case Presentation We present a case of fulminant ADEM which is treated with combination of corticosteroid, intravenous immunoglobulin and cyclosporine. Conclusion Immunosuppressive agents such as cyclosporine may be effective especially in fulminant form of the disease. PMID:23056845

  18. [Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients].

    Science.gov (United States)

    Isla Tejera, B; Aumente Rubio, M D; Martínez-Moreno, J; Reyes Malia, M; Arizón, J M; Suárez García, A

    2009-01-01

    To determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients. We selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G. Being a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele. Our results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients.

  19. Edoxaban drug-drug interactions with ketoconazole, erythromycin, and cyclosporine.

    Science.gov (United States)

    Parasrampuria, Dolly A; Mendell, Jeanne; Shi, Minggao; Matsushima, Nobuko; Zahir, Hamim; Truitt, Kenneth

    2016-12-01

    Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three edoxaban drug-drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition. In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. Administration of dual inhibitors of P-gp and CYP3A4 increased edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects. © 2016 Daiichi Sankyo. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  20. Place of cyclosporin A in the therapy of rheumatic diseases

    Directory of Open Access Journals (Sweden)

    Zemfira Sadullaevna Alekberova

    2011-01-01

    Full Text Available The paper considers the major effects of cyclosporin A (CsA in rheumatic diseases (RD. CsA is noted to be effective for a number of RDs and all types of rheumatoid arthritis (RA, including in early RA in adults and juvenile RA; uveitis associated with Behcet's disease (BD (as the drug of choice; in combination with other disease-modifying drugs; in RD with concomitant viral hepatitis C. The diagnostic criteria for (BD and the efficacy of CsA for this disease are given according to different authors.

  1. Movement disorders secondary to long-term treatment with cyclosporine A.

    Science.gov (United States)

    Munhoz, Renato P; Teive, Helio A G; Germiniani, Francisco M B; Gerytch, Júlio C; Sá, Daniel S; Bittencourt, Marco A; Pasquini, Ricardo; Camargo, Carlos H F; Werneck, Lineu César

    2005-09-01

    To analyze the prevalence, severity and functional interference of movement disorders (MD) secondary to chronic use of cyclosporine A (CsA). We conducted a cross-sectional study of 60 patients (58.3% male) with mean age 23.1 (3-75) years, followed at the Bone Marrow Transplantation Service of the Hospital de Clínicas of the Federal University of Paraná, Brazil, taking CsA for at least six months. Our protocol included clinical data, assessment of functional interference of symptoms and neurological examination including observation and grading of MD. Eight (13.3%) subjects reported the presence of tremor at the moment of interview and 29 (48.3%) recalled this symptom at some point during treatment. Neurological examination identified 14 (23.3%) subjects with MD: upper limb symmetric action tremor in 13 (21.6%) and parkinsonism (rigidity and bradykinesia) in 1 (1.7%). No other MD was detected. The mean scores indicated mild clinical signs in all cases. Symptoms were considered subjectively mild with no functional interference. Almost one quarter of patients using CsA chronically presented MD, almost always mild and transitory action tremor, with minimal interference on daily living activities, not requiring any form of intervention in the majority of cases.

  2. Nephrotoxic effects of designer drugs: synthetic is not better!

    Science.gov (United States)

    Luciano, Randy L; Perazella, Mark A

    2014-06-01

    Designer drugs are synthetic, psychoactive substances with similar structures and activity to existing scheduled drugs or controlled chemical compounds. The use of these drugs is not generally considered illegal and they cannot be detected using standard toxicology tests--essentially they are considered to be 'legal highs'. Over the past several years, increasing numbers of designer drugs have become available. These drugs are classified as amphetamine derivatives, phenylpiperazine derivatives, synthetic cathinones, synthetic cannabinoids, phencyclidine derivatives and synthetic opioids. Although euphoria is the desired effect, neuropsychiatric and cardiac manifestations are frequently observed in individuals using these drugs at high doses or using drugs that are contaminated with other substances. Some designer drugs are also associated with adverse renal effects, including acute kidney injury from pigment nephropathy, acute tubular necrosis, obstructive nephropathy and hyponatraemia. The misuse of these drugs should be recognized and clinicians made aware of the potential for acute nephrotoxicity as the health burden of these compounds increases.

  3. Oral administration of ginseng ameliorates cyclosporine-induced pancreatic injury in an experimental mouse model.

    Directory of Open Access Journals (Sweden)

    Sun Woo Lim

    Full Text Available 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.

  4. Garlic supplemented diet attenuates gentamicin nephrotoxicity ın rats

    Directory of Open Access Journals (Sweden)

    Ilker Seckiner

    2014-08-01

    Full Text Available Purpose To demonstrate the effect of a 4% pulverized garlic supplemented diet on the nephrotoxicity induced by gentamicin in rats. Materials and Methods Twenty four healthy male Wistar rats, weighing between 220 - 260grams, were divided into three groups. The rats were randomly assigned to either the gentamicin injection without garlic supplementation group (Group I, n = 8, gentamicin injection with garlic supplementation group (Group II, n = 8, and control group (Group III, n = 8. Urine from the rats was collected and the volume (mL, microalbumin (mg/L, creatinine (mg/dL, Na (mmol/L, K (mmol/L, Cl (mmol/L, P (mg/dL, N-acetyl glucosamine (NAG (U/L and pH values were measured. Then urea (mg/dL, creatinine (mg/dL, total protein (g/dL and cystatin (mg/L values were measured for the blood samples obtained from tail veins. Results The median NAG value for the control group (52.050 U/L was similar to value for Group II (56.400 U/L, which received gentamicin and the garlic diet. However, the median NAG value for Group I (77.030 U/L, which received gentamicin without garlic supplementation, was determined to be statistically significantly higher (p = 0.010 than the value for the control group. In addition, the mean cystatin value for Group II (1.360 U/L was found to be statistically significantly lower than the value for the Group I (2.240 U/L (p = 0.015. Conclusions In this study we showed the effect of 4% pulverized garlic supplemented diet for preventing nephrotoxicity induced by gentamicin in rats by using as parameters NAG in urine samples and cystatin C in serum samples.

  5. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites.

    Science.gov (United States)

    Kharasch, Evan D; Schroeder, Jesara L; Liggitt, H Denny; Ensign, Dustin; Whittington, Dale

    2006-10-01

    Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites. Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed. Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone. Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These

  6. Topical cyclosporine a 0.05% eyedrops in the treatment of vernal keratoconjunctivitis - randomized placebo-controlled trial.

    Science.gov (United States)

    Keklikci, Ugur; Dursun, Birgul; Cingu, Abdullah Kursat

    2014-01-01

    Vernal keratoconjunctivitis (VKC) is a chronic, bilateral inflammation of the conjunctiva that mostly affects children and young adult males. Management of VKC is primarily aimed at reducing symptoms and preventing serious vision threatening sequelae. To assess the efficacy of topical cyclosporine A (CsA) 0.05% on the signs and symtomps in the management of VKC. This is a placebo-controlled, randomized prospective study. Sixty-two patients with VKC were included in this study. Patients were randomly assigned (1 : 1) to treatment with topical 0.05% CsA eyedrops or a placebo (artificial tears) for a period of 4 weeks, 4 times daily. Ocular signs and symptoms were in all patients scored at entry and at the end of 4 weeks. When pre-treatment mean signs and symptoms scores were compared in both groups, there was no significant difference (p > 0.05). However, mean post-treatment scores as regards signs and symptoms were found to be lower in cyclosporine group than those in placebo group (p < 0.001). No side effects of the treatment with CsA 0.05% eyedrops were observed. It was found that topical CsA 0.05% eyedrops were safe and effective in the treatment of patients with VKC.

  7. Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone.

    Science.gov (United States)

    Staub, J; Pfannschmidt, N; Strohal, R; Braun-Falco, M; Lohse, P; Goerdt, S; Leverkus, M

    2015-11-01

    The group of autoinflammatory syndromes associated with Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis are poorly defined and difficult to control with currently available treatment modalities. We describe a patient with PASH syndrome and report about the successful multimodal treatment with infliximab, cyclosporine, and dapsone. A review of the available literature to date about this group of autoinflammatory diseases was performed. We performed genetic analysis for PSTPIP1 mutations associated with PAPA syndrome. A 22-year-old woman presented to our department with pyoderma gangrenosum, concomitant acne, and suppurative hidradenitis. She had previously been treated unsuccessfully with etanercept, adalimumab, fumaric acid and the IL-1 receptor antagonist (IL-1RA) anakinra without prolonged remission. Treatment with intravenous infliximab in combination with cyclosporine and dapsone lead to sudden and prolonged improvement of the clinical symptoms that we classified as PASH syndrome. We review the literature about this group of diseases and report the third case of PASH syndrome to date. PASH syndrome and associated diseases should be considered whenever hidradenitis suppurativa is found in association with pyoderma gangrenosum. We provide a systematic overview about PASH syndrome and suggest a novel multimodal therapeutic regimen beyond isolated inhibition of TNF or IL-1. © 2014 European Academy of Dermatology and Venereology.

  8. Effect of Topical Cyclosporine in grading of Vernal keratoconjunctivitis.

    Directory of Open Access Journals (Sweden)

    Dr Krupali Raol

    2017-06-01

    Full Text Available Background & Objective: To evaluate efficacy of topical aqueous solution of 0.05% cyclosporine in first time diagnosed vernal keratoconjunctivitis (VKC including palpebral, bulbar and mixed form. Methods: 25 patients of VKC received CsA 0.05% aqueous ophthalmic solution in a dosage of one drop every 12 hours in both eyes for 6 months. Follow up visits (day 1, 2 weeks, 1 month, 2 months, 3 months and 6 months. Five symptoms were evaluated and six clinical signs were charted. Total objective score of 13 or more over atleast 3 variables was included (CART – scoring system. Results: Comparison of 1st Day with 2 weeks score showed no significant effect in the score value (t=0.90, df = 24, p<0.1. 1st Day with 3rd month score showed maximum effect in the score value (t = 35.76, df = 24, p<0.0001. 3rd month with 6th month score showed sustained effect of cyclosporine showing no major change in the score line (t test, t = 1.80, df = 24, p <0.05. Conclusion: Topical application of a 0.05% CsA aqueous solution has been shown to be effective in the treatment of patients with VKC. CsA could be an important alternative to steroid treatment.

  9. Effect of nettle (Urtica dioica extract on gentamicin induced nephrotoxicity in male rabbits

    Directory of Open Access Journals (Sweden)

    Nadia Abdulkarim Salih

    2015-09-01

    Conclusions: Therefore, it can be assumed that the nephroprotective effect shown by nettle in gentamicin-induced nephrotoxicity can reserve intracellular levels of biological pathways and supportively enhance excretion of toxic levels of gentamicin.

  10. [Cyclosporine eye drops: A 4-year retrospective study (2009-2013)].

    Science.gov (United States)

    Kauss Hornecker, M; Charles Weber, S; Brandely Piat, M-L; Darrodes, M; Jomaa, K; Chast, F

    2015-10-01

    The University Hospitals Paris Centre Pharmacy compounds three concentrations of cyclosporine eye drops: 20mg/mL (=2%); 5mg/mL (=0.5%) and 0.5mg/mL (=0.05%). Cyclosporine A 2% drops were developed in 1995 to prevent the rejection of high-risk cornea transplants after failure of topical steroids. The other concentrations of eye drops were developed for the treatment of various immune or inflammatory diseases of the cornea, conjunctiva and uvea. These eye drops are dispensed with a physician's prescription to hospitalized or ambulatory patients. A retrospective study over 4 years (2009-2013) was conducted to analyze the details of prescription and possible adverse events. Dispensations made from January 1st, 2009 through December 31st, 2013 were studied, including patient age, dose of cyclosporine and practice location of prescribing physician. We also recorded the indications for cyclosporine eye drops in a sample of ambulatory patients. The analysis of local tolerability and the effect on visual comfort was based on questionnaires sent to the patients on cyclosporine 2% over a period of 2 months. Cyclosporine eye drops prescription grew continuously from 2009 through 2013 for all concentrations. In 2013, 5,859 patients were treated, among which 3,616 patients with topical cyclosporine 2%, 1,681 patients with 0.5%, and 562 patients with 0.05%. In total, this represents 62,621 eye drops. Treated patients ranged from 1 week to 100 years old. Topical 2% cyclosporine is indicated in 61% of cases to prevent high-risk corneal graft rejection. Other indications are corneal ulcer (6%), atopic keratoconjunctivitis (5%), vernal keratoconjunctivitis (5%) and herpetic keratitis (4%). Topical 0.5% cyclosporine is prescribed primarily for dry eye syndrome (20%) and to prevent rejection of high-risk corneal transplantation (11%), to treat ocular rosacea (10%), vernal keratoconjunctivitis (10%), atopic keratoconjunctivitis (8%) and Sjögren's syndrome (7%). Topical 0

  11. Enhancement of physicochemical properties of nanocolloidal carrier loaded with cyclosporine for topical treatment of psoriasis: in vitro diffusion and in vivo hydrating action.

    Science.gov (United States)

    Musa, Siti Hajar; Basri, Mahiran; Fard Masoumi, Hamid Reza; Shamsudin, Norashikin; Salim, Norazlinaliza

    2017-01-01

    Psoriasis is a chronic autoimmune disease that cannot be cured. It can however be controlled by various forms of treatment, including topical, systemic agents, and phototherapy. Topical treatment is the first-line treatment and favored by most physicians, as this form of therapy has more patient compliance. Introducing a nanoemulsion for transporting cyclosporine as an anti-inflammatory drug to an itchy site of skin disease would enhance the effectiveness of topical treatment for psoriasis. The addition of nutmeg and virgin coconut-oil mixture, with their unique properties, could improve cyclosporine loading and solubility. A high-shear homogenizer was used in formulating a cyclosporine-loaded nanoemulsion. A D-optimal mixture experimental design was used in the optimization of nanoemulsion compositions, in order to understand the relationships behind the effect of independent variables (oil, surfactant, xanthan gum, and water content) on physicochemical response (particle size and polydispersity index) and rheological response (viscosity and k-value). Investigation of these variables suggests two optimized formulations with specific oil (15% and 20%), surfactant (15%), xanthan gum (0.75%), and water content (67.55% and 62.55%), which possessed intended responses and good stability against separation over 3 months' storage at different temperatures. Optimized nanoemulsions of pH 4.5 were further studied with all types of stability analysis: physical stability, coalescence-rate analysis, Ostwald ripening, and freeze-thaw cycles. In vitro release proved the efficacy of nanosize emulsions in carrying cyclosporine across rat skin and a synthetic membrane that best fit the Korsmeyer-Peppas kinetic model. In vivo skin analysis towards healthy volunteers showed a significant improvement in the stratum corneum in skin hydration.

  12. Effects of aspirin, prednisolone and indomethacin on nephrotoxic serum nephritis in the rat.

    OpenAIRE

    Kurokawa, H.; Sakamoto, K.

    1982-01-01

    1 The effects of aspirin, prednisolone, and indomethacin on nephrotoxic serum nephritis in rats was studied. The nephritis was induced by a single intravenous injection of nephrotoxic serum (NTS, rabbit anti-serum against the water-soluble renal antigen of the rat). The injection of NTS induced the heterologous phase of proteinuria (within a day after NTS injection) and then the autologous phase (5 to 7 days after NTS injection). The effect of drugs given before the NTS (i.e. prophylactically...

  13. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway.

    Science.gov (United States)

    Kharasch, Evan D; Schroeder, Jesara L; Liggitt, H Denny; Park, Sang B; Whittington, Dale; Sheffels, Pamela

    2006-10-01

    Methoxyflurane nephrotoxicity results from biotransformation; inorganic fluoride is a toxic metabolite. Concern exists about potential renal toxicity from volatile anesthetic defluorination, but many anesthetics increase fluoride concentrations without consequence. Methoxyflurane is metabolized by both dechlorination to methoxydifluoroacetic acid (MDFA, which may degrade to fluoride) and O-demethylation to fluoride and dichloroacetatic acid. The metabolic pathway responsible for methoxyflurane nephrotoxicity has not, however, been identified, which was the aim of this investigation. Experiments evaluated methoxyflurane metabolite formation and effects of enzyme induction or inhibition on methoxyflurane metabolism and toxicity. Rats pretreated with phenobarbital, barium sulfate, or nothing were anesthetized with methoxyflurane, and renal function and urine methoxyflurane metabolite excretion were assessed. Phenobarbital effects on MDFA metabolism and toxicity in vivo were also assessed. Metabolism of methoxyflurane and MDFA in microsomes from livers of pretreated rats was determined in vitro. Phenobarbital pretreatment increased methoxyflurane nephrotoxicity in vivo (increased diuresis and blood urea nitrogen and decreased urine osmolality) and induced in vitro hepatic microsomal methoxyflurane metabolism to inorganic fluoride (2-fold), dichloroacetatic acid (1.5-fold), and MDFA (5-fold). In contrast, phenobarbital had no influence on MDFA renal effects in vivo or MDFA metabolism in vitro or in vivo. MDFA was neither metabolized to fluoride nor nephrotoxic. Barium sulfate diminished methoxyflurane metabolism and nephrotoxicity in vivo. Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride

  14. Effects of cyclosporine on osteoclast activity: inhibition of calcineurin activity with minimal effects on bone resorption and acid transport activity.

    Science.gov (United States)

    Williams, John P; McKenna, Margaret A; Thames, Allyn M; McDonald, Jay M

    2003-03-01

    Cyclosporine results in rapid and profound bone loss in transplant patients, an effect ascribed to osteoclasts. Cyclosporine, complexed with the appropriate immunophilin, inhibits calcineurin (the calcium/calmodulin dependent serine/threonine phosphatase) activity. We tested the hypothesis that cyclosporine inhibits calcineurin activity in osteoclasts, resulting in stimulation of osteoclast activity. We compared the effects of cyclosporine A and the calmodulin antagonist, tamoxifen, on bone resorption by avian osteoclasts. Tamoxifen inhibits bone resorption approximately 60%, whereas cyclosporine A only inhibited bone resorption 12%. One-hour treatment with 100 nM cyclosporine inhibited osteoclast calcineurin activity 70% in whole cell lysates, whereas 10 microM tamoxifen only inhibited calcineurin activity 25%. We compared the effects of cyclosporine A and tamoxifen on acid transport activity in isolated membrane vesicles and in isolated membrane vesicles obtained from osteoclasts treated with cyclosporine A or tamoxifen under conditions that inhibit calcineurin activity. Direct addition of cyclosporine A in the acid transport assay, or pretreatment of cells with cyclosporine A followed by membrane isolation, had no effect on acid transport activity in membrane vesicles. In contrast, direct addition of tamoxifen to membranes inhibits acid transport activity, an effect that can be prevented by addition of exogenous calmodulin. Furthermore, acid transport activity was also inhibited in membrane vesicles isolated from cells treated with tamoxifen. In conclusion, cyclosporine A inhibits osteoclast calcineurin activity; however, calcineurin inhibition does not correspond to a significant effect on acid transport activity in isolated membrane vesicles or bone resorption by osteoclasts.

  15. Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity.

    Science.gov (United States)

    Choi, Yookyung Christy; Saw, Stephen; Soliman, Daniel; Bingham, Angela L; Pontiggia, Laura; Hunter, Krystal; Chuang, Linda; Siemianowski, Laura A; Ereshefsky, Benjamin; Hollands, James M

    2017-11-01

    A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] obesity class I and II (BMI 30-39.9kg/m 2 ), and obesity class III (BMI≥40 kg/m 2 ) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P20 mg/L ( Pobesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

  16. Clinical experience with systemic cyclosporine A treatment in severe childhood psoriasis.

    Science.gov (United States)

    Bulbul Baskan, Emel; Yazici, Serkan; Tunali, Sukran; Saricaoglu, Hayriye

    2016-08-01

    Severe forms of psoriasis including erythrodermic or pustular psoriasis, which require a more aggressive therapeutic approach such as phototherapy or systemic therapies, are rarely seen. Systemic toxicity and long-term safety of these agents are serious concerns in children. We report our experience on the efficacy and safety of cyclosporine A treatment in 22 patients of childhood psoriasis. We retrospectively analyzed the records of all patients less than 18 years of age treated with systemic cyclosporine A therapy at our clinic between January 2000 and March 2009. Demographic features as well as other relevant data including previous therapies, the dosage and duration of cyclosporine A therapy, response to treatment and side effects were retrieved from the patients' records. A total of 22 children were treated with systemic cyclosporine A therapy. Seventeen patients were found to be excellent responders. The mean therapeutic dosage of cyclosporine A was 3.47 ± 0.62 mg/kg/day. The mean duration of cyclosporine A therapy was 5.68 ± 3.29 months. The median time to total clearance of the lesions was 4.0 weeks. We conclude that cyclosporine A therapy is equally effective and safe in pediatric psoriasis patients as in adults.

  17. Treatment relapsed subcutaneous panniculitis-like T-cell lymphoma together HPS by Cyclosporin A

    Directory of Open Access Journals (Sweden)

    Ren'an Chen

    2010-11-01

    Full Text Available A 25-year-old man was diagnosised subcutaneous panniculitis-like T-cell lymphoma (SPTCL through biopsy of a nodule from the anterior chest. After the treatment with prednisone 90 mg 3 weeks and tapered off in 1 month, the disease released, but relapsed together with symptions of hemophagocytic syndrome eight months after the termination of prednisone. CHOEP recipe was given but with unsatisfactory result until cyclosporine was prescribed. Cyclosporine was removed 6 months later. There is no evidence of clinical relapse 1 year later. This case suggest that cyclosporine could be a selectable treatment even in relapsed SPTCL.

  18. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  19. Contrast-media-induced nephrotoxicity: a consensus report

    Energy Technology Data Exchange (ETDEWEB)

    Morcos, S.K.; Thomsen, H.S.; Webb, J.A.W. [Department of Diagnostic Imaging, Northern General Hospital NHS Trust, Sheffield (United Kingdom)

    1999-10-01

    The purpose of this study was, using consensus methodology, to document current understanding of contrast media nephrotoxicity (CMN) and to identify areas where there is disagreement or confusion. To draw up guidelines for avoiding CMN based on the current understanding of the condition established by the survey. One hundred sixty-four statements were mailed to 148 members of the European Society of Urogenital Radiology (ESUR) and to 48 experts in the field of CMN. They were asked about the definition, clinical features, predisposing factors and pathophysiology of CMN and about prophylactic measures. The importance of the statements was rated on a scale from 1 to 10 (1 least important, 10 most important). Fifty-three members (38 %) and 23 experts (48 %) responded. Both groups considered that an increase in serum creatinine that peaks within 3-4 days and a decrease in creatinine clearance are the most important (rating > 7) features of CMN. Enzymuria was not considered important (rating < 6). Pre-existing renal insufficiency, diabetic nephropathy, dehydration, congestive heart failure, concurrent administration of nephrotoxic drugs and the dose and type of contrast media were considered to be risk factors. Reduction in renal perfusion and damage to tubular cells were considered the main factors in the pathophysiology of CMN (rating > 6). Hydration and the use of low osmolar contrast media were thought to minimize the incidence of CMN (rating > 6). The majority of the responders (84.6 % of members and 95.5 % of experts) believe that the incidence of CMN in patients with normal renal function is less than 5 %. Of the members, 62.5 %, and 35.3 % of experts, believe that the incidence of CMN is 20-30 % in the presence of risk factors. There was disagreement about the definition of CMN, the threshold dose of contrast media above which renal complications may develop, the safe period between repeat injections, the relevance of contrast media renal retention shown on CT

  20. Cyclosporine increases muscular force generation in Duchenne muscular dystrophy.

    Science.gov (United States)

    Sharma, K R; Mynhier, M A; Miller, R G

    1993-03-01

    We investigated the effect of cyclosporine (CsA) on force generation in 15 boys with Duchenne muscular dystrophy (DMD) by obtaining monthly measures of tetanic force and maximum voluntary contraction (MVC) of both anterior tibial muscles. During 4 months of a natural history phase, both tetanic force and MVC declined significantly. During 8 weeks of CsA treatment (5 mg/kg/day), significantly increased tetanic force (25.8 +/- 6.6%) and MVC (13.6 +/- 4.0%) occurred within 2 weeks. The maximum mean increase during treatment was 35.2 +/- 5.9% (tetanic force) and 19.0 +/- 4.6% (MVC). Side effects from CsA, gastrointestinal and flu-like symptoms, were transient and self-limiting. Thus, as previously reported with prednisone, CsA increases muscular force generation in the anterior tibial muscles of DMD patients.

  1. Cyclosporin-A induced Posterior Reversible Encephalopathy Syndrome

    Directory of Open Access Journals (Sweden)

    Saeed Bassam

    2008-01-01

    Full Text Available Posterior reversible encephalopathy syndrome (PRES is a recently proposed clinico-neuroradiological entity observed in a variety of clinical settings such as cyclosporin A (CsA neurotoxicity. We report a 3.5-year-old Syrian boy in whom steroid-resistant focal segmental glomerulosclerosis (FSGS was recently diagnosed. The patient remitted his nephrotic syndrome after 10 days of CsA administration. However, he shortly developed altered mental status, visual impairment, focal neurological deficits and seizures. We discontinued CsA that resulted in complete reversal of the patient′s encephalopathical condition over a period of 4 months. We conclude that PRES should be suspected in immunosuppresed patients with kidney disease if they have a sudden episode of neurological symptoms.

  2. Cyclosporine monotherapy in cardiac transplantation: review of the literature.

    Science.gov (United States)

    Sansone, Fabrizio; Rinaldi, Mauro

    2011-10-01

    The immunosuppressive therapy after organ transplantation should be tailored to balance the tolerance and the reaction of the recipient against the graft to avoid lack of immunosuppression or an excess of drugs. The drugs currently used may induce serious side effects with negative impact on recipient's survival and quality of life even if lack of immunosuppression may induce acute graft rejection and patient's death. The introduction of new drugs as mammalian target of rapamycin (mTOR) inhibitors allows tailoring of the immunosuppressive therapy on patient characteristics, by the use of drug association and the reduction of the overall dose. There are few cases where the necessity of reduction of the immunosuppressive therapy should be considered, as what happens in cases of severe systemic infections. Some anecdotal reports of the use of cyclosporine monotherapy (CM) in heart transplantation have been presented many years ago: the main limitations of these reports were the reasons of the switch to CM and the limited number of patients that did not allow clarification of the indications and the applicability of the CM. The aim of our review is to offer an up-to-date research of the use of CM after heart transplantation for physicians enrolled in the management of such complicated patients. The discussion will start from the kidney and liver transplantation and will arrive to the heart transplantation. However, we suggest a very careful selection of patients to be treated with CM because the use must be restricted to cases of severe side effects caused by multiple therapies because the multiple approaches has the main advantage of the synergistic action of the drugs. In conclusion, CM must be use for selected low-immunologic-risk patients, and it could be carefully used for stable patients over the long-term follow-up when the risk of acute rejection has nearly disappeared. Our article is of historical interest since we do not use anymore cyclosporine monotherapy

  3. P-Glycoprotein Induction Ameliorates Colistin Induced Nephrotoxicity in Cultured Human Proximal Tubular Cells

    Science.gov (United States)

    Lee, Sun-hyo; Kim, Jin-sun; Ravichandran, Kameswaran; Gil, Hyo-Wook; Song, Ho-yeon; Hong, Sae-yong

    2015-01-01

    The pathogenesis of colistin induced nephrotoxicity is poorly understood. Currently there are no effective therapeutic or prophylactic agents available. This study was aimed to determine the mechanism of colistin induced nephrotoxicity and to determine whether P-glycoprotein (P-gp) induction could prevent colistin induced nephrotoxicity. Colistin induced cell toxicity in cultured human proximal tubular cells in both dose and time dependent manner. Colistin provoked ROS in a dose dependent manner as measured by DCF-DA. To investigate apoptosis, caspase 3/7 activity was determined. Caspase 3/7 activity was increased dose dependently (25, 50, 100 μg/ml) at 6 h. Autophagosome formation was assessed by measuring LC3- II/LC3-I ratio. The ratio of LC3-II to LC3- I was increased at 2 h (25 μg/ml). Suppression of autophagosome formation increased colistin induced nephrotoxicity. The expression of P-gp and the cell toxicity was determined in colistin with or without dexamethasone (P-gp inducer) and verapamil (selective P-gp inhibitor). Colistin itself suppressed the expression of P-gp. P-gp expression and activity decreased colistin induced nephrotoxicity with dexamethasone treatment. In addition induced P-gp transporter was shown to improve the efflux effect on colistin treated HK2 cell line, which was demonstrated by calcein-AM fluorescence accumulation assay. The increased activity could be blocked by N-acetylcysteine. In conclusion, colistin induces nephrotoxicity by suppressing P-gp. Induction of P-gp could ameliorate colistin induced nephrotoxicity by decreasing apoptosis. PMID:26287374

  4. P-Glycoprotein Induction Ameliorates Colistin Induced Nephrotoxicity in Cultured Human Proximal Tubular Cells.

    Directory of Open Access Journals (Sweden)

    Sun-hyo Lee

    Full Text Available The pathogenesis of colistin induced nephrotoxicity is poorly understood. Currently there are no effective therapeutic or prophylactic agents available. This study was aimed to determine the mechanism of colistin induced nephrotoxicity and to determine whether P-glycoprotein (P-gp induction could prevent colistin induced nephrotoxicity. Colistin induced cell toxicity in cultured human proximal tubular cells in both dose and time dependent manner. Colistin provoked ROS in a dose dependent manner as measured by DCF-DA. To investigate apoptosis, caspase 3/7 activity was determined. Caspase 3/7 activity was increased dose dependently (25, 50, 100 μg/ml at 6 h. Autophagosome formation was assessed by measuring LC3- II/LC3-I ratio. The ratio of LC3-II to LC3- I was increased at 2 h (25 μg/ml. Suppression of autophagosome formation increased colistin induced nephrotoxicity. The expression of P-gp and the cell toxicity was determined in colistin with or without dexamethasone (P-gp inducer and verapamil (selective P-gp inhibitor. Colistin itself suppressed the expression of P-gp. P-gp expression and activity decreased colistin induced nephrotoxicity with dexamethasone treatment. In addition induced P-gp transporter was shown to improve the efflux effect on colistin treated HK2 cell line, which was demonstrated by calcein-AM fluorescence accumulation assay. The increased activity could be blocked by N-acetylcysteine. In conclusion, colistin induces nephrotoxicity by suppressing P-gp. Induction of P-gp could ameliorate colistin induced nephrotoxicity by decreasing apoptosis.

  5. Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity.

    Science.gov (United States)

    Dayan, A D

    2016-01-01

    Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity. © The Author(s) 2015.

  6. Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity

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    Blanca Humanes

    2015-01-01

    Full Text Available Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs. Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

  7. Prevention of contrast media nephrotoxicity--the story so far

    Energy Technology Data Exchange (ETDEWEB)

    Morcos, S.K. E-mail: sameh.morcos@sth.nhs.uk

    2004-05-01

    Contrast media nephrotoxicity (CMN) in patients with pre-existing renal impairment remains a clinically significant problem. The first step to reduce the chance of CMN is to identify patients at risk through the use of screening questionnaires and renal function measurement. Patients at risk requiring injection of contrast medium (CM) because of important clinical indications should receive a small dose of either non-ionic iso-osmolar dimeric or non-ionic low osmolar monomeric CM and hydration. Intravenous infusion (1 ml/kg body weight/h) of 0.9% saline starting 4 h before CM injection and continuing for at least 12 h afterwards is effective in reducing the incidence of CMN. Prophylactic haemodialysis does not lower the risk of this complication. The value of pharmacological manipulation with renal vasodilators (calcium channel blockers, dopamine, atrial natriuretic peptide, fenoldopam (selective dopamine-1 receptor agonist), prostaglandin E{sub 1}, non-selective adenosine receptors antagonist (theophylline), non-selective endothelin receptor antagonist or the antioxidant acetylcysteine has not been fully proven. However, haemofiltration for several hours before and after contrast medium injection offers good protection against CMN in patients with advanced renal disease.

  8. [Effect of cyclosporine and simulect mono and combination therapy on cardiac allo-transplantation in rats].

    Science.gov (United States)

    Xiong, Hai-Bo; Xia, Sui-Sheng; Huang, Zu-Fal; Ye, Qi-Fa; Wen, Hao

    2005-10-01

    To observe the effect of cyclosporine and simulect mono or combination therapy on cardiac allo-transplantation in rats. Recipients with allografts were treated with different doses of cyclosporine and/or simulect after cardiac allo-transplantation. Graft survival time was observed; the histopathological examination of graft tissues was performed; and levels of serum IL-2 and IL-4 were determined. Mono or combination therapy with cyclosporine and/or simulect increased the survival of cardiac allografts. With the prolongation of survival time of the grafts, the rejection of grafts was moderated. The serum IL-2 level increased in acute rejected grafts; the serum IL-4 level increased evidently in long survival grafts. Cyclosporine and simulect have an effect in the prolongation of cardiac allograft survival in rats, and the combination therapy shows an evident synergistic effect.

  9. Acute effect of nitroglycerin on cyclosporine-induced hypertension after cardiac transplantation

    National Research Council Canada - National Science Library

    Sudano, I; Farshad, M; Flammer, A J; Spieker, L; Periat, D; Enseleit, F

    2010-01-01

    .... The sample included 18 cyclosporine-induced hypertensive patients (HTX group) scheduled for elective cardiac catheterization following heart transplantation, as well as 6-matched essential hypertensive patients (HT group...

  10. OF THE APPLICATION OF THE CYCLOSPORINE GENERICS IN THE PEDIATRIC RHEUMATOLOGY

    Directory of Open Access Journals (Sweden)

    S.I. Valieva

    2007-01-01

    Full Text Available The article presents the findings of the research dedicated to the efficacy, bioavailability and safety of the generic medications and authentic cyclosporine a. it shows that the application of the generic medications leads both to the reduction in the treatment efficacy and development of the severe side effects. It also presents the information on the qualitative and quantitative contents of cyclosporine a generic medications. Neither of the tested medications complied with authentic Sandimmune Neoral in terms of qualitative and quantitative contents. Likewise, neither of the generic medications has the microemulsive form, which provides for the uniform absorption of a medication and its bioavailability. There are also clinical examples of the application experience, regarding cyclosporine a generic medications among the patients with severe systemic rheumatoid arthritis. The application of the generic medications proved to be ineffective and was accompanied by the growth of renal toxicity.Key words: cyclosporine generics, children, juvenile rheumatoid arthritis.

  11. Intermittent oral cyclosporin for recurrent herpes simplex-associated erythema multiforme.

    Science.gov (United States)

    Bakis, Sophie; Zagarella, Samuel

    2005-02-01

    Recurrent erythema multiforme is one of three distinct clinical subtypes of erythema multiforme. We present a 42-year-old man with a 10-year history of recurrent herpes simplex virus-induced erythema multiforme. Our patient was debilitated by the frequency of his attacks and the associated pain, for which he often required leave from work. The frequency, duration and morbidity of the attacks were poorly controlled using oral prednisone and oral aciclovir. Three episodes of his recurrent herpes simplex virus-induced erythema multiforme were treated with intermittent oral cyclosporin. Oral cyclosporin rapidly reduced his symptoms and led to rapid resolution of his erythema multiforme, provided the cyclosporin was commenced on day 1 or 2 of the erythema multiforme episode. Consequently, his quality of life has dramatically improved. We recommend the use of intermittent oral cyclosporin for recurrent, debilitating episodes of erythema multiforme.

  12. Vernal shield ulcers treated with frequently installed topical cyclosporine 0.05% eyedrops.

    Science.gov (United States)

    Westland, Tim; Patryn, Eliza K; Nieuwendaal, Carla P; van der Meulen, Ivanka J E; Mourits, Maarten P; Lapid-Gortzak, Ruth

    2017-01-24

    To report on the beneficial results of an intense regimen of 0.05% cyclosporine eye drops, eight times a day in patients with therapy resistant vernal shield ulcers. Case cohort of four eyes of three male children with vernal keratoconjunctivitis complicated by shield ulcers, who were treated with frequent cyclosporine 0.05% eye drops and observed for up to 5 years. Quick resolution of the shield ulcers and complete re-epithelialization within 14-25 days was observed after adding intensive treatment with cyclosporine 0.05% to regular anti-inflammatory, histamine blocking, and surgical therapy. In one patient, additional scraping of the bottom of the ulcer was needed. In patients with vernal shield ulcers, frequent installation of low-concentration cyclosporine eye drops seems to have a promising therapeutical value.

  13. Transglutaminase 2 expression is significantly increased in cyclosporine-induced gingival overgrowth

    OpenAIRE

    Asioli, Sofia; Righi, Alberto; Cardone, Pietro; Aimetti, Mario; Maletta, Francesca; Coda, Renato; Carossa, Stefano; Navone, Roberto; Cassoni, Paola

    2011-01-01

    Cyclosporine A is a potent immunosuppressant used to prevent organ transplant rejection and treat various autoimmune diseases. However, cyclosporine A can also induce gingival overgrowth, which is characterized by increased extracellular matrix due to an altered balance between collagen synthesis and degradation. This study proposed to verify whether trans-glutaminase 2, an enzyme thought to be responsible for the assembly and remodelling of extracellular matrix, plays any role in the path...

  14. Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis

    DEFF Research Database (Denmark)

    Sjöberg, Mats; Walch, Andrea; Meshkat, Mina

    2012-01-01

    Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives.......Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives....

  15. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation.

    Science.gov (United States)

    Rosenberg, Paul B; Vriesendorp, Ank E; Drazner, Mark H; Dries, Daniel L; Kaiser, Patricia A; Hynan, Linda S; Dimaio, J Michael; Meyer, Daniel; Ring, W Steves; Yancy, Clyde W

    2005-09-01

    Cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-sparing cyclosporine-free induction regimen consisting of the early administration basiliximab, an interleukin-2 receptor monoclonal antibody, followed by the late initiation of cyclosporine on post-operative Day 4. Between September 1998 and December 1999, we treated 25 patients at risk for post-operative renal dysfunction (high-risk basiliximab group) with the new induction regimen and another 33 patients not at risk (low-risk CsA group) for renal dysfunction with our standard cyclosporine protocol. We identified a historical control group (1996 through 1998) of 32 patients at risk for renal dysfunction (high-risk CsA group) who had received our standard cyclosporine protocol. The increase in serum creatinine levels after transplantation was less in the high-risk basiliximab group (-0.1 +/- 0.7) than in the high-risk CsA group (0.5 +/- 1.0, p cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.

  16. Immunosuppressive and antiparasitic effects of cyclosporin A on Hymenolepis nana infection in mice.

    Science.gov (United States)

    Matsuzawa, K; Nakamura, F; Abe, M; Okamoto, K

    1998-04-01

    The effect of cyclosporin A, which is known to act both as immunosuppressant and as an antiparasitic drug in many host-parasite systems, was examined in a mouse-Hymenolepis nana system. When BDF1 mice were injected s.c. with cyclosporin A (100 mg kg-1 day-1) every 48 h from 11 days p.i. with eggs, expulsion of the adult worms from the intestines of mice was prevented completely until at least 30 days p.i. Worm burden, dry weight and the number of gravid proglottids were not significantly reduced. By contrast, in untreated mice most of the worms were eliminated by 19 days p.i. The drug also completely abolished acquired resistance to a challenge infection with eggs when mice were injected s.c. with cyclosporin A (100 mg kg-1 day-1) around the time of challenge infection (Days -2, -1, 0, 1 and 2 relative to challenge). Such immunosuppressive effects of cyclosporin A on worm expulsion and protective immunity to reinfection were similar to those of another immunosuppressant, cyclophosphamide. As for the antiparasitic action of cyclosporin A against H. nana, a smaller number of cysticercoids developed from eggs in mice given cyclosporin A (100 mg kg-1 day-1) for 5 days beginning 1 day before infection, than in untreated controls.

  17. Effects of cyclosporin at various concentrations on dexamethasone intracellular uptake in multidrug resistant cells

    Science.gov (United States)

    Maillefert, J; Duchamp, O; Solary, E; Genne, P; Tavernier, C

    2000-01-01

    BACKGROUND—The multidrug resistance phenomenon results from the expression of P-glycoprotein (P-gp), a drug-efflux pump. Corticosteroids are substrates for P-gp, whose function can be inhibited by cyclosporin. This study evaluates the ability of cyclosporin to modulate dexamethasone uptake in multidrug resistant cells.
METHODS—The K 562 cell line, which does not express P-gp and a P-gp expressing clone, K562/ADM, were used. Cells were incubated with H3-dexamethasone in the absence or presence of cyclosporin at various concentrations. Then, cells were washed, lysed, and radioactivity was measured.
RESULTS—The uptake of dexamethasone alone was higher in sensitive than in resistant cells. Addition of cyclosporin induced a dose dependent increase of dexamethasone uptake in resistant cells, whereas the drug did not influence dexamethasone uptake in parental cells.
CONCLUSION—Cyclosporin, at therapeutic concentrations induces a moderate, but significant increase in dexamethasone accumulation in multidrug resistant cells. Thus, cyclosporin might increase the intestinal absorption of corticosteroids or their accumulation in mononuclear cells, or both, thereby increasing their therapeutic efficacy.

 PMID:10666173

  18. Topical Use of Olopatadine and Cyclosporine a in Treatment of Vernal Keratoconjunctivitis

    Directory of Open Access Journals (Sweden)

    Zaure Knatova

    2016-07-01

    Full Text Available Aim: To compare the efficacy and safety of Olopatadine hydrochloride (0.1% with Cyclosporine A ophthalmic solution (0.05% in treating the signs and symptoms of VKC. Material and Method: Twenty-five patients with VKC were included in a prospective study. One eye of each patient was treated with Olopatadine while the other eye was treated with Cyclosporine A. Subjective symptoms of the patients such as itching, tearing, foreign body sensation, and mucus discharge were recorded and scored. The objective signs, such as the presence of giant papillae on the tarsal conjunctiva, bulbar conjunctival hyperemia, keratitis, limbal hypertrophy, corneal vascularization, and conjunctival cicatrization, were scored. Results: There was no significant difference between the Olopatadine group and the Cyclosporine A group regarding subjective symptoms at the 3rd, 6th, 12th, and 18th month. There was a significant improvement in the subjective symptoms of both groups. No significant difference was seen between the groups with regard to objective signs. A significant improvement was observed in the Cyclosporine group in the late period of the study. Discussion: In long-term therapy of VKC, similar effects were seen regarding improvement in the subjective symptoms during the use of topical Olopatadine and Cyclosporine A. In terms of improvement regarding the objective signs, Cyclosporine A was seen to be more effective in the late period.

  19. Effects of immunosuppression induced by thalidomide and cyclosporine in heterotopic heart transplantation in rabbits.

    Science.gov (United States)

    Carvalho, J B V; Petroianu, A; Travolo, E; de Oliveira, B H; Duarte, A B B; Alberti, L R

    2007-06-01

    Because of its anti-inflammatory and immunodepressive effects, thalidomide has been used for the treatment of dermatologic diseases and of host-versus-graft reactions in patients undergoing bone marrow transplantation. We evaluated the immunosuppressive action of thalidomide alone or in combination with cyclosporine on the prevention of rejection of heterotopic cardiac allografts in rabbits. Fifty rabbits were used including 25 donors and 25 recipients. Recipient animals were divided into five groups (n = 5 each): group 1 (control), non-immunosuppressed animals; group II, animals immunosuppressed with cyclosporine (10 mg/kg per day); group III, immunosuppressed with thalidomide (100 mg/kg per day); group IV, immunosuppressed with cyclosporine (5.0 mg/kg per day); and group V, immunosuppressed with cyclosporine (5.0 mg/kg per day) in combination with thalidomide (50 mg/kg per day). The medications were administered through an orogastric catheter starting on the day before the transplant. The heart of the donor was implanted into the recipient's abdomen. The combination of thalidomide and cyclosporine showed the lowest histopathological rejection score (P cyclosporine was effective against rejection, significantly increasing survival (P < .01). Thalidomide may be considered to be an adjuvant immunosuppressant.

  20. Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism.

    Science.gov (United States)

    Wang, Yimin; Luo, Xiao; Pan, Hao; Huang, Wei; Wang, Xueping; Wen, Huali; Shen, Kezhen; Jin, Baiye

    2015-09-01

    Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1β followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice. Copyright © 2015. Published by Elsevier Ltd.

  1. Melatonin can attenuate ciprofloxacin induced nephrotoxicity: Involvement of nitric oxide and TNF-α.

    Science.gov (United States)

    Shaki, Fatemeh; Ashari, Sorour; Ahangar, Nematollah

    2016-12-01

    Ciprofloxacin is a synthetic broad-spectrum antimicrobial agent of fluoroquinolone family. The aim of our investigation was to evaluate the role of oxidative damage and inflammation in nephrotoxic potential of Ciprofloxacin and protective effects of melatonin against its nephrotoxicity in male Wistar rats. The animals were divided into six groups: Control, ciprofloxacin (100mg/kg/day, i.p), ciprofloxacin with three doses (2.5, 5 and 10mg/kg/day) of melatonin and a group which received ciprofloxacin (100mg/kg/day) plus vitamin E (100mg/kg/day) for 8 consecutive days. 24h after last injection, the animals were euthanized and kidney tissues were separated. Finally reactive oxygen species, glutathione content, lipid peroxidation, protein carbonyl, nitric oxide and TNF-α were evaluated. Also, pathological examination and measuring of kidney biochemical markers (BUN and Cr) were done. The administration of ciprofloxacin for 8days resulted in significant increase (Pmelatonin was able to protect against deterioration in nephrotoxic markers and suppressed the increase in oxidative stress and inflammatory markers. Our study showed the critical role of oxidative damage and inflammation in ciprofloxacin-induced nephrotoxicity that markedly inhibited by administration of melatonin. So, melatonin can be suggested for prevention of ciprofloxacin-induced nephrotoxicity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Effect of Coenzyme-Q10 on Doxorubicin-Induced Nephrotoxicity in Rats

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    Azza A. K. El-Sheikh

    2012-01-01

    Full Text Available Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10 on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology. Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.

  3. Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Mohan, Mahalaxmi; Kamble, Sarika; Gadhi, Prakash; Kasture, Sanjay

    2010-01-01

    Nephrotoxicity is one of the important side effects of anthracycline antibiotics. The aim of the study was to determine the protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats using biochemical and histopathological approaches. Oxidative stress is the main factor in doxorubicin (DOX) induced nephrotoxicity. Wistar rats received either DOX (67.75 mg/kg, i.v, 2 days before sacrifice) or S. torvum (100mg/kg and 300 mg/kg, p.o.) prior to DOX treatment or S. torvum (100mg/kg and 300 mg/kg, p.o.) extract alone for 4 weeks. Nephrotoxicity was assessed by measuring the abnormal levels of serum creatinine and blood urea nitrogen (BUN). The anti-oxidant defence enzymes superoxide dismutase (SOD) and catalase (CAT) of kidney tissue were also measured at the end of the treatment schedule. Treatment with S. torvum (100mg/kg and 300 mg/kg) significantly (ptorvum. The results suggest that S. torvum has the potential in preventing the nephrotoxicity induced by doxorubicin. Copyright 2009 Elsevier Ltd. All rights reserved.

  4. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    Science.gov (United States)

    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-01-01

    Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality. PMID:26371029

  5. Nephroprotection of lacidipine against gentamycin-induced nephrotoxicity in albino rats.

    Science.gov (United States)

    Kamal, Sahar

    2010-01-01

    Gentamycin, a widely-used aminoglycoside antibiotic, is recognized as possessing significant nephrotoxic potential in human beings. Gentamycin-induced nephrotoxicity is suggested to be mediated via reactive oxygen species. The present study investigated the possible antioxidant nephroprotective effect of lacidipine as a calcium-channel blocker in a gentamycin-induced nephrotoxicity model in albino rats. Albino rats were divided into 3 groups. Group 1 received normal saline. Group 2 received gentamycin 80 mg/kg intraperitoneally for 14 days. Group 3 received lacidipine 1 mg/kg intraperitoneally 3 days before and 14 days concurrently with gentamycin. This dose does not affect the blood pressure of rats, as evidenced in the pilot study. Gentamycin-induced nephrotoxicity was evidenced by a marked reduction in creatinine clearance. Treatment with lacidipine improved creatinine clearance compared to the gentamycin-treated group. In addition, it reduced thiobarbituric acid reactive substance, as an index of lipid peroxidation, with significant increases in superoxide dismutase enzyme in erythrocyte lysates and kidney catalase enzyme activities. This study recommends the use of lacidipine in prophylaxis against gentamycin-induced nephrotoxicity.

  6. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not?

    Science.gov (United States)

    Ruggiero, Antonio; Rizzo, Daniela; Trombatore, Giovanna; Maurizi, Palma; Riccardi, Riccardo

    2016-01-01

    Platinum compounds are very effective drugs for the treatment of childhood malignancies, and their use has contributed to an increase in the long-term survival of children with cancer. Unfortunately, the risk of severe disabling effects such as nephrotoxicity is well known among children receiving cisplatin-based chemotherapy. The main pharmacodynamics and clinical characteristics of cisplatin nephrotoxicity are described in order to explore the real ability of mannitol to prevent cisplatin-related nephrotoxicity. Currently, the choice of hydration alone or hydration plus mannitol to prevent nephrotoxicity is controversial. No guidelines are available to provide recommendations on this issue either in adults or in children. Appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. In conventional treatment regimens employing doses of cisplatin of less than 100 mg/m(2) in patients with normal renal function, pre- and post-hydration (3 l/m(2) at least 12 h pre-cisplatin and 24 h post-cisplatin) alone should be routinely used. In higher doses, pre- and post-hydration plus mannitol should be considered in order to ensure a valid diuresis.

  7. Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study.

    Science.gov (United States)

    Blot, F; Tavakoli, R; Sellam, S; Epardeau, B; Faurisson, F; Bernard, N; Becquemin, M H; Frachon, I; Stern, M; Pocidalo, J J

    1995-01-01

    With regard to limiting the systemic effects of cyclosporine A and obtaining better control of acute pulmonary allograft rejection, local immunosuppressive therapy with aerosolized cyclosporine A seems of interest. Given the in situ immunologic mechanisms of acute rejection, as well as the anatomic structure of the lung, this therapy is feasible as previously described by others. The aim of our study is to determine the pharmacokinetic parameters of nebulized cyclosporine A and the best modalities of administration. In a pharmacokinetic study, the cyclosporine A was given either by intramuscular injection (10 mg/kg) or by aerosol at 10 and 25 mg/kg doses; 70 rats were killed at 25 and 50 minutes and 2, 4, 6, 8, 12, 24, or 48 hours after cyclosporine A administration. Cyclosporine A levels were measured in whole blood and in the lung. The areas under the concentration time curves were determined. Twenty-four lung transplantations were then performed. The rats were killed on postoperative day 9. Acute rejection was scored on a scale of 0 to 4, and cyclosporine A trough levels were measured in the lung and in the blood. With a jet nebulizer, the mass median aerodynamic diameter was 2.5 microns, with a standard geometric deviation of 2.3. In blood, the area under the concentration curve was greater for intramuscular (80.6 ng.hr/ml) than for aerosol administrations at 10 (15.1 ng.hr/ml) and 25 mg/kg (41.0 ng.hr/ml) doses. In the lungs, the area under the concentration curve was greater for the aerosol route at 25 mg/kg doses (588 ng.hr/mg) than for the low-dose (200 ng.hr/mg) or intramuscular administration (200 ng.hr/mg). The lung targeting index of cyclosporine A (ratio area under the concentration curve-lungs/area under the concentration curve-blood) was greater for both aerosol administrations than for the intramuscular route. In the study of the prevention of acute rejection, rats without immunosuppression (n = 6), rats receiving daily doses of cyclosporine A

  8. Cyclosporine A eye drops inhibit the early-phase reaction in a type-I allergic conjunctivitis model in mice.

    Science.gov (United States)

    Shii, Daisuke; Oda, Tomoko; Shinomiya, Katsuhiko; Katsuta, Osamu; Nakamura, Masatsugu

    2009-08-01

    The effects of cyclosporine A eye drops on the early-phase reaction were investigated in a type-I allergic conjunctivitis model. Mice were actively sensitized with ragweed (RW) absorbed on aluminium hydroxide gel and challenged with RW for 10 days (single challenge model) or 10-14 days (repetitive challenge model) after the first sensitization. For the evaluation of itching, ovalbumin was used as an antigen instead of RW. The effects of cyclosporine A eye drops on increased vascular permeability, mast cell degranulation, and itching were evaluated and compared with those of other anti-allergic eye drops. In the single challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and histological evaluations showed suppressed degranulation of mast cells. Disodium cromoglycate (DSCG) eye drops showed only a slight tendency to inhibit the increase in both pathophysiological parameters. Ketotifen or betamethasone eye drops significantly inhibited the increase in vascular permeability. The order of potency in the single challenge model was ketotifen > cyclosporine A > betamethasone. In the repetitive challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and DSCG eye drops showed only slight inhibition. Ketotifen or betamethasone significantly inhibited the increase in vascular permeability. The order of potency in the repetitive challenge model was cyclosporine A > betamethasone > ketotifen. The effect of cyclosporine A eye drops on the itch-scratch response was studied. Cyclosporine A and DSCG significantly reduced the itch-scratch response in the single and repetitive challenge models; the effect of cyclosporine A in the repetitive challenge model was more potent than in the single challenge model. Those results suggest that administration of cyclosporine A eye drops inhibit the early-phase reaction in type-I allergic conjunctivitis, which may be mediated by the suppression of

  9. Role of Nigella sativa and Its Constituent Thymoquinone on Chemotherapy-Induced Nephrotoxicity: Evidences from Experimental Animal Studies

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    Marco Cascella

    2017-06-01

    Full Text Available Background: Most chemotherapeutic drugs are known to cause nephrotoxicity. Therefore, new strategies have been considered to prevent chemotherapy-induced nephrotoxicity. It is of note that Nigella sativa (NS, or its isolated compound Thymoquinone (TQ, has a potential role in combating chemotherapy-induced nephrotoxicity. AIM: To analyze and report the outcome of experimental animal studies on the protective effects of NS/TQ on chemotherapy-associated kidney complications. Design: Standard systematic review and narrative synthesis. Data Sources: MEDLINE, EMBASE databases were searched for relevant articles published up to March 2017. Additionally, a manual search was performed. Criteria for a study’s inclusion were: conducted in animals, systematic reviews and meta-analysis, containing data on nephroprotective effects of NS/TQ compared to a placebo or other substance. All strains and genders were included. Results: The database search yielded 71 studies, of which 12 (cisplatin-induced nephrotoxicity 8; methotrexate-induced nephrotoxicity 1; doxorubicin-induced nephrotoxicity 2; ifosfamide-induced nephrotoxicity 1 were included in this review. Conclusions: Experimental animal studies showed the protective effect of NS, or TQ, on chemotherapy-induced nephrotoxicity. These effects are caused by decreasing lipid peroxidation and increasing activity of antioxidant enzymes in renal tissue of chemotherapy-treated animals.

  10. Allium sativum aqueous extract prevents potassium dichromate-induced nephrotoxicity and lipid oxidation in rats

    Directory of Open Access Journals (Sweden)

    Sergio L. Becerra-Torres

    2014-04-01

    Full Text Available Context: The potassium dichromate (K2Cr2O7 induces nephrotoxicity by oxidative stress mechanisms. Aims: To study the potential protection of an aqueous extract of Allium sativum against the K2Cr2O7-induced nephrotoxicity and lipid oxidation in rats. Methods: Twenty four hours after treatment, biomarkers such as proteinuria, creatinine clearance, malondialdehyde production, specific enzyme activity of gamma glutamyl transpeptidase and alanine aminopeptidase, and renal clearance of para-aminohippuric acid and inulin were measured. Results: The K2Cr2O7 caused significant renal dysfunction, but A. sativum extract prevented this condition by improving all measured biomarkers. Conclusions: A single injection of K2Cr2O7 induced nephrotoxicity in rats, but the supply of an Allium sativum aqueous extract prevented the disorders caused by this metal.

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

    Science.gov (United States)

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

    2015-09-23

    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. 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. 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). 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.

  12. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  13. MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.

    Science.gov (United States)

    Hao, Jielu; Lou, Qiang; Wei, Qingqing; Mei, Shuqin; Li, Lin; Wu, Guangyu; Mi, Qing-Sheng; Mei, Changlin; Dong, Zheng

    2017-03-17

    Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Insuficiência renal aguda nefrotóxica: prevalência, evolução clínica e desfecho Nephrotoxic acute renal failure: prevalence, clinical course and outcome

    Directory of Open Access Journals (Sweden)

    Patrícia S. Pinto

    2009-09-01

    nephrotoxic ARF. PATIENTS AND METHODS: Historical cohort carried out in a tertiary school hospital from February to November, 1997. Patients over 12 years of age, diagnosed with ARF, and followed up by a team of nephrologists were included. The exclusion criteria were as follows: renal transplantation, chronic renal failure, dialysis due to exogenous poisoning, and those transferred to hospital during treatment. RESULTS: Of the 234 patients followed up, 12% had nephrotoxic ARF and 24% multifactorial ARF associated with the use of nephrotoxic drugs. The most prevalent comorbidities were as follows: hypertension, hepatopathy, neoplasias, congestive heart failure, and diabetes mellitus. Fifteen percent of the patients required dialysis, and the most commonly used type was continuous venovenous hemodialysis; 42% of the patients were oliguric; 44.7% died; and 33% recovered renal function. The most prevalent nephrotoxic drugs were antibiotics, nonsteroidal anti-inflammatory drugs, and radiographical contrast media. In order of frequency, the nephrotoxic drugs were as follows: vancomycin, aminoglycosides, acyclovir, chemotherapy agents, and radiographical contrast media. In multivariate analysis, hepatopathy was the only statistically significant variable (p = 0.03, CI = 1.08 to 6.49. The comparison of non-nephrotoxic and nephrotoxic ARF showed an increase in mortality proportional to the length of hospitalization. CONCLUSION: Nephrotoxic ARF is common, serious, and must be continuously monitored both in hospital and on an outpatient basis.

  15. Beta-2-microglobulin excretion: an indicator of long term nephrotoxicity during cis-platinum treatment?

    DEFF Research Database (Denmark)

    Sørensen, P G; Nissen, Mogens Holst; Groth, S

    1985-01-01

    To evaluate the value of beta-2-microglobulin as an indicator of acute and long-term cis-platinum-induced nephrotoxicity, 51Cr-EDTA clearance and serum concentration and urinary excretion of beta-2-microglobulin were measured in 18 patients treated with a regimen including cis-platinum. Before......-microglobulin remained unchanged. The decrease in 51Cr-EDTA clearance was not correlated to either the peak increase in the beta-2-microglobulin excretion or to the time of occurrence of the peak (R = 0.3). Thus, it is not possible to predict the long-term nephrotoxicity of cis-platinum by measuring the beta-2...

  16. Single high dose gentamicin for perioperative prophylaxis in orthopedic surgery: Evaluation of nephrotoxicity

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    Yanina Dubrovskaya

    2015-10-01

    Full Text Available Background: Recent studies described an increase in acute kidney injury when high dose gentamicin was included in perioperative prophylaxis for orthopedic surgeries. To this effect, we compared the rate of nephrotoxicity for selected orthopedic surgeries where gentamicin was included (Gentamicin Group to those where it was not included (Control Group for perioperative prophylaxis and evaluated risk factors for nephrotoxicity. Methods: Spine, hip and knee surgeries performed between April 2011 and December 2013 were reviewed retrospectively. Gentamicin was given to eligible patients based on age, weight and Creatinine Clearance. Nephrotoxicity was assessed using Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE criteria. Results: Among selected surgeries (N = 1590 in Gentamicin Group: hip = 926, spine = 600, knee = 64; N = 2587 in Control Group: hip = 980, spine = 902, knee = 705, patients’ body weight, serum creatinine, comorbidities and surgery duration were similar in Gentamicin Group and Control Group. Gentamicin median dose was 4.5 mg/kg of dosing weight. Nephrotoxicity rate was 2.5% in Gentamicin Group and 1.8% in Control Group, p = 0.17. Most cases of nephrotoxicity were Risk category by RIFLE criteria (67% in Gentamicin Group and 72% in Control Group, p = 0.49. In logistic regression, risk factors for nephrotoxicity were hospital stay >1 day prior to surgery (odds ratio = 8.1; 95% confidence interval = 2.25–28.97, p = 0.001, knee or hip surgery (odds ratio = 4.7; 95% confidence interval = 2.9–9.48, p = 0.0005 and diabetes (odds ratio = 1.95; 95% confidence interval = 1.13–3.35, p = 0.016. Receipt of gentamicin was not an independent predictor of nephrotoxicity (odds ratio = 1.5; 95% confidence interval = 0.97–2.35, p = 0.07. Conclusion: In this cohort, rate of nephrotoxicity was similar between Gentamicin Group and Control

  17. Health claims database study of cyclosporine ophthalmic emulsion treatment patterns in dry eye patients

    Directory of Open Access Journals (Sweden)

    Stonecipher KG

    2013-10-01

    Full Text Available Karl G Stonecipher,1 Jenny Chia,2 Ahunna Onyenwenyi,2 Linda Villanueva,2 David A Hollander2 1TLC Laser Eye Centers, Greensboro, NC, 2Allergan, Inc., Irvine, CA, USA Background: Dry eye is a multifactorial, symptomatic disease associated with ocular surface inflammation and tear film hyperosmolarity. This study was designed to assess patterns of topical cyclosporine ophthalmic emulsion 0.05% (Restasis® use in dry eye patients and determine if there were any differences in use based on whether dry eye is physician-coded as a primary or nonprimary diagnosis. Methods: Records for adult patients with a diagnosis of dry eye at an outpatient visit from January 1, 2008 to December 31, 2009 were selected from Truven Health MarketScan® Research Databases. The primary endpoint was percentage of patients with at least one primary versus no primary dry eye diagnosis who filled a topical cyclosporine prescription. Data analyzed included utilization of topical corticosteroids, oral tetracyclines, and punctal plugs. Results: The analysis included 576,416 patients, accounting for 875,692 dry eye outpatient visits: 74.7% were female, 64.2% were ages 40-69 years, and 84.4% had at least one primary dry eye diagnosis. During 2008–2009, 15.9% of dry eye patients with a primary diagnosis versus 6.5% with no primary diagnosis filled at least one cyclosporine prescription. For patients who filled at least one prescription, the mean months’ supply of cyclosporine filled over 12 months was 4.44. Overall, 33.9% of dry eye patients filled a prescription for topical cyclosporine, topical corticosteroid, or oral tetracycline over 2 years. Conclusion: Patients with a primary dry eye diagnosis were more likely to fill a topical cyclosporine prescription. Although inflammation is key to the pathophysiology of dry eye, most patients seeing a physician for dry eye may not receive anti-inflammatory therapies. Keywords: corticosteroids, cyclosporine, dry eye syndromes

  18. Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics

    Science.gov (United States)

    Meissner, Konrad; Blood, Jane; Francis, Amber M.; Yermolenka, Viktar; Kharasch, Evan D.

    2015-01-01

    Background Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans. Methods Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 hr). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis, or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution. PMID:25072223

  19. Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.

    Science.gov (United States)

    Meissner, Konrad; Blood, Jane; Francis, Amber M; Yermolenka, Viktar; Kharasch, Evan D

    2014-12-01

    Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans [corrected]. Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4±0.4 and 1.3±0.5 mm/mg, respectively) and IV methadone (3.1±1.0 and 3.2±0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.

  20. Treatment of Chronic Spontaneous Urticaria

    Science.gov (United States)

    2012-01-01

    Chronic spontaneous urticaria is defined as persistent symptoms of urticaria for 6 weeks or more. It is associated with autoimmunity in approximately 45 percent of patients. Therapy is often difficult however the initial approach should employ high-dose non-sedating antihistamines; 4-6 tablets/day may be necessary. It has been shown that the response to 4 tablets/day exceeds 3, and exceeds 2, which exceeds 1. However the dose that corresponds to the maximal dose of first generation antihistamines (hydroxyzine, diphenhydramine) used previously, is 6/day. Yet over half the patients are refractory to antihistamines and other agents should be tried next. Whereas current guidelines (published) often add leukotriene antagonists and/or H2 receptor antogonists next, these are of little utility. Likewise drugs effective for urticarial vasculitis (colchicine, dapsone, sulfasalazine, hydroxychloroquine) are effective in a small percentage of patients and no study suggests that the response rate of any of them exceeds the 30% placebo responses seen in most double-blind, placebo controlled studies. The drugs that are effective for antihistamine-resistant chronic spontaneous urticaria are corticosteroids, cyclosporine, and Omalizumab. Use of steroids is limited by toxicity. If used at all, a dose of no more than 10 mg/day should be employed with a weekly reduction of 1 mg. The response rates to cyclosporine and Omalizumab are each close to 75%. Cyclosporine can be used effectively if care is taken to monitor blood pressure, urine protein, blood urea nitrogen, and creatinine, every 6 weeks. Omalizumab has the best profile in terms of efficacy/toxicity and, once approved by federal agencies for use in chronic spontaneous urticaria, a dramatic change in the treatment paradigm, whether associated with autoimmunity or not, is predicted. A phase 3 trial is currently in place. Refractoriness to both Omalizumab and cyclosporine is expected to be less than 5 percent of patients. Other

  1. Suppression of feline coronavirus replication in vitro by cyclosporin A

    Directory of Open Access Journals (Sweden)

    Tanaka Yoshikazu

    2012-04-01

    Full Text Available Abstract The feline infectious peritonitis virus (FIPV is a member of the feline coronavirus family that causes FIP, which is incurable and fatal in cats. Cyclosporin A (CsA, an immunosuppressive agent that targets the nuclear factor pathway of activated T-cells (NF-AT to bind cellular cyclophilins (CyP, dose-dependently inhibited FIPV replication in vitro. FK506 (an immunosuppressor of the pathway that binds cellular FK506-binding protein (FKBP but not CyP did not affect FIPV replication. Neither cell growth nor viability changed in the presence of either CsA or FK506, and these factors did not affect the NF-AT pathway in fcwf-4 cells. Therefore, CsA does not seem to exert inhibitory effects via the NF-AT pathway. In conclusion, CsA inhibited FIPV replication in vitro and further studies are needed to verify the practical value of CsA as an anti-FIPV treatment in vivo.

  2. Cyclosporine in the Management of Esophageal Lichen Planus

    Directory of Open Access Journals (Sweden)

    M Chaklader

    2009-01-01

    Full Text Available Lichen planus (LP is an uncommon disorder of unknown etiology, mostly affecting patients in their fifth and sixth decade of life. It is believed to be an autoimmune process involving T cells directed against basal keratinocytes. It affects the skin, nails, oral pharynx and genitals. Esophageal involvement is quite rare and can cause strictures, ulcerations and squamous cell cancer. The present article describes the case of a 54-year-old woman who was referred for assessment of dysphagia that initially occurred with solids, which then progressed to soft foods but spared liquids. The patient reported a weight loss of 9.1 kg. An esophagogastroduodenoscopy was performed and she was subsequently diagnosed with pill esophagitis. At the same time, she was also diagnosed with oral LP, with no involvement of the esophagus. She was treated with a proton pump inhibitor that resolved her gastrointestinal symptoms. The symptoms returned one year later and a repeat esophagogastroduodenoscopy revealed white plaques due to LP. She was treated with intermittent glucocorticoids. Diagnosis of esophageal LP is crucial for the proper treatment. Some patients may require systemic immunosuppression and mechanical dilation to prevent weight loss. Surveillance endoscopies should be performed to monitor for squamous cell cancer. Cyclosporine has been used for genital and oral LP, but the present case is the first in which it has been used successfully to treat esophageal LP.

  3. Cyclosporin safety in a simplified rat brain tumor implantation model

    Directory of Open Access Journals (Sweden)

    Francisco H. C. Felix

    2012-01-01

    Full Text Available Brain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate. This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08±6.7 mm³ on the 7th day and 67.25±19.8 mm³ on 9th day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated.

  4. Porous mannitol carrier for pulmonary delivery of cyclosporine A nanoparticles.

    Science.gov (United States)

    Leung, Sharon Shui Yee; Wong, Jennifer; Guerra, Heloisa Victorino; Samnick, Kevin; Prud'homme, Robert K; Chan, Hak-Kim

    2017-03-01

    This study employed the ultrasonic spray-freeze-drying technique to prepare porous mannitol carriers that incorporated hydrophobic cyclosporine A (CsA) nanoparticles (NPs) for pulmonary delivery. Two nanosuspension stabilization systems, (1) a combination of lecithin and lactose system and (2) a D-α-tocopheryl polyethylene glycol succinate (TPGS) system, were investigated. The ability of the lecithin and TPGS in anchoring the hydrophobic CsA NPs to the porous hydrophilic mannitol structure was first reported. Formulations stabilized by TPGS provided a much better dose uniformity, suggesting that TPGS is a better anchoring agent compared with lecithin. The effects of mannitol carrier density and CsA loading (4.9-27%) on aerosol performance and dissolution profiles were assessed. The fine particle fraction (FPF) increased from 44 to 63% as the mannitol concentration decreased from 1 to 5%. All formulations achieved full dissolution within an hour without significant influence from the mannitol content and CsA loading. The initial dissolution rates of the present formulations were almost double than that of the spray-dried counterpart, with 90% of the drug dissolved in 10 min. Overall, the CsA NPs were successfully incorporated into the porous mannitol which demonstrated good aerosol performance and enhanced dissolution profiles. These spray-freeze-drying (SFD) powders were stable after 2-year storage under desiccation at 20 ± 3°C.

  5. Protective potential of Tamarindus indica against gentamicin-induced nephrotoxicity.

    Science.gov (United States)

    Ullah, Naveed; Azam Khan, Mir; Khan, Taous; Ahmad, Waqar

    2014-01-13

    Abstract Context: Gentamicin is an antibiotic that is effective against Gram-negative microorganisms. However, its clinical applications are often limited due to nephrotoxic effects. Objective: This study investigated the protective effects of aqueous-ethanol extract of Tamarindus indica L. (Leguminosae) fruits against gentamicin-induced renal toxicity. Materials and methods: A daily dose of 200 mg/kg of 70% aqueous-ethanol extract derived from T. indica was employed in male rabbits as a co-therapy with gentamicin (80 mg/kg) for a period of three weeks. Serum and urinary renal function parameters and histological assessments were carried out and compared with one way analysis of variance (Graphpad prism version 5.00, Graphpad Software, San Diego, CA). Results: The results showed that gentamicin-treated animals had significantly elevated blood urea nitrogen (54.1 ± 2.6 mg/dl), serum creatinine (4.0 ± 0.1 mg/dl), serum uric acid (2.3 ± 0.1 mg/dl) and urinary protein excretion (3.8 ± 0.3 mg/dl) with a fall in body weight (10 ± 1%), creatinine clearance (0.7 ± 0.09 ml/min), serum potassium (3.4 ± 0.1 mEq/l), serum calcium (7.6 ± 0.2 mg/dl), urinary volume (126 ± 9 ml/24 h) and urinary lactate dehydrogenase secretion (103.1 ± 4.2 U/l). However, animals treated by co-therapy with gentamicin and T. indica had significantly improved renal structure and function. Discussion and conclusion: Co-therapy of 200 mg/kg/d of T. indica for a period of three weeks successfully prevented functional and morphological derangements caused by gentamicin as assessed by different renal function parameters and histological examinations.

  6. Treatment of presumptive primary immune-mediated thrombocytopenia with mycophenolate mofetil versus cyclosporine in dogs.

    Science.gov (United States)

    Cummings, F O; Rizzo, S A

    2017-02-01

    The objective of this study was to compare hospitalisation duration, survival times, adverse events and cost of therapy in dogs with presumptive primary immune-mediated thrombocytopenia undergoing therapy with mycophenolate mofetil and corticosteroids versus cyclosporine and corticosteroids. A retrospective study of medical case records of dogs with presumed primary immune-mediated thrombocytopenia was conducted. Data collected included signalment, presenting complaints, haematologic and biochemical profiles, vector-borne disease testing, thoracic and abdominal radiographs, abdominal ultrasound, medications administered, duration of hospitalisation, 30- and 60-day survival, adverse events and cost of therapy. Variables were compared between dogs treated solely with mycophenolate mofetil and corticosteroids or cyclosporine and corticosteroids. A total of 55 dogs with primary immune-mediated thrombocytopenia were identified. Eighteen were excluded because multiple immunosuppressive medications were used during treatment. Hospitalisation times, 30-day survival and 60-day survival times were similar between both groups. Dogs in the mycophenolate mofetil/corticosteroid group experienced fewer adverse events than the cyclosporine/corticosteroid group. Therapy with mycophenolate mofetil was less expensive than that with cyclosporine. These results suggest that using the combination of mycophenolate mofetil and corticosteroids appears to be as effective as cyclosporine and corticosteroids in the treatment of presumed primary immune-mediated thrombocytopenia in dogs. Adverse events were less common and cost of therapy was lower in the mycophenolate mofetil group. Additional larger prospective, controlled, double-masked, outcome-based, multi-institutional studies are required to substantiate these preliminary findings. © 2017 British Small Animal Veterinary Association.

  7. Comparison of architect I 2000 for determination of cyclosporine with axsym.

    Science.gov (United States)

    Serdarevic, Nafija; Zunic, Lejla

    2012-12-01

    Cyclosporine has been shown effective drug in suppressing acute rejection in recipients of allograft organ transplants. The cyclosporine concentration of 96 blood samples was determined using CMIA (chemiluminesecent microparticle immnoassay) Architect i 2000 and FPIA (fluorescence polarization immunoassay) AxSYM Abbott diagnostic. All patients have transplantation of kidneys and were hospitalized at Department of Nephrology at the Clinical center of University of Sarajevo. The reference serum range of cyclosporine for kidney organ transplantation for maintenance lies between 50 and 150 ng/mL. The quality control, precision and accurancy of Architect i 2000 were assessed. The quality control was done using quality control serums for low (= 91 ng/mL), medium (= 328 ng/mL) and high (= 829 ng/mL). We have used commercial BIORAD controls and got reproducibility CV 5.83 % to 13 % for Architect i 2000. It was established that the main difference between Architect i 2000 and AxSYM and it was statistically significant for P Architect assay has significant reduced cyclosporine metabolite interference relative to other immunoassay and is a convenient and sensitive automated method to measure cyclosporine in whole blood.

  8. Topical cyclosporin as an alternative treatment for vision threatening blepharokeratoconjunctivitis: a case report

    Directory of Open Access Journals (Sweden)

    Ismail AS

    2012-06-01

    Full Text Available Abdul-Salim Ismail,1,2 Rohana Taharin,2 Zunaina Embong11Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 2Department of Ophthalmology, Hospital Pulau Pinang, Jalan Resindensi, Pulau Pinang, MalaysiaAbstract: Here, a case of vision threatening blepharokeratoconjunctivitis that responded well to topical cyclosporin is reported. A 9-year-old Malay girl with a history of bilateral blepharokeratoconjunctivitis was regularly treated with lid scrubbing using diluted baby shampoo, fusidic acid gel, and topical steroids as well as an intermittent course of oral doxycycline for the past year. She developed acute onset bilateral eye redness associated with poor vision in her right eye. Both eyes showed marked diffuse hyperemic conjunctiva with corneal vascularization. The presence of corneal vascularization obscured the visual axis in the right eye. The condition did not improve with regular intensive lid hygiene using diluted baby shampoo, fusidic acid gel, and topical steroids. She was started on topical cyclosporin A 0.5% every 6 hours. There was a dramatic regression of corneal vascularization after 3 days on topical cyclosporin, with marked improvement in visual acuity. This is a single case in which cyclosporin improved the status of the ocular surface. A large cohort study is required to justify its effectiveness in treating blepharokeratoconjunctivitis and to test its potential as an alternative immunosuppressive agent in comparison to conventional corticosteroids.Keywords: blepharokeratoconjunctivitis, cyclosporin

  9. Early cyclosporin A treatment retards axonal degeneration in an experimental peripheral nerve injection injury model

    Directory of Open Access Journals (Sweden)

    Ibrahim Erkutlu

    2015-01-01

    Full Text Available Injury to peripheral nerves during injections of therapeutic agents such as penicillin G potassium is common in developing countries. It has been shown that cyclosporin A, a powerful immunosuppressive agent, can retard Wallerian degeneration after peripheral nerve crush injury. However, few studies are reported on the effects of cyclosporin A on peripheral nerve drug injection injury. This study aimed to assess the time-dependent efficacy of cyclosporine-A as an immunosuppressant therapy in an experimental rat nerve injection injury model established by penicillin G potassium injection. The rats were randomly divided into three groups based on the length of time after nerve injury induced by penicillin G potassium administration (30 minutes, 8 or 24 hours. The compound muscle action potentials were recorded pre-injury, early post-injury (within 1 hour and 4 weeks after injury and compared statistically. Tissue samples were taken from each animal for histological analysis. Compared to the control group, a significant improvement of the compound muscle action potential amplitude value was observed only when cyclosporine-A was administered within 30 minutes of the injection injury (P < 0.05; at 8 or 24 hours after cyclosporine-A administration, compound muscle action potential amplitude was not changed compared with the control group. Thus, early immunosuppressant drug therapy may be a good alternative neuroprotective therapy option in experimental nerve injection injury induced by penicillin G potassium injection.

  10. Low-dose cyclosporine treatment for sight-threatening uveitis: Efficacy, toxicity, and tolerance

    Directory of Open Access Journals (Sweden)

    Mathews D

    2010-01-01

    Full Text Available Aim : To ascertain the effectiveness, tolerability, and safety of low-dose cyclosporine in the management of sight-threatening uveitis. Materials and Methods: This was a retrospective clinical case series of patients using oral low-dose cyclosporine for the management of sight-threatening uveitis in the uvea clinic (UC. Patients receiving cyclosporine were identified from the clinic database. Main outcome measures were degree of intraocular inflammation, visual acuity and dose reduction of oral steroid for effectiveness and adverse symptoms, systemic hypertension, and raised serum creatinine for tolerability and safety. Results: Intraocular inflammation was improved or stable in 97% of patients, visual acuity was improved or stable in 91%, and oral steroid dosage was reduced in 73% (by half or more in 51%. Adverse symptoms were almost universal, the commonest being peripheral paresthesia/burning in 70% and fatigue in 67%. Significant systemic hypertension developed in 27% and raised creatinine in 30%, necessitating dose reduction. Cyclosporine was discontinued in 35%, being intolerable in 20% and ineffective in 15%. Conclusions: Cyclosporine was found to be effective in reducing inflammation and protecting vision in sight-threatening uveitis. It was safe with proper monitoring, including in children. It had a significant toxicity profile and a high incidence of adverse symptoms which required close supervision, and a prompt dose reduction or drug exchange.

  11. Low-dose cyclosporine treatment for sight-threatening uveitis: efficacy, toxicity, and tolerance.

    Science.gov (United States)

    Mathews, D; Mathews, John; Jones, N P

    2010-01-01

    To ascertain the effectiveness, tolerability, and safety of low-dose cyclosporine in the management of sight-threatening uveitis. This was a retrospective clinical case series of patients using oral low-dose cyclosporine for the management of sight-threatening uveitis in the uvea clinic (UC). Patients receiving cyclosporine were identified from the clinic database. Main outcome measures were degree of intraocular inflammation, visual acuity and dose reduction of oral steroid for effectiveness and adverse symptoms, systemic hypertension, and raised serum creatinine for tolerability and safety. Intraocular inflammation was improved or stable in 97% of patients, visual acuity was improved or stable in 91%, and oral steroid dosage was reduced in 73% (by half or more in 51%). Adverse symptoms were almost universal, the commonest being peripheral paresthesia/burning in 70% and fatigue in 67%. Significant systemic hypertension developed in 27% and raised creatinine in 30%, necessitating dose reduction. Cyclosporine was discontinued in 35%, being intolerable in 20% and ineffective in 15%. Cyclosporine was found to be effective in reducing inflammation and protecting vision in sight-threatening uveitis. It was safe with proper monitoring, including in children. It had a significant toxicity profile and a high incidence of adverse symptoms which required close supervision, and a prompt dose reduction or drug exchange.

  12. Cyclosporine decreases vascular progenitor cell numbers after cardiac transplantation and attenuates progenitor cell growth in vitro.

    Science.gov (United States)

    Davies, William R; Wang, Shaohua; Oi, Keiji; Bailey, Kent R; Tazelaar, Henry D; Caplice, Noel M; McGregor, Christopher G A

    2005-11-01

    Recent experimental evidence suggests that the neointimal proliferation seen in cardiac allograft vasculopathy may in part derive from recipient progenitor cells. The effect of cyclosporine on these circulating progenitors in the setting of cardiac transplantation is currently unknown. Three surgical series were performed: sham operation alone, sham operation with immunosuppression, and heterotopic porcine cardiac transplantation with immunosuppression. The sham operation involved laparotomy and consecutive clamping of the abdominal aorta and inferior vena cava. Post-operative immunosuppression consisted of cyclosporine at therapeutic levels (100-300 ng/ml) and 0.5 mg/kg methylprednisolone. Endothelial outgrowth colony numbers (EOC(CFU)) and smooth muscle outgrowth colony numbers (SOC(CFU)) were quantified weekly for 4 weeks post-operatively. A series of in vitro experiments were performed to determine the effect of cyclosporine on the differentiation, migration, and proliferation of EOCs and SOCs. In the sham alone series there were no changes to either EOC(CFU) or SOC(CFU). In the sham with immunosuppression and the transplant series, both EOC(CFU) and SOC(CFU) fell in the first 2 weeks (p Cyclosporine, even at a low dose, prevented differentiation, inhibited proliferation, and attenuated migration of both EOCs and SOCs. Immunosuppression in the setting of cardiac transplantation causes a profound reduction in circulating progenitor cells capable of differentiating into endothelial and smooth muscle cells. This effect can in part be explained by the inhibitory effects of cyclosporine on progenitor growth and differentiation seen in this study.

  13. Reversion by ozone treatment of acute nephrotoxicity induced by cisplatin in rats

    Directory of Open Access Journals (Sweden)

    Ricardo González

    2004-01-01

    Full Text Available BACKGROUND: Ozone therapy has become a useful treatment for pathological processes, in which the damage mediated by reactive oxygen species is involved. Several lines of evidence suggest that cisplatin-induced acute nephrotoxicity is partially mediated by reactive oxygen species.

  14. Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation.

    Science.gov (United States)

    Hamad, Rania; Jayakumar, Calpurnia; Ranganathan, Punithavathi; Mohamed, Riyaz; El-Hamamy, Mahmoud M I; Dessouki, Amina A; Ibrahim, Abdelazim; Ramesh, Ganesan

    2015-08-01

    Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose-limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin-induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey-treated group as compared to the cisplatin alone-treated group. Interestingly, honey feeding significantly reduced cisplatin-induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin-induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation. © 2015 Wiley Publishing Asia Pty Ltd.

  15. Nephroprotective, Diuretic and Antioxidant Effects of Some Medicinal Herbs in Gentamicin-Nephrotoxic Rats

    Directory of Open Access Journals (Sweden)

    Mostafa Abbas Shalaby

    2014-02-01

    Conclusion: Aqueous extracts of Petroselinum sativum, Eruca sativa and Curcuma longa produce nephroprotective, diuretic and antioxidant effects in GM - nephrotoxic rats. These herbs may be beneficial for patients who suffer from kidney diseases and those on GM therapy. [J Intercult Ethnopharmacol 2014; 3(1.000: 1-8

  16. Multisite analytical evaluation of the Abbott ARCHITECT cyclosporine assay.

    Science.gov (United States)

    Wallemacq, Pierre; Maine, Gregory T; Berg, Keith; Rosiere, Thomas; Marquet, Pierre; Aimo, Giuseppe; Mengozzi, Giulio; Young, Julianna; Wonigeit, Kurt; Kretschmer, Robert; Wermuth, Bendicht; Schmid, Rainer W

    2010-04-01

    The objective of this study was to evaluate the analytical performance of the Abbott ARCHITECT Cyclosporine (CsA) immunoassay in 7 clinical laboratories in comparison to liquid chromatography/tandem mass spectrometry (LC/MS/MS), Abbott TDx, Cobas Integra 800, and the Dade Dimension Xpand immunoassay. The ARCHITECT assay uses a whole blood specimen, a pretreatment step with organic reagents to precipitate proteins and extract the drug, followed by a 2-step automated immunoassay with magnetic microparticles coated with anti-CsA antibody and an acridinium-CsA tracer. Imprecision testing at the 7 evaluation sites gave a range of total % coefficient of variations of 7.5%-12.2% at 87.5 ng/mL, 6.6%-14.3% at 411 ng/mL, and 5.2%-10.7% at 916 ng/mL. The lower limit of quantification ranged from 12 to 20 ng/mL. Purified CsA metabolites AM1, AM1c, AM4N, AM9, and AM19 were tested in whole blood by the ARCHITECT assay and showed minimal cross-reactivity at all 7 sites. In particular, AM1 and AM9 cross-reactivity in the ARCHITECT assay, ranged from -2.5% to 0.2% and -0.8% to 2.2%, respectively, and was significantly lower than for the TDx assay, in which the values were 3.2% and 16.1%, respectively. Comparable testing of metabolites in the Dade Dimension Xpand assay at 2 evaluation sites showed cross-reactivity to AM4N (6.4% and 6.8%) and AM9 (2.6% and 3.6%) and testing on the Roche Integra 800 showed cross-reactivity to AM1c (2.4%), AM9 (10.7%), and AM19 (2.8%). Cyclosporine International Proficiency Testing Scheme samples, consisting of both pooled specimens from patients receiving CsA therapy as well as whole-blood specimens supplemented with CsA, were tested by the ARCHITECT assay at 6 sites and showed an average bias of -24 to -58 ng/mL versus LC/MSMS CsA and -2 to -37 ng/mL versus AxSYM CsA. Studies were performed with the ARCHITECT CsA assay on patient specimens with the following results: ARCHITECT CsA assay versus LC/MSMS, average bias of 31 ng/mL; ARCHITECT versus the

  17. Effects of Cyclosporine, Tacrolimus, and Rapamycin on Osteoblasts.

    Science.gov (United States)

    Martín-Fernández, M; Rubert, M; Montero, M; de la Piedra, C

    2017-11-01

    One factor that can contribute to severe bone loss after transplantation is the direct action of immunosuppressants on bone cells. The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on the release of three local factors directly implicated in bone-remodeling regulation and apoptosis of human osteoblasts: interleukin (IL)-6, osteoprotegerin, and receptor activator of nuclear factor κβ (RANKL). Human osteoblasts were obtained from five different patients who underwent orthopedic surgery. These cells were treated with what are considered to be a clinically high dose and an acceptable dose of each immunosuppressant-RAPA 50 ng/mL and 12 ng/mL, FK-506 20 ng/mL and 5 ng/mL, CsA 1000 ng/mL and 250 ng/mL-or vehicle. Apoptotic cell death was quantified using flow cytometry of DNA content in permeabilized, propidium iodide-stained cells. IL-6 was measured using enzyme-linked immunosorbent assay (ELISA; Quantikine Human IL6, R&D Systems, Minneapolis, Minn, United States). Messenger RNA (mRNA) expression of osteoprotegerin, RANKL, and IL-6 was measured using quantitative RT-PCR. A significant increase in IL-6 (mRNA and released protein) was observed in the presence of FK-506 and RAPA. Addition of RAPA to the cultures of osteoblasts produced a significant increase in the OPG/RANKL ratio. A significant increase in osteoblast apoptosis was observed in the cells treated with FK-506 and RAPA 24 hours after the addition of immunosuppressants. CsA did not produce any significant changes in osteoblasts. These results suggest that an increase in osteoblast apoptosis by osteoblasts may be one of the mechanisms by which bone loss occurs after RAPA and FK-506 treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Cyclosporin A preferentially attenuates skeletal slow-twitch muscle regeneration

    Directory of Open Access Journals (Sweden)

    Miyabara E.H.

    2005-01-01

    Full Text Available Calcineurin, a Ca2+/calmodulin-dependent phosphatase, is associated with muscle regeneration via NFATc1/GATA2-dependent pathways. However, it is not clear whether calcineurin preferentially affects the regeneration of slow- or fast-twitch muscles. We investigated the effect of a calcineurin inhibitor, cyclosporin A (CsA, on the morphology and fiber diameter of regenerating slow- and fast-twitch muscles. Adult Wistar rats (259.5 ± 9 g maintained under standard conditions were treated with CsA (20 mg/kg body weight, ip for 5 days, submitted to cryolesion of soleus and tibialis anterior (TA muscles on the 6th day, and then treated with CsA for an additional 21 days. The muscles were removed, weighed, frozen, and stored in liquid nitrogen. Cryolesion did not alter the body weight gain of the animals after 21 days of regeneration (P = 0.001 and CsA significantly reduced the body weight gain (15.5%; P = 0.01 during the same period. All treated TA and soleus muscles showed decreased weights (17 and 29%, respectively, P < 0.05. CsA treatment decreased the cross-sectional area of both soleus and TA muscles of cryoinjured animals (TA: 2108 ± 930 vs 792 ± 640 µm²; soleus: 2209 ± 322 vs 764 ± 439 m²; P < 0.001. Histological sections of both muscles stained with Toluidine blue revealed similar regenerative responses after cryolesion. In addition, CsA was able to minimize these responses, i.e., centralized nuclei and split fibers, more efficiently so in TA muscle. These results indicate that calcineurin preferentially plays a role in regeneration of slow-twitch muscle.

  19. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity.

    Science.gov (United States)

    Kharasch, E D; Hankins, D C; Thummel, K E

    1995-03-01

    Methoxyflurane nephrotoxicity is mediated by cytochrome P450-catalyzed metabolism to toxic metabolites. It is historically accepted that one of the metabolites, fluoride, is the nephrotoxin, and that methoxyflurane nephrotoxicity is caused by plasma fluoride concentrations in excess of 50 microM. Sevoflurane also is metabolized to fluoride ion, and plasma concentrations may exceed 50 microM, yet sevoflurane nephrotoxicity has not been observed. It is possible that in situ renal metabolism of methoxyflurane, rather than hepatic metabolism, is a critical event leading to nephrotoxicity. We tested whether there was a metabolic basis for this hypothesis by examining the relative rates of methoxyflurane and sevoflurane defluorination by human kidney microsomes. Microsomes and cytosol were prepared from kidneys of organ donors. Methoxyflurane and sevoflurane metabolism were measured with a fluoride-selective electrode. Human cytochrome P450 isoforms contributing to renal anesthetic metabolism were identified by using isoform-selective inhibitors and by Western blot analysis of renal P450s in conjunction with metabolism by individual P450s expressed from a human hepatic complementary deoxyribonucleic acid library. Sevoflurane and methoxyflurane did undergo defluorination by human kidney microsomes. Fluoride production was dependent on time, reduced nicotinamide adenine dinucleotide phosphate, protein concentration, and anesthetic concentration. In seven human kidneys studied, enzymatic sevoflurane defluorination was minima, whereas methoxyflurane defluorination rates were substantially greater and exhibited large interindividual variability. Kidney cytosol did not catalyze anesthetic defluorination. Chemical inhibitors of the P450 isoforms 2E1, 2A6, and 3A diminished methoxyflurane and sevoflurane defluorination. Complementary deoxyribonucleic acid-expressed P450s 2E1, 2A6, and 3A4 catalyzed methoxyflurane and sevoflurane metabolism, in diminishing order of activity

  20. Aminoglycosides in septic shock: an overview, with specific consideration given to their nephrotoxic risk.

    Science.gov (United States)

    Boyer, Alexandre; Gruson, Didier; Bouchet, Stéphane; Clouzeau, Benjamin; Hoang-Nam, Bui; Vargas, Frédéric; Gilles, Hilbert; Molimard, Mathieu; Rogues, Anne-Marie; Moore, Nicholas

    2013-04-01

    Aminoglycoside nephrotoxicity has been reported in patients with sepsis, and several risk factors have been described. Once-daily dosing and shorter treatment have reduced nephrotoxicity risk, and simplified aminoglycoside monitoring. This review focuses on nephrotoxicity associated with aminoglycosides in the subset of patients with septic shock or severe sepsis. These patients are radically different from those with less severe sepsis. They may have, for instance, renal impairment due to the shock per se, sepsis-related acute kidney injury, frequent association with pre-existing risk factors for renal failure such as diabetes, dehydration and other nephrotoxic treatments. In this category of patients, these risk factors might modify substantially the benefit-risk ratio of aminoglycosides. In addition, aminoglycoside administration in critically ill patients with sepsis is complicated by an extreme inter- and intra-individual variability in drug pharmacokinetic/pharmacodynamic characteristics: the volume of distribution (Vd) is frequently increased while the elimination constant can be either increased or decreased. Consequently, and although its effect on nephrotoxicity has not been explored, a different administration schedule, i.e. a high-dose once daily (HDOD), and several therapeutic drug monitoring (TDM) options have been proposed in these patients. This review describes the historical perspective of these different options, including those applying to subsets of patients in which aminoglycoside administration is even more complex (obese intensive care unit [ICU] patients, patients needing continuous or discontinuous renal replacement therapy [CRRT/DRRT]). A simple linear dose adjustment according to aminoglycoside serum concentration can be classified as low-intensity TDM. Nomograms have also been proposed, based on the maximum (peak) plasma concentration (Cmax) objectives, weight and creatinine clearance. The Sawchuk and Zaske method (based on the

  1. Prevention of mouse-rat brain xenograft rejection by a combination therapy of cyclosporin A, prednisolone and azathioprine

    DEFF Research Database (Denmark)

    Pedersen, E B; Poulsen, F R; Zimmer, J

    1995-01-01

    Embryonic mouse hippocampal tissue was grafted as tissue blocks to the hippocampal region of adult rats and the effect of two different immunosuppressive treatments compared. Immunosuppression with cyclosporin A, prednisolone and azathioprine or with cyclosporin A alone was compared with placebo ...

  2. Obesity in transplant patients: case report showing interference of orlistat with absorption of cyclosporine and review of literature.

    Science.gov (United States)

    Barbaro, Daniele; Orsini, Paola; Pallini, Stefania; Piazza, Francesca; Pasquini, Cristina

    2002-01-01

    To report a case of an obese patient who had undergone renal transplantation and who had subtherapeutic levels of serum cyclosporine after treatment with orlistat. The clinical and laboratory findings are presented, and the few cases reported in the literature are reviewed. A 29-year-old woman had subtherapeutic plasma levels of cyclosporine after orlistat treatment (360 mg/day) was initiated. The subtherapeutic levels persisted even though orlistat was administered the recommended 2 hours before ingestion of cyclosporine and even though the dosage of orlistat was decreased to only 240 mg/day. Because an increase of body weight is common after organ transplantation, treatment with orlistat has been used. In such patients, however, six cases of reduced therapeutic plasma levels of cyclosporine have been reported. Although a drug-drug interaction has been suggested, this case suggests that the decreased plasma cyclosporine levels are due to reduced absorption of fats rather than a drug-drug interaction. Because this patient was unable to adhere to a low-fat diet, she experienced severe diarrhea, a factor that may have dramatically diminished the absorption of cyclosporine. Adherence to a low-fat diet should be strongly recommended if orlistat is prescribed to patients taking cyclosporine. Moreover, strict surveillance of the plasma concentration of cyclosporine is important.

  3. Optimization of cyclosporin A production by Beauveria nivea in continuous fed-batch fermentation

    Directory of Open Access Journals (Sweden)

    Dong Huijun

    2011-01-01

    Full Text Available To develop the effective control method for fed-batch culture of cyclosporin A production, we chose fructose, L-valine and (NH42HPO4 as feeding nutrients and compared their productivities in relation to different concentrations. The feeding rate of three kinds of feeding materials was controlled to maintain the suitable residual concentration. The fed-batch fermentation results indicated that the optimal concentrations of fructose, L-valine and (NH42HPO4 were about 20 g/L, 0.5 g/L and 0.6 g/L for cyclosporin A production, respectively. The cultivation of Beauveria nivea could produce cyclosporin A up to 6.2 g/L for 240 hrs through a continuous feeding-rate-controlled-batch process under the optimal feeding conditions.

  4. The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients

    DEFF Research Database (Denmark)

    Koefoed-Nielsen, PB; Karamperis, N; Hojskov, C

    2006-01-01

    Cyclosporin and tacrolimus remain the cornerstone immunosuppressive drugs in organ transplantation. Dosing and monitoring these drugs is based on pharmacokinetic protocols, but measuring a pharmacodynamic parameter, calcineurin phosphatase (CaN) activity, could be a valuable supplement...... in determining optimal doses. Forty stable renal transplant patients were investigated three times in a 6-month period. Blood samples were drawn at 0, 1, 2, 3 and 4 h after oral intake of tacrolimus (FK) or cyclosporin at days 1 and 180. At day 90, one blood sample at trough level (FK) or C2 level (cyclosporin A...... significantly different effects on calcineurin activity in renal transplant patients with stable, well-functioning grafts and that tacrolimus-treated patients can maintain good, stable graft function with minimal CaN inhibition....

  5. Preventing or attenuating amphotericin B nephrotoxicity with dopamine receptor agonists: a literature review

    Directory of Open Access Journals (Sweden)

    Iman Karimzadeh

    2016-09-01

    Full Text Available Nephrotoxicity is generally considered as the most clinically significant and dose-limiting adverse reaction of amphotericin B. Currently, only the clinical effectiveness of salt loading and administering lipid formulations of amphotericin B have been clearly demonstrated to prevent its nephrotoxicity. In this review, we collected the published data related to dopamine receptor agonists in preventing amphotericin B nephrotoxicity. A literature search was conducted by the relevant keywords like ‘‘amphotericin B”, “nephrotoxicity’’, and ‘‘dopamine’’in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. Four relevant articles were considered. Results of all the 3 experimental studies demonstrated that co-administration of dopamine (0.5-10 μg/kg/min as continuous intravenous infusion, SK&F R-105058, a prodrug of fenoldopam (10 mg/kg twice daily, orally or fenoldopam, a relatively selective dopamine receptor type 1 agonist, (0.5 or 1 μg/kg/min as continuous intravenous infusion can at least significantly mitigate the decrease in creatinine clearance caused by amphotericin B. Furthermore, fenoldopam and SK&F R-105058 can also protect against or delay amphotericin B-induced tubular damage. In contrast, the only clinical trial published until now found that simultaneous continuous intravenous infusion of low dose dopamine (3 μg/kg/min had no beneficial effect on the incidence, severity and time onset of developing amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Considering the lack of beneficial effects in different settings such as acute kidney injury of any cause, negative results of the only clinical trial, and risk of significant adverse reactions, continuous intravenous infusion of low dose dopamine (1-3 μg/kg/min or selective dopamine receptor type 1 agonists (e.g., fenoldopam currently appears to have no promising clinical role in preventing or attenuating

  6. Preliminary Clinical Study of the Effect of Ascorbic Acid on Colistin-Associated Nephrotoxicity

    Science.gov (United States)

    Sirijatuphat, Rujipas; Limmahakhun, Samornrod; Sirivatanauksorn, Vorapan; Nation, Roger L.; Li, Jian

    2015-01-01

    Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-d-glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P = 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.) PMID:25801556

  7. Retrospective review of relapse after systemic cyclosporine in children with atopic dermatitis.

    Science.gov (United States)

    Sibbald, Cathryn; Pope, Elena; Ho, Nhung; Weinstein, Miriam

    2015-01-01

    Cyclosporine is a systemic therapy used for control of severe atopic dermatitis (AD) in children. Although traditionally recommended at a dose of 5 mg/kg/day for 6 months, a longer duration of treatment may be necessary to bring a child with active and severe disease into remission. There are few data on the short- and long-term effectiveness of longer courses of therapy. This was a retrospective chart review of children treated with cyclosporine at a Canadian hospital-affiliated clinic between 2000 and 2013. Fifteen patients with adequate follow-up were identified. Twelve (80%) were male and the mean age at initiation of cyclosporine was 11.2 ± 3.4 years. The mean duration of cyclosporine therapy was 10.9 ± 2.7 months (range 7-15 months) at a starting dose of 2.8 ± 0.6 mg/kg/day. Of 12 patients (80%) who responded to cyclosporine, 5 patients (42%) had relapsed at a follow-up of 22.7 ± 15.0 months. The duration of therapy was longer in patients who did not relapse (17.7 ± 10.7 months) than in those who did (10.2 ± 2.7 months) (p = 0.06). Adverse events led to discontinuation in three patients (20%) and included infection-related complications in two patients and reversible renal toxicity in one. These results suggest that a longer duration of low-dose cyclosporine may help decrease the risk of relapse in patients with severe AD who are resistant to topical therapies. © 2014 Wiley Periodicals, Inc.

  8. Stability of cyclosporine solutions stored in polypropylene-polyolefin bags and polypropylene syringes.

    Science.gov (United States)

    Li, Mengqing; Forest, Jean-Marc; Coursol, Christian; Leclair, Grégoire

    2011-09-01

    The stability of cyclosporine diluted to 0.2 or 2.5 mg/mL with 0.9% sodium chloride injection or 5% dextrose injection and stored in polypropylene-polyolefin containers or polypropylene syringes was evaluated. Intravenous cyclosporine solutions (0.2 and 2.5 mg/mL) were aseptically prepared and transferred to 250-mL polypropylene-polyolefin bags or 60-mL polypropylene syringes. Chemical stability was measured using a stability-indicating high-performance liquid chromatography (HPLC) assay. Physical stability was assessed by visual inspection and a dynamic light scattering (DLS) method. After 14 days, HPLC assay showed that the samples of i.v. cyclosporine stored in polypropylene-polyolefin bags remained chemically stable (>98% of initial amount remaining); the physical stability of the samples was confirmed by DLS and visual inspection. The samples stored in polypropylene syringes were found to contain an impurity (attributed to leaching of a syringe component by the solution) that could be detected by HPLC after 1 day; on further investigation, no leaching was detected when the syringes were exposed to undiluted i.v. cyclosporine 50 mg/mL for 10 minutes. Samples of i.v. cyclosporine solutions of 0.2 and 2.5 mg/mL diluted in 0.9% sodium chloride injection or 5% dextrose injection and stored at 25 °C in polypropylene-polyolefin bags were physically and chemically stable for at least 14 days. When stored in polypropylene syringes, the samples were contaminated by an impurity within 1 day; however, the short-term (i.e., ≤10 minutes) use of the syringes for the preparation and transfer of i.v. cyclosporine solution is considered safe.

  9. Reversible fibroadenomatous mammary hyperplasia in male and female New Zealand white rabbits associated with cyclosporine A administration.

    Science.gov (United States)

    Krimer, P M; Harvey, S B; Blas-Machado, U; Lauderdale, J D; Moore, P A

    2009-11-01

    All male and female New Zealand white rabbits in a limbal cell graft study developed marked generalized mammary gland hypertrophy. Postprocedural medications included ophthalmic 0.1% dexamethasone, ophthalmic 0.5% cyclosporine, and subcutaneous cyclosporine A. Cytologic examination revealed epithelial clusters with minimal malignant criteria. On histologic evaluation, there was diffuse glandular hyperplasia with mild cellular atypia and ductal ectasia separated by abundant hypercellular fibrous stroma, consistent with fibroadenomatous mammary gland hyperplasia. The hyperplasia resolved within 2 weeks of cessation of cyclosporine, and at necropsy identifiable mammary masses were not found. Very little has been reported about the use of cyclosporine in laboratory rabbits and its association with development of mammary gland hyperplasia. This is the first report in which administration of cyclosporine to male and female rabbits at a dose as low as 5 mg/kg/day induced benign fibroadenomatous mammary gland hyperplasia. This change regressed after cessation of the drug.

  10. Comparison of the pharmacokinetics of tacrolimus and cyclosporine at equivalent molecular doses

    DEFF Research Database (Denmark)

    Karamperis, N; Povlsen, J V; Højskov, Carsten Schriver

    2003-01-01

    Even though calcineurin inhibitors, namely Tacrolimus (FK) and Cyclosporine (CsA) share similar physicochemical properties and a common mechanism of action, their pharmacokinetics (pk) are different and unpredictable. Both drugs are metabolized by cytochrome P450-3A4 isoforms in the liver...... in the study. Comparing the pharmacokinetic parameters obtained from the drugs, it appeared that cyclosporine has an greater primary volume of distribution and clearance rate compared to tacrolimus. No other statistically significant differences were observed regarding bioavailability, absorption rate...

  11. Treatment of nephrotic syndrome associated with idiopathic rapidly progressive glomerulonephritis and cyclosporin A.

    Science.gov (United States)

    Maduell, F; Sánchez-Alcaraz, A; Sigüenza, F; Caridad, A; Sangrador, G

    1993-02-01

    Recent reports suggest that cyclosporin A is beneficial in inducing remission of idiopathic nephrotic syndrome. Nephrotic syndrome is seen in 10-30% of patients with rapidly progressive glomerulonephritis. We report a case of a 69-year-old man with nephrotic syndrome, associated with idiopathic rapidly progressive glomerulonephritis, who was treated initially with corticosteroid and cyclophosphamide. Three months later he developed thrombophlebitis and leucopenia and cyclophosphamide was suspended. Relapse of nephrotic syndrome associated with rapidly progressive glomerulonephritis developed and therapy with cyclosporin A was used with a good response.

  12. Design and Methods of the Pan-Canadian Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE Nephrotoxicity Study

    Directory of Open Access Journals (Sweden)

    Kelly R. McMahon

    2017-02-01

    Full Text Available Background: Childhood cancer survivors experience adverse drug events leading to lifelong health issues. The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE team was established to validate and apply biomarkers of cancer treatment effects, with a goal of identifying children at high risk of developing cancer treatment complications associated with thrombosis, graft-versus-host disease, hearing loss, and kidney damage. Cisplatin is a chemotherapy well known to cause acute and chronic nephrotoxicity. Data on biomarkers of acute kidney injury (AKI and late renal outcomes in children treated with cisplatin are limited. Objective: To describe the design and methods of the pan-Canadian ABLE Nephrotoxicity study, which aims to evaluate urine biomarkers (neutrophil gelatinase–associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1] for AKI diagnosis, and determine whether they predict risk of long-term renal outcomes (chronic kidney disease [CKD], hypertension. Design: This is a 3-year observational prospective cohort study. Setting: The study includes 12 Canadian pediatric oncology centers. Patients: The target recruitment goal is 150 patients aged less than 18 years receiving cisplatin. Exclusion criteria: Patients with an estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m2 or a pre-existing renal transplantation at baseline. Measurements: Serum creatinine (SCr, urine NGAL, and KIM-1 are measured during cisplatin infusion episodes (pre-infusion, immediate post-infusion, discharge sampling. At follow-up visits, eGFR, microalbuminuria, and blood pressure are measured and outcomes are collected. Methods: Outcomes: AKI is defined as per SCr criteria of the Kidney Disease: Improving Global Outcomes (KDIGO guidelines. CKD is defined as eGFR <90 mL/min/1.73m2 or albumin-to-creatinine ratio≥3mg/mmol. Hypertension is defined as per guidelines. Procedure: Patients are recruited before their

  13. Cyclosporine therapy for uveitis: long-term followup.

    Science.gov (United States)

    Nussenblatt, R B; Palestine, A G; Chan, C C

    1985-01-01

    Long term followup in 52 uveitis patients treated with Cyclosporine (CsA) is presented here. The patients included in this study all had intermediate or posterior uveitis of noninfectious etiology; and all were considered therapeutic failures to systemic corticosteroids and/or cytotoxic agents. Patients were considered a therapeutic success if the visual acuity in either eye improved two lines or more and/or the vitreal haze improved more than two grading levels. While five patients stopped therapy before the three month interval, 41 of 52 patients or 79% were therapeutic successes at three months after the initiation of CsA as the sole systemic immunosuppressive agent for their disease. Twenty-five of a potential 35 patients (71%) remained on CsA after one year's time, with 63% (22/35) of these individuals receiving the medication considered a therapeutic success. The patients who appeared to respond particularly well to CsA therapy were those with pars planitis, intermediate uveitis of the non-pars planitis type, VKH, and Behcet's disease. In vitro S-antigen (S-Ag) testing did not appear to have a predictive value in determining which patients would be therapeutic successes (improvement in visual acuity), however the S-Ag responder group did appear to have a statistically greater improvement in vitreal haze. Renal toxicity was by far the most common adverse effect, which we have found to be reversible with our approach to therapy. However, adverse reactions required a reduction in CsA dosage in some patients, making it not feasible to maintain therapeutically effective CsA levels. In those patients, low dose prednisone was added to these patients' CsA regimens with generally good results. We did not observe opportunistic infections nor CsA associated neoplasms in our patients. This long term study demonstrates the potential efficacy of CsA in the treatment of severe intra-ocular inflammatory disorders. However, we firmly believe that only in the context of a

  14. Erythrophagocytosis of lead-exposed erythrocytes by renal tubular cells: possible role in lead-induced nephrotoxicity

    National Research Council Canada - National Science Library

    Kwon, So-Youn; Bae, Ok-Nam; Noh, Ji-Yoon; Kim, Keunyoung; Kang, Seojin; Shin, Young-Jun; Lim, Kyung-Min; Chung, Jin-Ho

    ...) externalization on the erythrocyte membrane and generation of PS-bearing microvesicles. Increased oxidative stress and up-regulation of nephrotoxic biomarkers, such as NGAL, were observed in HK-2 cells undergoing erythrophagocytosis...

  15. Colistin nephrotoxicity in the ICU: Is it different in the geriatric patients?

    Science.gov (United States)

    Aydoğan, Burcu Başarık; Yıldırım, Fatma; Zerman, Avşar; Gönderen, Kamil; Türkoğlu, Melda; Aygencel, Gülbin

    2017-09-02

    Most significant side effect of colistin therapy which is used for the treatment of multi-drug resistant Gram-negative infections is nephrotoxicity. Our aim was to investigate the differences of colistin nephrotoxicity between the geriatric age group (≥65 years) and the younger age group (patients. The medical records of the 76 patients who were taken colistin therapy due to multi-resistant Gram-negative infections between January 2010 and June 2014 in the our medical ICU were retrospectively investigated. Demographic characteristics, reasons for colistin use, daily colistin dose, duration of colistin use were recorded. Colistin-dependent renal dysfunction was evaluated according to the risk, injury, failure, loss and end-stage renal failure (RIFLE) criterias. The median age of the patients was 65 (65.8% male). Nephrotoxicity was developed in 36 (47.4%) patients. Thirty-nine (51.3%) patients were in geriatric age group, 37 (48.7%) were in younger age group. In geriatric age group, the rates of male gender (53.8 vs 78.4%, p = 0.031), pulmonary (48.7 vs 16.2%, p = 0.003) and cardiac diseases (71.8 vs 29.7%, p patients of geriatric age group, and in 14 (37.8%) patients in younger age group (p = 0.115). The presence of cardiac disease, renal pathology and high creatinin value on admission, daily amount of colistin per body mass, total amount of colistin, use of colistin for pulmonary infection, use of amphotericin and vasopressor on admission were found as risk factors for colistin nephrotoxicity development in all study group; the daily amount of colistin per body mass (risk ratio:0.41; 95% CI 0.19-0.89) and vasopressor use during hospitalization were found independent risk factors (risk ratio:13.54; 95% CI 2.21-83.09). In our study, in geriatric patient group colistin nephrotoxicity was not different from the younger age group. In the ICU, the age for nephrotoxicity does not appear to be a point to be considered for the initiation of colistin.

  16. Intragastric exposure to titanium dioxide nanoparticles induced nephrotoxicity in mice, assessed by physiological and gene expression modifications

    OpenAIRE

    Gui, Suxin; Sang, Xuezi; Zheng, Lei; Ze, Yuguan; Zhao, Xiaoyang; Sheng, Lei; Sun, Qingqing; Cheng, Zhe; Cheng, Jie; Hu, Renping; Wang, Ling; Hong, Fashui; Tang, Meng

    2013-01-01

    Background Numerous studies have demonstrated that titanium dioxide nanoparticles (TiO2 NPs) induced nephrotoxicity in animals. However, the nephrotoxic multiple molecular mechanisms are not clearly understood. Methods Mice were exposed to 2.5, 5 and 10 mg/kg TiO2 NPs by intragastric administration for 90 consecutive days, and their growth, element distribution, and oxidative stress in kidney as well as kidney gene expression profile were investigated using whole-genome microarray analysis te...

  17. Recurrent impetigo herpetiformis with diabetes and hypoalbuminemia successfully treated with cyclosporine, albumin, insulin and metformin

    Directory of Open Access Journals (Sweden)

    Lakshmi Chembolli

    2010-01-01

    Full Text Available We report the case of a patient with recurrent impetigo herpetiformis associated with diabetes mellitus, hypoalbuminemia, and hypocalcaemia; who was refractory to corticosteroids. Cyclosporine along with other supportive measures proved to be life-saving with maintenance of pregnancy.

  18. Vernal shield ulcers treated with frequently installed topical cyclosporine 0.05% eyedrops

    NARCIS (Netherlands)

    Westland, Tim; Patryn, Eliza K.; Nieuwendaal, Carla P.; van der Meulen, Ivanka J. E.; Mourits, Maarten P.; Lapid-Gortzak, Ruth

    2017-01-01

    To report on the beneficial results of an intense regimen of 0.05% cyclosporine eye drops, eight times a day in patients with therapy resistant vernal shield ulcers. Case cohort of four eyes of three male children with vernal keratoconjunctivitis complicated by shield ulcers, who were treated with

  19. Efficacy of a new pulmonary cyclosporine a powder formulation for prevention of transplant rejection in rats

    NARCIS (Netherlands)

    Zijlstra, Gerrit S.; Wolting, Joske; Prop, Jochum; Petersen, Arjen H.; Hinrichs, Wouter L.J.; Uges, Donald R.A.; Kerstjens, Huib A.M.; van der Bij, Wim; Frijlink, Henderik W.

    2009-01-01

    Background: The aim of this pilot study was to determine the pharmacokinetics of cyclosporine A powder for inhalation (iCsA) and its rejection prevention efficacy in an experimental lung transplantation model in rats. Methods: Single-dose pharmacokinetics (10 mg/kg) of pulmonary and orally

  20. Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis

    NARCIS (Netherlands)

    de Rie, M. A.; Meinardi, M. M.; Bos, J. D.

    1991-01-01

    Since oral cyclosporin A (CsA) has demonstrated its effectiveness in psoriasis and atopic dermatitis, efforts have been made to develop a topical CsA formulation, thus avoiding systemic adverse events. A limited number of publications are available on the use of topical CsA in allergic contact

  1. Cyclosporine and Extracorporeal Photopheresis are Equipotent in Treating Severe Atopic Dermatitis

    DEFF Research Database (Denmark)

    Koppelhus, Uffe; Poulsen, Johan; Grunnet, Niels

    2014-01-01

    BACKGROUND: Severe atopic dermatitis (AD) is a recurrent and debilitating disease often requiring systemic immunosuppressive treatment. The efficacy of cyclosporine A (CsA) is well proven but potential side effects are concerning. Several reports point at extracorporeal photopheresis (ECP) as an ...

  2. Cyclosporine a withdrawal during follow-up after pediatric liver transplantation

    NARCIS (Netherlands)

    Scheenstra, R; Torringa, MLJ; Waalkens, HJ; Middelveld, EH; Peeters, PMJG; Slooff, MJH; Gouw, ASH; Verkade, HJ; Bijleveld, CMA

    It is unclear whether cyclosporine A (CsA) can be withdrawn safely during follow-up after pediatric liver transplantation. In our transplant program we have been using a strict protocol to withdraw CsA. The aim of this study was to retrospectively assess the effects of CsA withdrawal after pediatric

  3. Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration : relation to efficacy in kidney allografting

    NARCIS (Netherlands)

    Schuurman, HJ; Slingerland, W; Mennninger, K; Ossevoort, M; Hengy, JC; Dorobek, B; Vouderscher, J; Ringers, J; Odeh, M; Jonker, Margreet

    In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values (+/- SD) of C-max, 24-h area-under-the curve (AUC) and 24-h trough

  4. Efficacy of 1.25% and 1% topical cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood.

    Science.gov (United States)

    Spadavecchia, Laura; Fanelli, Pietro; Tesse, Riccardina; Brunetti, Luigia; Cardinale, Fabio; Bellizzi, Mario; Rizzo, Giovanna; Procoli, Ugo; Bellizzi, Gianfranco; Armenio, Lucio

    2006-11-01

    Cyclosporine eyedrops 2% have been used for treatment of corticosteroid-resistant vernal keratoconjunctivitis (VKC) cases. The purpose of our study was to verify the efficacy of 1.25% vs. 1% topical cyclosporine in improving severe form of VKC in childhood. Twenty children with severe VKC, were enrolled in a double-blind, placebo-controlled study and received cyclosporine 1.25% in one eye for 2 wk. Then an open trial was conducted during the next 3 months and 2 wk. Thirty-two more patients were recruited the next year into a new open trial and they received cyclosporine 1% for 4 months. Ocular subjective symptoms and objective signs were scored in all children at entry, 2 wk and 4 months. Skin prick tests and conjunctival scraping tests were also performed; serum immunological and biochemical markers were assessed. The mean score values for severity of subjective symptoms and objective signs were significantly decreased after 2 wk, and 4 months, compared with those at entry (p < 0.001), in both groups of children who received cyclosporine eyedrops 1.25% and 1%, respectively. Serum markers did not differ from the beginning to the end of treatment. Conjunctival eosinophils and cyclosporine serum levels were not detectable at the end of therapy, nor were endothelial corneal cells damaged. Our findings suggest that 1% cyclosporine concentration might be the minimal effective treatment regimen to control symptoms and local inflammation in severe forms of VKC.

  5. Protective Effect of Carvacrol on Renal Functional and Histopathological Changes in Gentamicin-Induced-Nephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Hassan Ahmadvand

    2016-04-01

    Full Text Available Background Nephrotoxicity is one of the most important side effects of the use of gentamicin sulphate (GS resulted in reactive oxygen species generation. Antioxidant compounds played effective roles in reduction of renal injuries caused by using of gentamicin. Carvacrol is a strong antioxidant compound. Objectives The aim of this study is to explore the effect of carvacrol inhibition in lesions of gentamicin-induced nephrotoxicity. Materials and Methods In this experimental study, 32 male mature Sprague-Dawley rats were divided into 4 groups of 8; group1: control, group 2 sham received daily carvacrol injection (74 mg/kg for 12 days, group 3 received daily GS injection (100 mg/kg for 12 days, group 4 received daily GS (100 mg/kg and carvacrol (74 mg/kg for 12 days. After 12 days, rats were anaesthetized, blood sample were obtained and kidneys were removed then stained with hematoxylin and eosin method and then were studied histophatologically. Serum creatinine and urea were measured. Results Flow treatment of nephrotoxic animals with carvacrol could significantly inhibit leukocyte infiltration (9.42% and tubular necrosis (38.18% in comparison with the nephrotoxic untreated group. Carvacrol significantly decreased the levels of urea and creatinine in treated group compared with the nephrotoxic untreated group. Conclusions The findings showed that carvacrol alleviates loss of leukocyte infiltration (9.42% and tubular necrosis and exerts beneficial effects on kidney function test in nephrotoxic group.

  6. Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration

    Science.gov (United States)

    Groseclose, M. Reid; Laffan, Susan B.; Frazier, Kendall S.; Hughes-Earle, Angela; Castellino, Stephen

    2015-06-01

    As part of an investigative nephrotoxicity study, kidney tissues from juvenile rats orally administered dabrafenib at different age intervals between postnatal day (PND) 7 to 35 were investigated by MALDI and LDI imaging mass spectrometry (IMS) to determine the chemical composition of tubular deposits. In the youngest age group (PND 7-13), MALDI IMS demonstrated that a dabrafenib carboxylic acid metabolite was diffusely localized to the regions of tubular deposits (medulla and corticomedullary junction); however, no dabrafenib-related material was detected directly from the deposits. Rather, the LDI IMS analysis determined that the deposits were composed primarily of calcium phosphate. Based on these data, the dabrafenib associated nephrotoxicity, including the formation of tubular deposits, was determined to be age dependent. Furthermore, immature renal function was hypothesized to be responsible for the susceptibility of the youngest pups.

  7. Evaluation of nephroprotective activity of Musa paradisiaca L. in gentamicin-induced nephrotoxicity.

    Science.gov (United States)

    Abbas, Khizar; Rizwani, Ghazala H; Zahid, Hina; Qadir, M Imran

    2017-05-01

    The objective of the study was to investigate the nephroprotective activity of methanolic extract of different morphological parts (bract, flower, trachea and tracheal fluid) of Musa paradisiaca L. (Family: Musaceae) against gentamicin-induced nephrotoxicity in mice. Gentamicin produced significant changes in biochemical (increased levels of blood urea nitrogen level, blood urea, and serum creatinine), and histological parameters in mice. Treatment with methanolic extract of bract (100 and 250mg/kg, b.w) and flowering stalk (trachea) (250 and 500mg/kg, b.w) significantly prevented biochemical and histological changes produced by gentamicin toxicity. The extracts of M. paradisiaca (bract and flowering stalk) could contribute a lead to discovery of a new drug for the treatment of drug-induced nephrotoxicity.

  8. Severe steroid-unresponsive ulcerative colitis: outcomes of restorative proctocolectomy in patients undergoing cyclosporin treatment.

    Science.gov (United States)

    Pinna-Pintor, M; Arese, P; Bona, R; Falletto, E; Schieroni, R; Villata, E; Massaioli, N; Selvaggi, P; Actis, G C; Lagget, M; Marzano, A; Ottobrelli, A; Sostegni, R; Torrani-Cerenzia, M R; Rizzetto, M

    2000-05-01

    The recent introduction of the immune suppressor cyclosporin for treatment of steroid-refractory ulcerative colitis has required surgeons to perform a colectomy in those patients who eventually fail this rescue treatment, thus raising questions as to the safety of surgery as performed in patients with a heavily manipulated immune system. To assess the rates of mortality and morbidity in this setting, we studied a cohort of consecutive patients who had surgery after failing cyclosporin for refractory ulcerative colitis at our center. Between January 1991 and December 1996, 25 patients with ulcerative colitis underwent restorative proctocolectomy performed in three steps (21 patients) and in two steps (4 patients). Seventeen of the 25 patients (68 percent) were initial nonresponders to a dose of 2 mg/kg/day of intravenous cyclosporin and underwent surgery immediately, the remaining 8 (32 percent) relapsed as outpatients on oral cyclosporin and were readmitted for surgery. There was no operative mortality. Nine patients of the 25 developed postoperative (early) complications (36 percent). The three-step operation subset had a 28 percent complication rate, the two-step 75 percent. Three patients needed reoperation. A total of 11 patients (44 percent) reported with late complications: two patients required surgical treatment, one for obstruction and one for pouch-perianal fistula. Three cases of pouchitis were recorded. No patient required pouch removal. Given the absence of postoperative mortality and a low overall complication rate, restorative proctocolectomy can safely be performed in patients who fail rescue treatment with a dose of 2 mg/kg of cyclosporin for steroid-refractory ulcerative colitis. Corollary evidence in this article hints but does not prove that the three-step procedure is safer than the two-step operation.

  9. Tear cytokine levels in vernal keratoconjunctivitis: the effect of topical 0.05% cyclosporine a therapy.

    Science.gov (United States)

    Oray, Merih; Toker, Ebru

    2013-08-01

    The aims of this study were to evaluate the efficacy of topical 0.05% cyclosporine A on clinical signs and symptoms of vernal keratoconjunctivitis (VKC) and to examine its effect on tear cytokine levels. Twenty-one patients with active VKC and 15 healthy volunteers were included. Patients were treated with topical 0.05% cyclosporine A. Symptoms and signs were scored on the day of enrollment and at the end of month 1 and month 3. Tear and serum samples were collected before and on the third month of treatment. Interleukin (IL)-2, soluble IL-2 receptor (sIL-2R), IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, IL-17, eotaxin, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) in cell-free tear and serum supernatants were measured by multiplex bead analysis. At the end of month 1 and month 3 with topical 0.05% cyclosporine A treatment, statistically a significant decrease was observed in sign and symptom scores of the patients (P < 0.0001). Tear IL-2, sIL-2R, IL-9, IL-17, IFN-γ, and eotaxin levels in VKC patients were significantly higher than those in controls (P < 0.05). IL-3, IL-4, IL-5, and TNFα levels tended to be higher in VKC patients. There was also statistically significant reduction from before 0.05% cyclosporine A treatment to after treatment in tear levels of IL-4, IL-5, IL-17A, TNFα, IFN-γ, and eotaxin (P < 0.05). IL-2 and sIL-2R levels tended to be lower than pretreatment levels. Topical 0.05% cyclosporine A is effective in alleviating signs and symptoms of VKC patients and shows its effect probably by decreasing the local production of some inflammatory mediators in tears.

  10. Design and Methods of the Pan-Canadian Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Nephrotoxicity Study: A Prospective Observational Cohort Study.

    Science.gov (United States)

    McMahon, Kelly R; Rod Rassekh, Shahrad; Schultz, Kirk R; Pinsk, Maury; Blydt-Hansen, Tom; Mammen, Cherry; Tsuyuki, Ross T; Devarajan, Prasad; Cuvelier, Geoff D E; Mitchell, Lesley G; Baruchel, Sylvain; Palijan, Ana; Carleton, Bruce C; Ross, Colin J D; Zappitelli, Michael

    2017-01-01

    Childhood cancer survivors experience adverse drug events leading to lifelong health issues. The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) team was established to validate and apply biomarkers of cancer treatment effects, with a goal of identifying children at high risk of developing cancer treatment complications associated with thrombosis, graft-versus-host disease, hearing loss, and kidney damage. Cisplatin is a chemotherapy well known to cause acute and chronic nephrotoxicity. Data on biomarkers of acute kidney injury (AKI) and late renal outcomes in children treated with cisplatin are limited. To describe the design and methods of the pan-Canadian ABLE Nephrotoxicity study, which aims to evaluate urine biomarkers (neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1]) for AKI diagnosis, and determine whether they predict risk of long-term renal outcomes (chronic kidney disease [CKD], hypertension). This is a 3-year observational prospective cohort study. The study includes 12 Canadian pediatric oncology centers. The target recruitment goal is 150 patients aged less than 18 years receiving cisplatin. Exclusion criteria: Patients with an estimated glomerular filtration rate (eGFR) study has a relatively moderate sample size and short follow-up duration. There is potential for variability in data collection since multiple sites are involved. ABLE will provide a national platform to study biomarkers of late cancer treatment complications. The Nephrotoxicity study is a novel study of AKI biomarkers in children treated with cisplatin that will greatly inform on late cisplatin renal outcomes and follow-up needs.

  11. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    OpenAIRE

    Arfat, Yasir; Mahmood, Nasir; Tahir, Muhammad Usman; Rashid, Maryam; Anjum, Sameer; Zhao, Fan; Li, Di-Jie; Sun, Yu-Long; Hu, Lifang; Zhihao, Chen; Yin, Chong; Shang, Peng; Qian, Ai-Rong

    2014-01-01

    Imidacloprid (IC) is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standa...

  12. Colistin-Induced Nephrotoxicity in Mice Involves the Mitochondrial, Death Receptor, and Endoplasmic Reticulum Pathways

    Science.gov (United States)

    Dai, Chongshan; Li, Jichang; Tang, Shusheng

    2014-01-01

    Nephrotoxicity is the dose-limiting factor for colistin, but the exact mechanism is unknown. This study aimed to investigate the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in colistin-induced nephrotoxicity. Mice were intravenously administered 7.5 or 15 mg of colistin/kg of body weight/day (via a 3-min infusion and divided into two doses) for 7 days. Renal function, oxidative stress, and apoptosis were measured. Representative biomarkers involved in the mitochondrial, death receptor, and endoplasmic reticulum pathways were investigated, and the key markers involved in apoptosis and autophagy were examined. After 7-day colistin treatment, significant increase was observed with blood urea nitrogen, serum creatinine, and malondialdehyde, while activities of superoxide dismutase (SOD) and catalase decreased in the kidneys. Acute tubular necrosis and mitochondrial dysfunction were detected, and colistin-induced apoptosis was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP-1), increase of 8-hydroxydeoxyguanosine (8-OHdG), and activation of caspases (caspase-8, -9, and -3). It was evident that colistin-induced apoptosis involved the mitochondrial pathway (downregulation of Bcl-2 and upregulation of cytochrome C [cytC] and Bax), death receptor pathway (upregulation of Fas, FasL, and Fas-associated death domain [FADD]), and endoplasmic reticulum pathway (upregulation of Grp78/Bip, ATF6, GADD153/CHOP, and caspase-12). In the 15-mg/kg/day colistin group, expression of the cyclin-dependent kinase 2 (CDK2) and phosphorylated JNK (p-JNK) significantly increased (P colistin group, a large number of autophagolysosomes and classic autophagy were observed. Western blot results of Beclin-1 and LC3B indicated that autophagy may play a protective role in colistin-induced nephrotoxicity. In conclusion, this is the first study to demonstrate that all three major apoptosis pathways and autophagy are involved in

  13. 3,4,5-Trichloroaniline Nephrotoxicity in Vitro: Potential Role of Free Radicals and Renal Biotransformation

    Directory of Open Access Journals (Sweden)

    Christopher Racine

    2014-11-01

    Full Text Available Chloroanilines are widely used in the manufacture of drugs, pesticides and industrial intermediates. Among the trichloroanilines, 3,4,5-trichloroaniline (TCA is the most potent nephrotoxicant in vivo. The purpose of this study was to examine the nephrotoxic potential of TCA in vitro and to determine if renal biotransformation and/or free radicals contributed to TCA cytotoxicity using isolated renal cortical cells (IRCC from male Fischer 344 rats as the animal model. IRCC (~4 million cells/mL; 3 mL were incubated with TCA (0, 0.1, 0.25, 0.5 or 1.0 mM for 60–120 min. In some experiments, IRCC were pretreated with an antioxidant or a cytochrome P450 (CYP, flavin monooxygenase (FMO, cyclooxygenase or peroxidase inhibitor prior to incubation with dimethyl sulfoxide (control or TCA (0.5 mM for 120 min. At 60 min, TCA did not induce cytotoxicity, but induced cytotoxicity as early as 90 min with 0.5 mM or higher TCA and at 120 min with 0.1 mM or higher TCA, as evidenced by increased lactate dehydrogenase (LDH release. Pretreatment with the CYP inhibitor piperonyl butoxide, the cyclooxygenase inhibitor indomethacin or the peroxidase inhibitor mercaptosuccinate attenuated TCA cytotoxicity, while pretreatment with FMO inhibitors or the CYP inhibitor metyrapone had no effect on TCA nephrotoxicity. Pretreatment with an antioxidant (α-tocopherol, glutathione, ascorbate or N-acetyl-l-cysteine also reduced or completely blocked TCA cytotoxicity. These results indicate that TCA is directly nephrotoxic to IRCC in a time and concentration dependent manner. Bioactivation of TCA to toxic metabolites by CYP, cyclooxygenase and/or peroxidase contributes to the mechanism of TCA nephrotoxicity. Lastly, free radicals play a role in TCA cytotoxicity, although the exact nature of the origin of these radicals remains to be determined.

  14. Renal oxidative stress status and histology in gentamicin nephrotoxicity: The effects of antioxidant vitamins

    Directory of Open Access Journals (Sweden)

    R. Ghaznavi

    2006-07-01

    Full Text Available Background: In recent publications, several mechanisms have been implicated in gentamicin (GM nephrotoxicity. Reactive oxygen species have been proposed as one of the causative factors of the drug renal side effects. This study was designed to evaluate the protective effects of the antioxidant vitamins against GM-mediated nephropathy in insitu isolated rat kidneys. Methods: Male Sprague-Dawley rats were randomly assigned to one of the following groups of seven rats: Group 1 (control was tyrode perfused kidneys. Group 2 (GM, 200µg/ml gentamicin was added to the perfusate. Group 3 (GM + Vit C, the same as group 2 but vitamin C (200 mg/L was added to the drinking water for 3 days and 100 mg/L to the perfusate. Group 4 (GM + Vit E, the same as group 2 but vitamin E (100 mg/100 g BW, ip was injected 12 h before experiments. Group 5 (GM + Vit C + Vit E the same as group 2 but Vit E and C were co-administered (same as Group 3 & 4. Urinary N-acetyle-B-D-glucosaminidas (NAG and renal cortex superoxide dismutase (SOD levels were measured and tissue histological evaluations were performed. Results: Gentamicin caused a significant nephrotoxicity demonstrated by increase in urinary NAG. Decline in SOD contents were observed comparing to controls. Vit C or Vit E inhibited the gentamicin-induced increased releases of NAG into urine but did not show a significant effect on the SOD levels. Conclusion: Co-administration of VitC&E significantly prevented the GM nephrotoxicity demonstrating by preservation of SOD levels and prevention of increase in urinary enzyme activities. Histological studies of renal tissues provided additional evidences for protective effects of antioxidant vitamins. We concluded that moderate doses of Vit C & E have protective effects in gentamicin nephrotoxicity and co-administration of these vitamins have additional beneficial effects.

  15. Time-series pattern of gene expression profile in gentamycin-induced nephrotoxicity.

    Science.gov (United States)

    Qiu, Yunliang; Hong, Min; Li, Hua; Tang, Naping; Ma, Jing; Hsu, Ching-Hung; Dong, Wenxin

    2014-02-01

    There have been many studies investigating the genomic biomarker and/or molecular mechanism of nephrotoxicity using microarray. However, most of these researches were carried out by studying gene expression changes at one specific time point. As gene expression varies with time and disease stage, the current study investigated the time-series pattern of gene expression in a rat model using a typical nephrotoxic compound. Rats were administrated with 80 mg/kg gentamycin or saline by intramuscular injection for 14 consecutive days followed by a 28-d recovery. Rats were scarified on D2, D4, D8, D15 and Recovery Day (R29), when kidneys were obtained for whole-genome microarray analysis and histological examination. Urine was collected at each necropsy for kidney injury molecular-1 (KIM-1) analysis. The KIM-1 detection and histological examination confirmed the nephrotoxicity. After differentially expression genes (DEGs) identification, there were 4360 and 4323 regulated genes for females and males, respectively. However, few overlapping expression genes co-regluated at each time point were found. By principle component analysis (PCA) and hierarchical cluster, the gene expression patterns were observed to be apparently associated with the disease stage. GO Annotation showed (1) immune response and related process, response to wounding, cell locomotion on D2; (2) cell death and apoptosis was also noted on D4; (3) processes of organic acid or carboxylic acid, apoptosis or cell death on D8 and D15; (4) processes of cell cycle, mitosis, division cell cycle on R29. In conclusion, the authors mapped the time-series gene expression patterns at the initiation, development and recovery stage of gentamycin-induced nephrotoxicity.

  16. Evaluation of ?Dream Herb,? Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells

    OpenAIRE

    Mossoba, Miriam E.; Flynn, Thomas J.; Vohra, Sanah; Wiesenfeld, Paddy; Sprando, Robert L.

    2016-01-01

    A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,” Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Addi...

  17. Effect of cyclosporine on drug transport and pharmacokinetics of nifedipine.

    Science.gov (United States)

    Dorababu, Madhura; Nishimura, Asako; Prabha, Thangavelu; Naruhashi, Kazumasa; Sugioka, Nobuyuki; Takada, Kanji; Shibata, Nobuhito

    2009-11-01

    Nifedipine (NFP) is an anti-hypersensitive drug and a well-known substrate of cytochrome P450 3A4 (CYP3A4), while cyclosporine (CSP) is a potent p-glycoprotein (P-gp) inhibitor. P-gp is a drug transporter, which determines the absorption and bioavailability of many drugs that are substrates for P-gp. Drugs that induce or inhibit P-gp may have a profound effect on the absorption and pharmacokinetics (PK) of drugs transported by P-gp within the body, possibly compromising their bioavailability. But the role of P-gp in the NFP efflux and its impact on PK profile is not known. Hence in our present study we attempted to investigate the effect of CSP on oral absorption and PK of NFP. Rhodamine 123 (Rho 123), a known P-gp substrate was used as a positive control. Male Wistar rats (350-400 g) were used for the study. Rats were divided into 4 groups (n=6 each); one group was treated with vehicle (cremophor) followed by NFP (0.2 mg/kg; i.v. bolus) and the other group with CSP (10 mg/kg; i.v.) followed by NFP. Group 3 and 4 were treated with vehicle (cremophor) followed by Rho 123 (0.2 mg/kg, i.v.) and CSP (10 mg/kg; i.v.) followed by Rho 123 (0.2 mg/kg, i.v.) respectively. The blood samples were collected at 0, 5, 10, 15, 30, 60, 90, 120, 180 and 240 min after NFP administration. NFP concentrations in plasma were analyzed by LC-MS-MS and Rho 123 was analyzed by fluorimetric detector. NFP efflux was significantly decreased in CSP treated rats (49.1% decrease, PNFP concentration in plasma were not changed. However the decrease in NFP efflux did not show any significant changes in NFP PK parameters (T(max); 2.0 vs. 2.5 min, C(max); 0.084 vs. 0.076 microg/ml, T(1/2); 84.0 vs. 91.4 min, AUC(0-t); 4.183 vs. 3.467 microg h/ml, AUC(infinity); 5.915 vs. 4.769 microg h/ml, AUMC(0-t); 224.073 vs. 173.063 microg h/ml, AUMC(infinity); 776.871 vs. 575.038 microg h/ml, MRT(0-t); 53.608 vs. 49.538 microg h/ml, MRT(infinity); 118.194 vs. 115.246 microg h/ml, CL(tot); 0.0375 vs. 0.0433 l

  18. [Safety and efficacy of treatment for severe atopic dermatitis with cyclosporin A and transfer factor].

    Science.gov (United States)

    Cordero Miranda, M A; Flores Sandoval, G; Orea Solano, M; Estrada Parra, S; Serrano Miranda, E

    1999-01-01

    The atopic dermatitis is a chronic skin disease that appears in patients with a personal or family history of allergic asthma and rhinitis. It is associated to the specific activation of a gene group. In most instances, the response to the conventional treatment is adequate. The are cases, though, know as refractory, where that is not the case. The study of two therapeutic alternatives, Transfer Factor (TF) and Cyclosporin A (CyA), was elaborated for this type of patients. Patients with severe refractory AD were studied, being admitted to the Allergic Service to the ISSSTE Lic. Adolfo López Mateos, ISSSTE, between September 1997 and june 1998. They were randomly divided in two groups. The first one was subjected to CyA, on a 4 mg/kg/day dosage, with monthly surveillance of kidney and hepatic functions and blood pressure twice a week. Group two was subjected to TF, as follows: one unit every third day for the first week, two units per week for the next three weeks and one monthly unit to complete six months. Initial and final clinical and immunologic testing was performed on both groups (eosinophils, total IgE, CD4 and CD8). Six patients included group A, and 12 patients in group B. Both groups showed a significant statistic reduction in the total eosinophils count, without an statistic difference between them. None showed changes in the total IgE. CyA reduced the CD4 levels, while the TF increased the levels of CD8 cells, both with a p 0.05 appeared between them. Tolerance to the treatments was adequate, and there was not need to suspend the treatment in any case. Only three patients showed hypertricosis and other one presented headaches, with CyA. Both treatments showed therapeutic benefits in the treatment of patients with severe refractory AD, with similar immunologic improvement. Both drugs present different action mechanisms, so their joint application could offer clinical benefit to the patient (synergetic action), cost reduction, and long term treatments

  19. Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease.

    Science.gov (United States)

    Laverdière, Isabelle; Guillemette, Chantal; Tamouza, Ryad; Loiseau, Pascale; Peffault de Latour, Regis; Robin, Marie; Couture, Félix; Filion, Alain; Lalancette, Marc; Tourancheau, Alan; Charron, Dominique; Socié, Gérard; Lévesque, Éric

    2015-02-01

    Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphosphate-binding cassette sub-family C1 and adenosine triphosphate-binding cassette sub-family C2 transporters, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase within the methotrexate pathway, and nuclear factor of activated T cells (cytoplasmic 1) loci exhibit a remarkable influence on severe acute graft-versus-host disease prevalence. Indeed, an increased risk of acute graft-versus-host disease was observed in association with single nucleotide polymorphisms located in 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (hazard ratio=3.04; P=0.002), nuclear factor of activated T cells (cytoplasmic 1) (hazard ratio=2.69; P=0.004), adenosine triphosphate-binding cassette sub-family C2 (hazard ratio=3.53; P=0.0018) and adenosine triphosphate-binding cassette sub-family C1 (hazard ratio=3.67; P=0.0005). While donor single nucleotide polymorphisms of dihydrofolate reductase and solute carrier family 19 (member 1) genes are associated with a reduced risk of acute graft-versus-host disease (hazard ratio=0.32-0.41; P=0.0009-0.008), those of nuclear factor of activated T cells (cytoplasmic 2) are found to increase such risk (hazard ratio=3.85; P=0.0004). None of the tested single nucleotide polymorphisms was associated with the occurrence of chronic graft-versus-host disease. In conclusion, by targeting drug-related biologically relevant genes, this work emphasizes the potential role of

  20. Biodegradable nanoparticles improve oral bioavailability of amphotericin B and show reduced nephrotoxicity compared to intravenous Fungizone.

    Science.gov (United States)

    Italia, J L; Yahya, M M; Singh, D; Ravi Kumar, M N V

    2009-06-01

    Amphotericin B (AMB), an effective antifungal and antileishmanial agent associated with low oral bioavailability (0.3%) and severe nephrotoxicity, was entrapped into poly(lactide-co-glycolide) (PLGA) nanoparticles to improve the oral bioavailability and to minimize the adverse effects associated with it. The AMB-nanoparticles (AMB-NP) were prepared by nanoprecipitation method employing Vitamin E-TPGS as a stabilizer. In vitro release was carried out using membrane dialysis method. The in vitro hemolytic activity of AMB-NP was evaluated by incubation with red blood cells (RBCs). The acute nephrotoxicity profile and oral bioavailability of AMB-NP were evaluated in rats. The prepared AMB-NP formulation contained monodispersed particles in the size range of 165.6 +/- 2.9 nm with 34.5 +/- 2.1% entrapment at 10% w/w initial drug loading. AMB-NP formulation showed biphasic drug release, an initial rapid release followed by a sustained release. The AMB-NP formulation exerted lower hemolysis and nephrotoxicity as compared to Fungizone. The relative oral bioavailability of the AMB-NP was found to be approximately 800% as compared to Fungizone. Together, these results offer a possibility of treating systemic fungal infection and leishmaniasis with oral AMB-NP, which could revolutionize the infectious disease treatment modalities.

  1. Carrot (Daucus carota L.): Nephroprotective against gentamicin-induced nephrotoxicity in rats

    Science.gov (United States)

    Sodimbaku, Vamsi; Pujari, Latha; Mullangi, Raviteja; Marri, Saisudheer

    2016-01-01

    Objectives: Daucus carota L.(DC) commonly known as carrot, folkorically used as ethnomedicine to treat nephrosis and other urinary disorders. Hence, the present study was aimed to investigate the nephroprotective effects of ethanolic root extract of DC against gentamicin-induced nephrotoxicity in Albino Wistar rats. Methods: Nephrotoxicity in rats was induced by intraperitoneal administration of gentamicin (100 mg/kg/day) for 8 days. Rats of either sex were divided into four groups (n = 6). Group 1 served as control that received normal saline (i.p.) whereas Group 2 (GM) was treated with gentamicin which served as gentamicin-intoxicated group. Group 3–4 (DC200, DC 400) were pretreated with DC at doses of 200 mg/kg and 400 mg/kg (p.o.), respectively, 1 h before the gentamicin intoxication. Following treatment, the nephroprotective effects of DC were evaluated by using serum levels of urea, blood urea nitrogen (BUN), uric acid, and creatinine levels; change in body weight and wet kidney weight along with the histological observations among the experimental groups. Results: Gentamicin intoxication induced elevated serum urea, BUN, uric acid, and creatinine levels which was found to be significantly (P < 0.01) decreased in a dose-dependent manner in groups received DC which was also evidenced by the histological observations. Conclusion: DC showed a significant nephroprotective effect in a dose-dependent manner by ameliorating the gentamicin-induced nephrotoxicity and thus authenticates its ethnomedicinal use. PMID:27127313

  2. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone

    Directory of Open Access Journals (Sweden)

    Atefeh Aminian

    2016-07-01

    Full Text Available Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg, animals received intraperitoneal injections of morphine (5 mg/kg/day and/or naltrexone (20 mg/kg/day, an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  3. Effect of creatine and pioglitazone on Hk-2 cell line cisplatin nephrotoxicity.

    Science.gov (United States)

    Genc, Gurkan; Kilinc, Veli; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Cisplatin is a chemotherapeutic agent, which is used in the treatment of various solid organ cancers, and its main dose limiting side effect of cisplatin is nephrotoxicity. The aim of this study is to investigate the role of pioglitazone and creatine on cisplatin nephrotoxicity in vitro. Real-time cell analyzer system (RTCA) was used for real-time and time-dependent analysis of the cellular response of HK-2 cells following incubation with cisplatin and combination with creatine or pioglitazone hydrochloride. First, half-maximal inhibitory concentrations (IC50) of cisplatin, creatine and pioglitazone were calculated by RTCA system. Afterwards creatine and pioglitazone was administered with serial dilutions under RTCA system. IC50 dose for cisplatin was 7.69 M × 10(-5) at 24th hour and 3.93 M × 10(-6) at 48th hour. IC50 dose for pioglitazone was 1.61 M × 10(-3) at 24th hour and 2.85 M × 10(-4) at 48th hour. Although cells were treated the dose of 40,225 mM creatine, IC50 dose could not been reached. Neither pioglitazone nor creatine had additional protective effect in any dose. Consequently, beneficial effect of creatine and pioglitazone on cisplatin-induced cell death could not be found. Further studies and clinical trials are needed to evaluate the effect of different doses of these drugs in cisplatin-induced nephrotoxicity.

  4. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference.

    Science.gov (United States)

    Zamani, Zohreh; Nematbakhsh, Mehdi; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Jilanchi, Sima; Navidi, Mitra; Shirdavani, Soheila; Ashrafi, Farzaneh

    2016-01-01

    The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats. Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes. CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P genders (P gender-dependent RAS response.

  5. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress.

    Science.gov (United States)

    Soliman, Amel M; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A

    2016-05-05

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  6. C-phycocyanin prevents cisplatin-induced nephrotoxicity through inhibition of oxidative stress.

    Science.gov (United States)

    Fernández-Rojas, Berenice; Medina-Campos, Omar Noel; Hernández-Pando, Rogelio; Negrette-Guzmán, Mario; Huerta-Yepez, Sara; Pedraza-Chaverri, José

    2014-03-01

    The aim of this study was to evaluate whether the antioxidant C-phycocyanin (C-PC, 5-30 mg kg(-1) i.p.) was able to prevent cisplatin (CP, 18 mg kg(-1) i.p.) induced nephrotoxicity by reducing oxidative stress in CD-1 mice. Nephrotoxicity was assessed by measuring blood urea nitrogen, plasma glutathione peroxidase, plasma creatinine, the renal activity of N-acetyl-β-d-glucosaminidase, apoptosis and histopathological changes. Oxidative stress was evaluated by measuring the content of glutathione, malondialdehyde, 4-hydroxynonenal and oxidized proteins in renal tissue. C-PC prevented CP-induced renal damage and oxidative stress in a dose-dependent manner. Moreover, C-PC prevented the decrease in the renal activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, glutathione-S-transferase and catalase induced by cisplatin. In vitro assays showed that C-PC was an effective scavenger of the following reactive species: hypochlorous acid, peroxynitrite anions, peroxyl radicals, diphenyl-1-picrylhydrazyl, hydroxyl radicals, superoxide anions, singlet oxygen and hydrogen peroxide. It is concluded that the protective effect of the nutraceutical C-PC against CP-induced nephrotoxicity was associated with the attenuation of oxidative stress and the preservation of the activity of antioxidant enzymes.

  7. Nephrotoxicity of concomitant use of tacrolimus and teicoplanin in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Mori, T; Shimizu, T; Kato, J; Kikuchi, T; Kohashi, S; Koda, Y; Toyama, T; Saburi, M; Iketani, O; Okamoto, S

    2014-04-01

    Both tacrolimus and glycopeptide antibiotics are known to be nephrotoxic, and are often concomitantly given after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. The aim of this study is to evaluate the nephrotoxicity of concomitant use of tacrolimus and glycopeptide antibiotics in HSCT recipients. We retrospectively evaluated 67 patients who received intravenous tacrolimus and teicoplanin concomitantly for >4 days after allogeneic HSCT for hematologic diseases. Therapeutic drug monitoring (TDM) was performed in all patients for both tacrolimus and teicoplanin. The median age of the patients was 48 years (range: 16-62), and the median duration of the co-administration of tacrolimus and teicoplanin was 11 days (range: 4-40). The mean serum creatinine (sCr) level tended to be elevated after the co-administration (from 0.69 ± 0.26 to 0.75 ± 0.30 mg/dL; P = 0.08); however, a 2-fold or greater increase in sCr was observed only in 2 (3.0%) patients. Increased sCr was reversible, and no patient required hemodialysis. These results suggest that the incidence of clinically significant nephrotoxicity can be minimized if the TDM of each drug is properly applied. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Physalis alkekengi and Alhagi maurorum ameliorate the side effect of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Changizi-Ashtiyani, S; Alizadeh, M; Najafi, H; Babaei, S; Khazaei, M; Jafari, M; Hossaini, N; Avan, A; Bastani, B

    2016-07-01

    Cisplatin is frequently being used for the treatment of different tumors, although the application of this agent is associated with nephrotoxicity. Here, we explored the antioxidant and anti-inflammatory activities of Physalis alkekengi and Alhagi maurorum; 400 mg kg(-1) per day P. alkekengi and 100 mg kg(-1) per day A. maurorum were administered in rats, orally for 10 days after a single dose of 7 mg kg(-1) intraperitoneal cisplatin. The concentrations of creatinine, urea-nitrogen, and relative and absolute excretion of sodium/potassium were evaluated before/after therapy. Levels of malondialdehyde (MDA) and ferric-reducing antioxidant power (FRAP) were measured to assess the oxidative stress induced by cisplatin. Moreover, tissues sections were used for histological analyses and evaluation of the degree of tissue damage. Cisplatin increased serum levels of creatinine and urea-nitrogen, relative/absolute excretion of sodium/potassium, and MDA, whereas decreased FRAP level. Interestingly, P. alkekengi or A. maurorum were able to reduce the level of the renal function markers as well as the levels of sodium/potassium. This effect was more pronounced by P. alkekengi. Moreover, cisplatin induced pathological damage in kidney, whereas treatment with these agents improved this condition. Our findings demonstrate the potential therapeutic impact of P. alkekengi and A. maurorum for improving cisplatin-induced nephrotoxicity, supporting further investigations on the novel potential clinical application of these agents for patients being treated with cisplatin to ameliorate cisplatin-induced nephrotoxicity.

  9. Potential of morin and hesperidin in the prevention of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Kaltalioglu, Kaan; Coskun-Cevher, Sule

    2016-09-01

    Oxidative stress is one of the important mechanisms of cisplatin-induced nephrotoxicity. Therefore, this study was designed to explore the potential protective effects of morin and/or hesperidin on oxidative stress in cisplatin-induced nephrotoxicity. This study was performed on 42 Wistar rats. Rats were divided into seven groups: control, morin, hesperidin, cisplatin, cisplatin + morin, cisplatin + hesperidin, and cisplatin + morin + hesperidin. Morin and/or hesperidin were given for 10 consecutive days by oral gavage and on the 4th day a single dose of cisplatin (7 mg/kg) was injected intraperitoneally. After administrations, on the 11th day of the experiment the animals were killed, and malondialdehyde (MDA), nitric oxide (NOx), glutathione (GSH) levels and myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD) activity were measured. Cisplatin-treated rats showed increased levels of MDA, and decreased levels of NOx also activity of CAT. Morin and/or hesperidin pretreatment prevent oxidative stress in kidney tissue, while they increase the NOx level, CAT activity, and decrease MPO activity. In conclusion, morin + hesperidin pretreatment may have a significant potential for protection of cisplatin-induced nephrotoxicity.

  10. Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat

    Directory of Open Access Journals (Sweden)

    Ebenezer Tunde Olayinka

    2016-08-01

    Full Text Available We investigated the protective effect of gallic acid (GA against methotrexate (MTX-induced hepatotoxicity and nephrotoxicity. Male Wistar rats were randomized into five groups (n = 6/group: I, control; II, MTX-treated for seven days; III, pre-treated with GA for seven days, followed by MTX for seven days; IV, co-treated with MTX and GA for seven days and V, GA for seven days. MTX caused a significant increase (P<0.05 in plasma biomarkers of nephrotoxicity (urea, creatinine and hepatotoxicity (Bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase when compared with control. Furthermore, MTX caused a significant decrease in the activities of hepatic enzymic antioxidants (superoxide dismutase, catalase, glutathione S-transferase and nonenzymic antioxidants (Vitamin C and glutathione, followed by a significant increase in hepatic malondialdehyde content. However, pretreatment and co-treatment with gallic acid ameliorated the MTX-induced biochemical changes observed. Taken together, GA protected against MTX-induced hepatotoxicity and nephrotoxicity in rats, by reducing the impact of oxidative damage to tissues.

  11. Fractional excretion of magnesium, a marker of aminoglycoside induced nephrotoxicity in neonates

    Directory of Open Access Journals (Sweden)

    Sheikh Farjana Sonia

    2016-01-01

    Full Text Available Aminoglycoside is a widely used antibiotic in neonatal age group at hospital setting in Bangladesh. It has underlying side effect and toxicity which is mostly unseen and ignored. The aim of the study was to evaluate the nephrotoxic effect of aminoglycoside in neonates. This study was conducted in fifty hospital admitted neonates of Dhaka Shishu Hospital from January 2012 to December 2013. Serum creatinine, blood urea nitrogen, and fractional excretion of magnesium (FEMg were measured before starting and after seven days of aminoglycoside treatment. Statistical analyses of the results were obtained by window-based computer software devised with Statistical Packages for Social Sciences (SPSS version 16. Statistical tests for significance of difference were done using Student′s paired t-test. Serum creatinine and blood urea nitrogen were not significantly changed after drug administration (P = 0.092, P = 0.247, respectively. None of the neonates in our study group had abnormal serum creatinine and blood urea nitrogen after aminoglycoside therapy. FEMg was significantly increased (P <0.001 after aminoglycoside treatment. In this study, conventional renal function test such as blood urea and serum creatinine did not reflect the nephrotoxicity of aminoglycoside. However, a biomarker of tubular damage, FEMg detected nephrotoxicity of aminoglycoside therapy.

  12. Sida rhomboidea.Roxb leaf extract ameliorates gentamicin induced nephrotoxicity and renal dysfunction in rats.

    Science.gov (United States)

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Devkar, Ranjitsinh V; Ramachandran, A V

    2010-10-28

    Sida rhomboidea.Roxb (SR) known as "Mahabala" in Ayurveda and marketed as "Shahadeyi" is used in ethnomedicine to treat ailments such as dysuria and urinary disorders. To evaluate nephroprotective potential of SR against gentamicin (GM) induced nephrotoxicity and renal dysfunction. Nephrotoxicity was induced in rats with GM (100 mg/kg bodyweight (i.p.) for 8 days) and were treated with SR extract (200 and 400 mg/kg bodyweight (p.o.) for 8 days) or 0.5% carboxymethyl cellulose (vehicle). Plasma and urine urea and creatinine, renal enzymatic and non-enzymatic antioxidants along with lipid peroxidation were evaluated in various experimental groups. GM treatment induced significant elevation (p<0.05) in plasma and urine urea, creatinine, renal lipid peroxidation along with significant decrement (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR treatment to GM treated rats (GM+SR) recorded significant decrement (p<0.05) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR leaf extract ameliorates GM induced nephrotoxicity and renal dysfunction and thus validates its ethnomedicinal use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  13. Capsaicin pretreatment increased the bioavailability of cyclosporin in rats: involvement of P-glycoprotein and CYP 3A inhibition.

    Science.gov (United States)

    Zhai, Xue-jia; Shi, Fang; Chen, Fen; Lu, Yong-ning

    2013-12-01

    Capsaicin (CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. This study investigated the effect of CAP on the pharmacokinetics of Cyclosporin A (CyA) in rats and the mechanism of this food-drug interaction. The results indicated that after 7 days of low or middle dose of CAP (0.3 or 1.0 mg/kg), the blood concentration of CyA was not significantly changed compared with that of vehicle-treated rats, whereas the blood concentration of CyA in high dose group (3.0 mg/kg) was significantly increased. The total clearance (CL/F) of CyA was decreased, and the bioavailability was significantly increased to about 1.44-fold of that in vehicle-treated rats after 7 days of high dose CAP treatment. At this time, the P-gp and CYP3A1/2 in the liver and intestine were decreased at both the mRNA and protein levels. These results demonstrated that chronic ingestion of high doses of CAP will increase the bioavailability of CyA to a significant extent in rats and the food-drug interaction between CAP and CyA appears to be due to modulation of P-gp and CYP3A gene expression by CAP, with differential dose-dependence. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  14. Administration of Cyclosporine A in Pregnant Rats - the Effect on Blood Pressure and on the Glomerular Number in Their Offspring

    Directory of Open Access Journals (Sweden)

    Natalia Slabiak-Blaz

    2015-07-01

    Full Text Available Background/Aims: Cyclosporine A (CsA is a commonly used immunosuppressive agent. In some patients treatment with CsA has to be continued during pregnancy. The aim of the study was to assess in an experimental model whether the exposure to CsA during fetal life influences the number and volume of glomeruli, kidney function and blood pressure in the offspring. Methods: Eight pregnant female Sprague-Dawley rats were allocated to 2 treatment regimens: with CsA or solvent. Blood pressure was measured in the offspring at 7 and 11 weeks of age and albuminuria was determined at 11 weeks of age. In the kidney the number and mean volume of glomeruli was assessed using stereological methods. Results: In the offspring of pregnant rats treated with CsA the number of glomeruli was significantly lower and the mean volume of glomeruli was higher when compared to the offspring of pregnant rats receiving solvent. Systolic and diastolic blood pressures as well as albuminuria were significantly higher in the offspring of mothers treated with CsA during gestation compared to the offspring from the control group. Conclusions: Exposure of rats to CsA during fetal life impairs kidney development, thus potentially predisposing to chronic kidney disease and hypertension in the adult life.

  15. Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

    Science.gov (United States)

    Eisen, H J; Hobbs, R E; Davis, S F; Carrier, M; Mancini, D M; Smith, A; Valantine, H; Ventura, H; Mehra, M; Vachiery, J L; Rayburn, B K; Canver, C C; Laufer, G; Costanzo, M R; Copeland, J; Dureau, G; Frazier, O H; Dorent, R; Hauptman, P J; Kells, C; Masters, R; Michaud, J L; Paradis, I; Renlund, D G; Vanhaecke, J; Mellein, B; Mueller, E A

    2001-01-15

    The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the Cs

  16. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.

    Science.gov (United States)

    van Hal, S J; Paterson, D L; Lodise, T P

    2013-02-01

    In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

  17. Validation of a colistin plasma concentration breakpoint as a predictor of nephrotoxicity in patients treated with colistin methanesulfonate.

    Science.gov (United States)

    Horcajada, Juan P; Sorlí, Luisa; Luque, Sonia; Benito, Natividad; Segura, Concepción; Campillo, Nuria; Montero, Milagro; Esteve, Erika; Mirelis, Beatriz; Pomar, Virginia; Cuquet, Jordi; Martí, Carmina; Garro, Pau; Grau, Santiago

    2016-12-01

    Nephrotoxicity limits the effective use of colistin for the treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections. We previously defined a steady-state colistin plasma concentration (Css) of 2.42 mg/L that predicted nephrotoxicity at end of treatment (EOT). The objective of this study was to validate this breakpoint in a prospective cohort. This was a multicentre, prospective, observational study conducted at three hospitals with a cohort of patients treated for MDR-GNB infection with colistin methanesulfonate from September 2011 until January 2015. Nephrotoxicity was evaluated at Day 7 and at EOT using the RIFLE criteria. Css values were measured and analysed using HPLC. Taking the previously defined breakpoint for colistin concentration as a criterion, patients were divided into two groups (Css, ≤2.42 mg/L vs. >2.42 mg/L). Sixty-four patients were included. Seven patients (10.9%) had a Css > 2.42 mg/L and were compared with the remaining patients. Bivariate analysis showed that patients with a Css > 2.42 mg/L were older and had a significantly higher incidence of nephrotoxicity at Day 7 and EOT. Although not statistically significant, nephrotoxicity occurred earlier in these patients (6.2 days vs. 9.2 days in patients with lower Css; P = 0.091). Multivariate analysis of nephrotoxicity showed that Css > 2.42 mg/L was the only predictive factor. Nephrotoxicity was more frequent and occurred earlier in patients with colistin plasma concentrations higher than the previously defined breakpoint (2.42 mg/L). Colistin therapeutic drug monitoring should be routinely considered to avoid reaching this toxicity threshold and potential clinical consequences. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  18. Cyclosporin A protects liver cells against phalloidin. Potent inhibition of the inward transport of cholate and phallotoxins.

    Science.gov (United States)

    Ziegler, K; Frimmer, M

    1984-10-12

    Cyclosporin A at concentrations of more than 10 nM protects isolated hepatocytes against the action of phalloidin. Cyclosporin A at 100 nM inhibits the uptake of demethyl[3H]phalloin by 50%, and at 5 microM also that of [14C]cholate. This inhibition is independent of the preincubation period and is not reversed by washing the cells. With a 30-60-fold excess of cyclosporin A, affinity labeling of plasma membrane proteins using 12 microM [3H]isothiocyanatobenzamido cholate was reduced to 40-60% of the control. These findings indicate that transport inhibition by cyclosporin A in liver cells cannot be explained by simple competition on the level of the membrane protein(s) involved.

  19. Levamisole-Adulterated Cocaine Nephrotoxicity:  Ultrastructural Features.

    Science.gov (United States)

    Liu, Yi-Wei Justin; Mutnuri, Sangeeta; Siddiqui, Sarah Batool; Weikle, Geoff Richard; Oladipo, Olajumoke; Ganti, Niharika; Beach, Robert E; Afrouzian, Marjan

    2016-05-01

    The issue of levamisole-adulterated cocaine is emerging as a rapidly growing public health concern due to an increasing number of reports describing its role in cutaneous vasculitis and agranulocytosis. Of note, levamisole is recognized as a contaminant in 69% of the cocaine used within the United States. We describe a patient who was a chronic cocaine user and developed systemic vasculitis characterized by polyarthralgia, bullous skin lesions, agranulocytosis, and antineutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis. The skin biopsy specimen demonstrated leukocytoclastic vasculitis. The renal biopsy specimen revealed pauci-immune necrotizing and crescentic glomerulonephritis and unusual deposits with medium electron density composed of granules, microspherules, and rare single fibrils on electron microscopy. The electron microscopic features of levamisole-adulterated cocaine toxicity are novel findings that are presented for the first time, to our knowledge, in this report. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Sperm abnormality toxicity due to cyclosporine A and the ameliorative effect of royal jelly in male rats

    Directory of Open Access Journals (Sweden)

    Azza M. Gawish

    2016-08-01

    Full Text Available The immunosuppressive drug, utilized widely in Egypt, cyclosporine A was studied to evaluate its toxicity in male rats. Animals were divided into a control (untreated, 3 groups treated intraperitoneally with 20, 40 and 60 m/kg cyclosporine A for 5, 10 and 15 days, respectively and 3 groups treated intraperitoneally with 20, 40 and 60 mg/kg of cyclosporine A plus 100 mg/kg royal jelly administrated orally. Toxicity evaluation was carried out using two main endpoints: reproductive study (sperm morphology and count abnormalities and biochemical changes in liver and testis (DNA amounts. The aim of this work is to study the protective role of royal jelly against sperm abnormalities in shape and count, and changes in DNA contents in liver and testis tissue induced in rats when treated by cyclosporine A with different doses (20–40–60 mg/kg/day for 5, 10, and 15 days in male rats and how the royal jelly can repair this changes. Our results showed that sperm abnormalities induced by cyclosporine A included deviation from normal shape in head and tail. Abnormal heads contained amorphous head and banana-shaped head, whereas the abnormal tails included divided and coiled tails. It also induced an insignificant effect on the total sperm counts after 5 days of injection with the drug combined with royal jelly. DNA contents were determined in rat liver and testis cells to illustrate the mutagenic effect of cyclosporine A and how the royal jelly can modulate this effect. From these results we concluded that cyclosporine A toxicity was dose and time dependent and should be administrated under special precautions and medical supervision. Using of royal jelly in combination with cyclosporine A drug decreased its toxic effect, so it's considered as protector.

  1. Chronic kidney disease in patients admitted to the medical ward of ...

    African Journals Online (AJOL)

    Chronic kidney disease in patients admitted to the medical ward of Mbarara Regional Referral Hospital in southwestern Uganda: Prevalence and associated factors. ... We collected socio-demographic and clinical data including presenting symptoms, history of diabetes, hypertension, and use of nephrotoxic medication.

  2. Treatment of Refractory Chronic Urticaria

    Science.gov (United States)

    Mehta, Aayushi; Godse, Kiran; Patil, Sharmila; Nadkarni, Nitin; Gautam, Manjyot

    2015-01-01

    Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second-generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature. PMID:26120147

  3. Treatment of refractory chronic urticaria

    Directory of Open Access Journals (Sweden)

    Aayushi Mehta

    2015-01-01

    Full Text Available Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second-generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature.

  4. Synergy between lysosomotropic amines and cyclosporin A on human T cell responses to an exogenous protein antigen, tetanus toxoid.

    Science.gov (United States)

    Schultz, K R; Nelson, D; Bader, S

    1996-09-01

    Previously, it has been shown that the lysosomotropic amine, chloroquine, is effective in the prevention of graft-versus-host disease (GVHD) using murine models. Because chloroquine and hydroxychloroquine suppress MHC class II antigen presentation, their mechanism of action is different to other immune suppressant drugs (cyclosporin A) currently used to control GVHD. It is possible that the use of cyclosporin A and chloroquine in combination may have an additive or synergistic effect on T cell responses to antigens presented in the context of MHC class II. We investigated the effects of chloroquine or hydroxychloroquine in combination with cyclosporin A on human T cell responses in vitro to tetanus toxoid, an exogenous protein antigen dependent on MHC class II presentation for proliferative responses. We demonstrate that similar levels of chloroquine and hydroxychloroquine suppress human T cell responses to tetanus toxoid and that the use of either agent in combination with cyclosporin A results in synergistic suppression. Evaluation for a direct effect by the lysosomotropic amines on T cells, in the absence of antigen presenting cells, revealed that there was inhibition of T cell responses but only at high concentrations. No significant decrease or increase was seen in surface MHC II or invariant chain expression or in cytoplasmic invariant chain after exposure to chloroquine. Thus, lysosomotropic amines in combination with cyclosporin A are synergistic in suppression of T cell proliferation. Use of these agents in combination with cyclosporin A may improve control of graft-versus-host disease.

  5. Combined treatment with chemokine receptor 5 blocker and cyclosporine induces prolonged graft survival in a mouse model of cardiac transplantation.

    Science.gov (United States)

    Jun, Li; Kailun, Zhang; Aini, Xie; Lei, Xu; Guohua, Wang; Sihua, Wang; Ping, Ye; Tucheng, Sun; Xionggang, Jiang; Wenwei, Chen; Jiahong, Xia

    2010-04-01

    Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is efficacious in modulating inflammation and immunity as well as in patients with human immunodeficiency virus infection. This study examined the effect and mechanism of CCR5 blockade in combination with cyclosporine in prolonging cardiac allograft survival in mice. Hearts from BALB/c mice were transplanted into C57BL/10 recipients. They were administrated with anti-CCR5 antibody (Ab) or control Ab and cyclosporine or phosphate-buffered (PBS) saline, respectively. To investigate the role of regulatory cells, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from anti-CCR5 Ab plus cyclosporine-treated recipients and cardiac allograft transplantation. Compared with recipients treated with control Ab plus PBS, allografts treated with anti-CCR5 Ab and cyclosporine showed significantly prolonged survival (p cyclosporine-treated recipients induced significantly prolonged survival in secondary recipients (p cyclosporine is effective in protecting the cardiac allograft in a robust murine model. This effect is partly mediated by regulatory cell recruitment and control of effector cell infiltration.

  6. Cyclosporine in the Management of Impetigo Herpetiformis: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Aikaterini Patsatsi

    2013-03-01

    Full Text Available 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.

  7. Unsuccessful cyclosporine plus prednisolone therapy for autoimmune meningoencephalitis in three dogs.

    Science.gov (United States)

    Jung, Dong-In; Lee, Hee-Chun; Ha, Jeongim; Jung, Hae-Won; Jeon, Joon-Hyeok; Moon, Jong-Hyun; Lee, Jae-Hoon; Kim, Na-Hyun; Sur, Jung-Hyang; Kang, Byeong-Teck; Cho, Kyu-Woan

    2013-12-30

    A 4-year-old female Maltese (case 1), a 9-year-old castrated male shih tzu (case 2) and 2-year-old female Pomeranian (case 3) presented with neurological signs, such as head tilt, ataxia, circling and paresis. The three cases were tentatively diagnosed as having meningoencephalitis of unknown etiology based on computed tomography scan and cerebrospinal fluid analysis. All patients were managed with cyclosporine plus prednisolone therapy. The survival times of the three patients were 170, 70 and 21 days, respectively. After the cases died, we performed necropsy and histopathological examination for definitive diagnosis. Based on the necropsy, histopathological and immunohistochemical examinations, cases 1, 2 and 3 were definitely diagnosed as having necrotizing meningoencephalitis, necrotizing leukoencephalitis and granulomatous meningoencephalitis, respectively. This case report demonstrated the clinical findings, brain CT characteristics and histopathological and immunohistochemical features of NME, NLE and GME in dogs and discussed the reason for the relatively short survival times under cyclosporine plus prednisolone therapy.

  8. Efficacy of topical 0.05% cyclosporine treatment in children with severe vernal keratoconjunctivitis.

    Science.gov (United States)

    Çoban-Karataş, Müge; Özkale, Yasemin; Altan-Yaycıoğlu, Rana; Sızmaz, Selçuk; Pelit, Aysel; Metindoğan, Sevda; Cantürk-Uğurbaş, Sılay; Aydın-Akova, Yonca

    2014-01-01

    We aimed to determine the efficacy of topical cyclosporine in children with vernal keratoconjunctivitis refractory to topical mast cell stabilizer and antihistamine therapy. Thirty-one patients, 24 boys and 7 girls younger than 16 years of age, were included in the study. All patients were scored on a four-point scale from 0 to 3 for symptoms and signs. Each patient received topical cyclosporine 0.05% emulsion (Restasis, Allergan Inc., Irvine, CA, USA) four times daily in addition to preservative-free artificial tears and was followed for 6 months. The data was recorded before the initiation of treatment (day 0) and at the 1st, 3rd, and 6th months following treatment. After six months of treatment, severity of all symptoms and signs showed a statistically significant decrease (pvernal keratoconjunctivitis in children.

  9. Direct effects of cyclosporin A on human pancreatic beta-cells

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Nerup, J; Nielsen, Jens Høiriis

    1986-01-01

    Cyclosporin A (CyA) may induce clinical remission in newly diagnosed insulin-dependent diabetes mellitus patients. Recently, however, adverse effects of high doses of CyA on rodent islets have been reported in vivo and in vitro. The possible direct effects of CyA on the human endocrine pancreas...... h after removal of the drug. We concluded that CyA has a direct inhibitory effect on insulin release from human pancreatic islets with a concomitant increase in the residual insulin content. If applicable to the in vivo condition, CyA may therefore, in addition to its immunosuppressive effect, have...... by 59% (range 3-268%). The glucagon content was not affected. Cyclosporin G inhibited the insulin release, whereas dihydrocyclosporin D had no consistent effects. Glucose-stimulated insulin release from perifused islets was markedly depressed in CyA-treated islets. This effect was not fully reversed 48...

  10. Ciclosporin metabolite pattern in blood and urine of liver graft recipients. I. Association of ciclosporin metabolites with nephrotoxicity.

    Science.gov (United States)

    Christians, U; Kohlhaw, K; Budniak, J; Bleck, J S; Schottmann, R; Schlitt, H J; Almeida, V M; Deters, M; Wonigeit, K; Pichlmayr, R

    1991-01-01

    Blood ciclosporin (Cs) metabolite pattern in 58 liver grafted patients was routinely monitored by HPLC from the first Cs dose after transplantation until discharge from hospital. Eighteen patients with normal kidney function were allocated to Group I and 14 patients in Group II suffered Cs nephrotoxicity during their clinical course. There were no significant differences between both groups in blood Cs level, kidney function before transplantation, liver function or co-administration of other potentially nephrotoxic drugs. A correlation matrix involving both groups showed a significant correlation between the blood concentration of metabolite M1c9 and serum creatinine and urea, and an inverse correlation with creatinine clearance. During a nephrotoxic episode the blood concentrations of metabolites M1c9 and M1A were significantly elevated in patients in Group II. Analysis of the time course revealed significantly higher blood levels of M19 and M1c9 in Group II patients compared with those in Group I for the first 10 days after transplantation. Serum creatinine and urea concentrations remained significantly elevated, the creatinine clearance being significantly reduced throughout the period of observation. The elevated blood concentrations of ciclosporin metabolites M1c9 and M19 during nephrotoxic episodes suggest that these metabolites are associated with ciclosporin nephrotoxicity. It could not be decided if the elevated metabolite concentrations were the result of and/or the reason for impaired kidney function.

  11. Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway.

    Science.gov (United States)

    Li, Hui; Tang, Yuling; Wen, Long; Kong, Xianglong; Chen, Xuelian; Liu, Ping; Zhou, Zhiguo; Chen, Wenhang; Xiao, Chenggen; Xiao, Ping; Xiao, Xiangcheng

    2017-03-11

    Cisplatin is one of the most effective chemotherapeutic agents; however, its clinical use is limited by serious side effects of which nephrotoxicity is the most important. Nephrotoxicity induced by cisplatin is closely associated with autophagy reduction and caspase activation. In this study, we investigated whether neferine, an autophagy inducer, had a protective effect against cisplatin-induced nephrotoxicity. In an in vitro cisplatin-induced nephrotoxicity model, we determined that neferine was able to induce autophagy and that pretreatment with neferine not only attenuated cisplatin-induced cell apoptosis but further activated cell autophagy. This pro-survival effect was abolished by the autophagic flux inhibitor chloroquine. Furthermore, neferine pretreatment activated the AMPK/mTOR pathway; however, pharmacological inhibition of AMPK abolished neferine-mediated autophagy and nephroprotection against cisplatin-induced apoptosis. Collectively, our findings suggest for the first time the possible protective mechanism of neferine, which is crucial for its further development as a potential therapeutic agent for cisplatin-induced nephrotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    OpenAIRE

    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 ca...

  13. Evaluation of cyclosporine A eye penetration after administration of liposomal or conventional forms in animal model

    Directory of Open Access Journals (Sweden)

    Sara Nikoofal-Sahlabadi

    2013-01-01

    Full Text Available Abstract A lot of researches have investigated the effects of topical cyclosporine A on the eye surface layers’ diseases. By now the main limitation in cyclosporine application is the low permeation of the drug into the posterior segments of the eye. The aim of present study was to formulate high permeable dosage form can be beneficial in the topical treatment of the uveitis. To reach higher corneal drug absorption and drug concentration in the posterior segments of the eye, 3 nanoliposomal formulations containing 0.5 mg/ml cyclosporine A were prepared. Liposomal formulations and the commercial product (Restasis® were instilled in the right and left eyes of the rabbits, respectively. The rabbits were killed in the 3, 7, 14 and 28 days of study and the aqueous humor and vitreous were extracted. Mean size of liposomal formulation number 1, number 2 and number 3 were 107.2 ± 0.7, 129.3±0.9 and 144.8±1.8 nm and their zeta potential were -5.0±1.7, -5.5±2.3 and 44.6±6.2 mV, respectively. Results of ocular analysis showed that the liposomal formulations could increase the concentration of the drug in the aqueous and vitreous like Restasis®. But, in contrast with what has been expected the findings of this study implicate nanoliposomal formulations prepared could not make a significant difference in concentration of the drug in aqueous and vitreous humor compared to Restasis® (anionic microemulsion. In conclusion, we can state that liposomes with the same composition as our formulations are not more efficient than microemulsion for cyclosporine as ophthalmic drug delivery.

  14. Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis.

    Science.gov (United States)

    Vichyanond, Pakit; Kosrirukvongs, Panida

    2013-06-01

    Vernal keratoconjunctivitis is a sight-threatening inflammatory disease of conjunctiva and cornea. It is frequently observed in young children with the onset usually occurring in the first decade of life. Mild cases of VKC tend to remit with nonspecific and supportive therapy. In contrast, severe cases are usually more protracted with remission/relapse occurring for a prolonged period of time. Although VKC is classified as an allergic eye condition, the role of allergens as an inciting factor is not clear. Pathogenesis of VKC involves roles for IgE, cytokines, chemokines, and inflammatory cells (T and B lymphocytes, mast cells, basophils, neutrophils, and eosinophils) with the release of their granular proteins, proliferation of fibroblasts, and laying down exuberant amounts of collagen fibers in the conjunctival tissue. In severe VKC cases-often of tarsal VKC-diagnostic giant papilla are classically observed on the upper tarsal plate, giving the classic 'cobble-stone' appearance. Corneal ulcer can occur from the effect of eosinophilic granular proteins on corneal epithelium and by physical trauma by intense eye rubbing. Topical corticosteroids, often required for controlling symptoms and signs in severe VKC, can lead to serious ocular complications. Immunomodulators that have been investigated for VKC treatment include topical ocular preparations of cyclosporine A and tacrolimus. Severe VKC responds promptly to topical cyclosporine A and tacrolimus, mostly within 1 month of therapy. Prolonged use of cyclosporine A and tacrolimus in VKC is safe and is tolerated by most patients without significant side effects. Recent investigations on the use of these two agents in VKC are the main purpose of this review. The use of cyclosporine A and tacrolimus are a major breakthrough in treatment for severe VKC, a debilitating allergic eye disease in children.

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

    Science.gov (United States)

    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.

  16. Cyclosporine-associated renal arteriopathy resulting in loss of allograft function

    Energy Technology Data Exchange (ETDEWEB)

    Sommer, B.G.; Innes, J.T.; Whitehurst, R.M.; Sharma, H.M.; Ferguson, R.M.

    1985-06-01

    Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

  17. Full factorial design, physicochemical characterisation and biological assessment of cyclosporine A loaded cationic nanoparticles.

    Science.gov (United States)

    Hermans, Kris; Van den Plas, Dave; Everaert, Arnout; Weyenberg, Wim; Ludwig, Annick

    2012-09-01

    Cyclosporine A loaded poly(lactide-co-glycolide) nanoparticles coated with chitosan were prepared using the o/w emulsification solvent evaporation method. A 2(3) full factorial design was used to investigate the effect of 3 preparation parameters on the particle size, polydispersity index, zeta potential and drug release. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the developed nanoparticles. Particle sizes varied from 156 nm to 314 nm, and polydispersity index values of 0.07-0.56 were obtained depending on the different preparation parameters. All nanoparticles showed positive zeta potential values. Nanoparticles prepared with the highest concentration chitosan retained a positive zeta potential after dispersion in simulated lachrymal fluid, which supports the possibility of an electrostatic interaction between these particles and the negatively charged mucus layer at the eye. The in vitro release profile of cyclosporine A from the chitosan-coated nanoparticles was strongly dependent on the release medium used. None of the cationic nanoparticle formulations showed significant cytotoxicity compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A encapsulated in the various nanoparticle formulations remained anti-inflammatory active as significant suppression of interleukine-2 secretion in concanavalin A stimulated Jurkat T cells was observed. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. [Hematologic response predictor factors in adults with myelodysplastic syndromes (SMD) treated with cyclosporin A (CSA)].

    Science.gov (United States)

    Zamora-Pérez, Elia; López-Karpovitch, Xavier

    2015-01-01

    Myelodysplastic syndromes (MDS) are clonal diseases of hematopoietic cells. The International Prognostic Scoring System (IPSS) is the risk scale most employed in MDS. Cyclosporin A (CsA) has been used in the treatment of cytopenias in MDS. To evaluate hematologic response and identify response predictive factors in adults with MDS treated with CsA. Patients with MDS diagnosed according World Health Organization (WHO) classification were recruited from January 1997 to June 2012. All patients were classified with IPSS, IPSS revised (IPSS-R),WHO Prognostic Scoring System (WPSS), and WPSS revised (WPSS-R) risk scales. Cyclosporin A was administered orally at a dose of 5 mg/kg/day. Hematologic response was evaluated following the International Working Group for MDS (2006 version) criteria. Inclusion criteria were met by 32 patients. Median age was 56.5 years, with a median follow-up of 3.1 years. Hematologic response was 56.2% and erythrocyte independence transfusion was found in 42.9% of patients. Age,hemoglobin level, and WPSS at diagnosis were independent predictive factors for CsA response. Survival was longer in responder than in nonresponder CsA patients (p=0.06). Cyclosporin A induced hematologic response in >50% of patients with MDS aged <57 years, with Hb<8 g/dl and low WPSS at diagnosis.

  19. Advantageous effects of immunosuppression with tacrolimus in comparison with cyclosporine A regarding renal function in patients after heart transplantation

    Directory of Open Access Journals (Sweden)

    Helmschrott M

    2015-02-01

    Full Text Available Matthias Helmschrott,1 Rasmus Rivinius,1 Arjang Ruhparwar,2 Bastian Schmack,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Department of Cardiac Surgery, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: Nephrotoxicity is a serious adverse effect of calcineurin inhibitor therapy in patients after heart transplantation (HTX.Aim: In this retrospective registry study, renal function within the first 2 years after HTX in patients receiving de novo calcineurin inhibitor treatment, that is, cyclosporine A (CSA or tacrolimus (TAC, was analyzed. In a consecutive subgroup analysis, renal function in patients receiving conventional tacrolimus (CTAC was compared with that of patients receiving extended-release tacrolimus (ETAC.Methods: Data from 150 HTX patients at Heidelberg Heart Transplantation Center were retrospectively analyzed. All patients were continuously receiving the primarily applied calcineurin inhibitor during the first 2 years after HTX and received follow-up care according to center practice.Results: Within the first 2 years after HTX, serum creatinine increased significantly in patients receiving CSA (P<0.0001, whereas in patients receiving TAC, change of serum creatinine was not statistically significant (P=not statistically significant [ns]. McNemar’s test detected a significant accumulation of patients with deterioration of renal function in the first half year after HTX among patients receiving CSA (P=0.0004. In patients receiving TAC, no significant accumulation of patients with deterioration of renal function during the first 2 years after HTX was detectable (all P=ns. Direct comparison of patients receiving CTAC versus those receiving ETAC detected no significant differences regarding renal function between

  20. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    Directory of Open Access Journals (Sweden)

    Yasir Arfat

    2014-01-01

    Full Text Available Imidacloprid (IC is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standard synthetic pellet diet. One group served as control, and the other three were served as experimental groups. Decrease in the body weight of the high dose group was observed at 15 mg/kg/day, and no mortality occurred during the treatment period. High dose of imidacloprid caused a significant elevation of serum clinical chemistry parameters, serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvate kinase (SGPT, alkaline phosphatase (ALP and total bilirubin (TBIL. Histology of liver and kidney indicates hepatotoxicity and nephrotoxicity at a high dose of imidacloprid. Based on the morphological, biochemical and histopathological analysis, it is evident that imidacloprid induced toxicological effects at 15 mg/kg/day to mice. The results of the present study demonstrate that IC had significant effects on body weight, liver functions and kidney (p < 0.05 at a dose of 15 mg/kg body weight. IC treatment 5 and 10 mg/kg/day may be considered as no observed adverse effect level (NOAEL for mice. It was concluded that IC can cause hepatotoxicity and nephrotoxicity at a dose much lower than the LD50 (131 mg/kg body weight in mice.

  1. In vivo protective effect of phosphatidylcholine on carbon tetrachloride induced nephrotoxicity.

    Science.gov (United States)

    Kim, Sokho; Na, Ji-Young; Song, Kibbeum; Kwon, Jungkee

    2016-11-01

    Phosphatidylcholine (PC) from egg yolk is a bioactive substance with various beneficial effects, including anti-inflammatory and anti-oxidant effects. Recently, this substance has been reported to prevent acute hepatotoxicity. In the present study, we aimed to evaluate the putative protective effect of PC on carbon tetrachloride (CCl4)-induced nephrotoxicity in ICR mice. Many previous studies demonstrated that CCl4 induces nephrotoxicity resulting in renal oxidative damage. CCl4 in corn oil (0.1ml, 1.2g/kg) was intra-peritoneally injected into 7-week-old ICR mice twice a week. PC in corn oil (0.1ml, 100mg/kg) was then orally injected daily for a week. In 7 days, blood urea nitrogen (BUN) and creatinine concentrations had significantly increased in the CCl4 group compared to the control group, whereas the PC and CCl4 co-injected group had significantly decreased BUN and creatinine concentrations compared to the CCl4 group. Comparative analysis of histopathological injuries revealed that PC abrogated the nephrotoxicity of CCl4 at 7 days. Accordingly, PC also improved renal fibrosis induced by CCl4. Various biomarkers associated with oxidative damage appeared to be up-regulated in the CCl4 group, whereas in the PC and CCl4 co-injected group, levels of oxidative damage significantly decreased. Aquaporin1 (AQP1), an important water transport protein in the kidney, was down regulated in the CCl4 group compared to the control group. PC counteracted this effect. These results strongly suggest that PC can protect against oxidative damage induced by CCl4 in the kidney and enhance recovery from renal disorders. Copyright © 2016 Elsevier GmbH. All rights reserved.

  2. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  3. EVALUATION OF THERAPEUTIC POTENTIAL OF PICRURHIZA KURROA GLYCOSIDAL EXTRACT AGAINST NIMESULIDE NEPHROTOXICITY: A PILOT STUDY.

    Science.gov (United States)

    Siddiqi, Afsheen; Alam, Saadia S; Begum, Sajada; Nazneen, Zainab; Aaqil, Bushra; Alam, Muhammad Adeel

    2015-01-01

    Picrorhiza kurroa (Pk) is a traditional Ayurvedic herb famous as a potent bepatoprotective agent, only few studies are available on the nephroprotective activity of this herb. The objective of this pilot study was to determine the therapeutic effectiveness of Pk against nimesulide induced toxicity. This laboratory based experimental study was conducted on mice at National Institute of Health, Islamabad from Dec 2012 to Jan 2013. The mice were divided in to 4 groups. One group was given only PK while the other three groups were given nimesulide in a dosage of 750 mg/kg body weight for 3 days to induce nephrotoxicity and protective effect of Pk was noted by giving 250 mg/kg and 500 mg/kg pk for 14 days to the two of the nimesulide induced nephrotoxicity groups. Biochemical assessment of kidney was done by measuring serum urea & creatinine. Also histology was done to confirm the findings of biochemical assessment. In our pilot study out of 20 mice, 19 mice survived. Only 1 mouse of nimesulide group died. Mean serum urea of nimesulide group was 60 mg/dl and was decreased to 23 mg/dI and 25 mg/dl by two doses of Pk. Mean creatinine in group 2 was 0.55 mg/dl and was decreased to 0.21 and 0.19 mg/dl by two doses of Pk. Our study shows that nimesulide is a potential nephrotoxic drug and its toxic effects on kidney can be minimized by using glycosidal extract of Pk.

  4. Protective effects of the Morus alba L. leaf extracts on cisplatin-induced nephrotoxicity in rat

    Science.gov (United States)

    Nematbakhsh, M; Hajhashemi, V; Ghannadi, A; Talebi, A; Nikahd, M

    2013-01-01

    Cisplatin (CP) as an important anti-tumor drug causes nephrotoxicity mainly by oxidative stress and renin-angiotensin system (RAS). Since flavonoids have high antioxidant activity and probable role in the inhibition of RAS, this study was designed to investigate the protective effect of hydroalcoholic extract and flavonoid fraction of Morus alba leaves on cisplatin-induced nephrotoxicity in rat. Extracts of Morus alba leaves were prepared and analyzed Phytochemically. Male rats (160-200 g) were used in this study (n=7-9). Normal group received 0.2 ml normal saline intraperitoneally (i.p.) once daily for ten days. Control animals received CP on the third day and saline in the remaining days. Other groups received either hydroalcoholic extract (200, 400 and 600 mg/kg, i.p.) or flavonoid fraction (50, 100 and 200 mg/kg, i.p.) for two days before CP administration and thereafter until tenth day. Serum concentrations of blood urea nitrogen (BUN), creatinine (Cr) and nitric oxide were measured using standard methods. Also left kidneys were prepared for pathological study. The serum levels of BUN and Cr increased in animals received CP. Hydroalcoholic extract was ineffective in reversing these alterations but flavonoid fraction (50 and 100 mg/kg) significantly inhibited CP-induced increases of BUN and Cr. None of the treatments could affect serum concentration of nitric oxide. Flavonoid fraction could also prevent CP-induced pathological damage of the kidney. It seems that concurrent use of flavonoid fraction of Morus alba with CP can protect kidneys from CP-induced nephrotoxicity. PMID:24019816

  5. Caffeic Acid Phenethyl Ester Protects against Amphotericin B Induced Nephrotoxicity in Rat Model

    Science.gov (United States)

    Altuntaş, Atila; Yılmaz, H. Ramazan; Altuntaş, Ayşegül; Uz, Efkan; Demir, Murat; Gökçimen, Alparslan; Aksu, Oğuzhan; Bayram, Dilek Şenol; Sezer, Mehmet Tuğrul

    2014-01-01

    The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on amphotericin B induced nephrotoxicity in rat models. Male Wistar-Albino rats were randomly divided into four groups: (I) control group (n = 10), (II) CAPE group (n = 9) which received 10 μmol/kg CAPE intraperitoneally (i.p.), (III) amphotericin B group (n = 7) which received one dose of 50 mg/kg amphotericin B, and (IV) amphotericin B plus CAPE group (n = 7) which received 10 μmol/kg CAPE i.p. and one dose of 50 mg/kg amphotericin B. The left kidney was evaluated histopathologically for nephrotoxicity. Levels of malondialdehyde (MDA), nitric oxide (NO), enzyme activities including catalase (CAT), and superoxide dismutase (SOD) were measured in the right kidney. Histopathological damage was prominent in the amphotericin B group compared to controls, and the severity of damage was lowered by CAPE administration. The activity of SOD, MDA, and NO levels increased and catalase activity decreased in the amphotericin B group compared to the control group (P = 0.0001, P = 0.003, P = 0.0001, and P = 0.0001, resp.). Amphotericin B plus CAPE treatment caused a significant decrease in MDA, NO levels, and SOD activity (P = 0.04, P = 0.02, and P = 0.0001, resp.) and caused an increase in CAT activity compared with amphotericin B treatment alone (P = 0.005). CAPE treatment seems to be an effective adjuvant agent for the prevention of amphotericin B nephrotoxicity in rat models. PMID:25032223

  6. Effect of pomegranate seed oil against gentamicin -induced nephrotoxicity in rat.

    Science.gov (United States)

    Boroushaki, Mohammad Taher; Asadpour, Elham; Sadeghnia, Hamid Reza; Dolati, Karim

    2014-11-01

    Gentamicin, an important aminoglycoside, is used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. It is a nephrotoxic antibiotic, which causes acute tubular necrosis, and its toxicity remains a major problem in clinical use. This study investigates the effect of pomegranate seed oil (PSO) on gentamicin-induced nephrotoxicity in adult male rats. Animals were randomly divided into four groups. Group one was treated with saline (1 ml/kg, i.p.), group 2 received gentamicin 80 mg/kg/day for 6 days and groups 3 and 4 received PSO 0.32 and 0.64 mg/kg/day i.p. respectively, 1 h before gentamicin. Serum urea, creatinine levels, urinary glucose and protein concentrations were evaluated as the markers of acute renal failure. Renal antioxidant indicators such as thiobarbituric acid-reactive substance (TBARS), and total thiol contents, were also determined. A significant elevation of serum creatinine and urea levels as well as urine glucose and protein concentrations were observed in gentamicin treated group. Gentamicin also caused a significant decrease in total thiol content and a significant increase in TBARS levels in kidney homogenate samples. PSO pretreatment resulted in a significant and dose-dependent decrease in serum creatinine and urea levels as well as urine glucose and protein concentrations when compared with gentamicin treated alone. PSO also significantly reversed the gentamicin-induced depletion in total thiol content and elevation in TBARS in kidney homogenate samples. The results of the present study indicate that PSO clearly attenuated gentamicin-induced nephrotoxicity, but elucidation of the mechanism(s) of this protection needs more investigation.

  7. Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Hosaka E.M.

    2004-01-01

    Full Text Available The frequent use of nonsteroidal anti-inflammatory drugs (NSAID in combination with gentamicin poses the additional risk of nephrotoxic renal failure. Cyclooxygenase-1 (COX-1 is the main enzyme responsible for the synthesis of renal vasodilator prostaglandins, while COX-2 participates predominantly in the inflammatory process. Both are inhibited by non-selective NSAID such as indomethacin. Selective COX-2 inhibitors such as rofecoxib seem to have fewer renal side effects than non-selective inhibitors. The objective of the present study was to determine whether the combined use of rofecoxib and gentamicin can prevent the increased renal injury caused by gentamicin and indomethacin. Male Wistar rats (250-300 g were treated with gentamicin (100 mg/kg body weight, ip, N = 7, indomethacin (5 mg/kg, orally, N = 7, rofecoxib (1.4 mg/kg, orally, N = 7, gentamicin + rofecoxib (100 and 1.4 mg/kg, respectively or gentamicin + indomethacin (100 and 5 mg/kg, respectively, N = 8 for 5 days. Creatinine clearance and alpha-glutathione-S-transferase concentrations were used as markers of renal injury. Animals were anesthetized with ether and sacrificed for blood collection. The use of gentamicin plus indomethacin led to worsened renal function (0.199 ± 0.019 ml/min, as opposed to the absence of a nephrotoxic effect of rofecoxib when gentamicin plus rofexicob was used (0.242 ± 0.011 ml/min. These results indicate that COX-2-selective inhibitors can be used as an alternative treatment to conventional NSAID, especially in situations in which risk factors for nephrotoxicity are present.

  8. Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics

    Science.gov (United States)

    Yousef, Jumana M.; Chen, Gong; Hill, Prue A.; Nation, Roger L.; Li, Jian

    2012-01-01

    Objectives The use of colistin in the treatment of life-threatening Gram-negative infections is associated with a high rate of nephrotoxicity that is dose limiting. This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity. Methods Rats were treated intravenously twice daily with saline, colistin (cumulative dose of 36.5 mg/kg), a combination of ascorbic acid (50 or 200 mg/kg) and colistin, or ascorbic acid (200 mg/kg) over 7 days. Colistin-induced apoptosis was examined in rats over 5 days and in vitro using rat renal proximal tubular cells NRK-52E over 24 h with and without ascorbic acid. The effect of co-administered ascorbic acid on colistin pharmacokinetics was investigated. Results The 24 h urinary excretion of N-acetyl-β-d-glucosaminidase, a sensitive marker for tubular damage, was significantly lower (P ascorbic acid 200 mg/kg group. Significant histological abnormalities (P ascorbic acid, which decreased the apoptotic effect in a concentration-dependent manner. Ascorbic acid (200 mg/kg) altered colistin pharmacokinetics, as the total body clearance decreased from 3.78 ± 0.36 mL/min/kg (colistin group) to 2.46 ± 0.57 mL/min/kg (P = 0.0024). Conclusions This is the first study demonstrating the protective effect of ascorbic acid against colistin-induced nephrotoxicity and tubular apoptosis. Co-administration of ascorbic acid has the potential to increase the therapeutic index of colistin. PMID:22127588

  9. Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.

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    Kim, Sejoong; LesherPerez, Sasha Cai; Kim, Byoung Choul C; Yamanishi, Cameron; Labuz, Joseph M; Leung, Brendan; Takayama, Shuichi

    2016-03-24

    Nephrotoxicity is often underestimated because renal clearance in animals is higher compared to in humans. This paper aims to illustrate the potential to fill in such pharmacokinetic gaps between animals and humans using a microfluidic kidney model. As an initial demonstration, we compare nephrotoxicity of a drug, administered at the same total dosage, but using different pharmacokinetic regimens. Kidney epithelial cell, cultured under physiological shear stress conditions, are exposed to gentamicin using regimens that mimic the pharmacokinetics of bolus injection or continuous infusion in humans. The perfusion culture utilized is important both for controlling drug exposure and for providing cells with physiological shear stress (1.0 dyn cm(-2)). Compared to static cultures, perfusion culture improves epithelial barrier function. We tested two drug treatment regimens that give the same gentamycin dose over a 24 h period. In one regimen, we mimicked drug clearance profiles for human bolus injection by starting cell exposure at 19.2 mM of gentamicin and reducing the dosage level by half every 2 h over a 24 h period. In the other regimen, we continuously infused gentamicin (3 mM for 24 h). Although junctional protein immunoreactivity was decreased with both regimens, ZO-1 and occludin fluorescence decreased less with the bolus injection mimicking regimen. The bolus injection mimicking regimen also led to less cytotoxicity and allowed the epithelium to maintain low permeability, while continuous infusion led to an increase in cytotoxicity and permeability. These data show that gentamicin disrupts cell-cell junctions, increases membrane permeability, and decreases cell viability particularly with prolonged low-level exposure. Importantly a bolus injection mimicking regimen alleviates much of the nephrotoxicity compared to the continuous infused regimen. In addition to potential relevance to clinical gentamicin administration regimens, the results are important in

  10. Anthocyanin – Rich Red Dye of Hibiscus Sabdariffa Calyx Modulates Cisplatin-induced Nephrotoxicity and Oxidative Stress in Rats

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    Ademiluyi, Adedayo O.; Oboh, Ganiyu; Agbebi, Oluwaseun J.; Akinyemi, Ayodele J.

    2013-01-01

    This study sought to investigate the protective effect of dietary inclusion of Hibiscus sabdariffa calyx red dye on cisplatin-induced nephrotoxicity and antioxidant status in rats. Adult male rats were randomly divided into four groups of six animals each. Groups I and II were fed basal diet while groups III and IV were fed diets containing 0.5% and 1% of the dye respectively for 20 days prior to cisplatin administration. Nephrotoxicity was induced by a single dose intraperitoneal administration of cisplatin (7 mg/kg b.w) and the experiment was terminated 3 days after. The kidney and plasma were studied for nephrotoxicity and oxidative stress indices. Cisplatin administration caused a significant (Psabdariffa dye could be attributed to its anthocyanin content. PMID:24711761

  11. The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

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    Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

    2017-08-01

    Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

  12. 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

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    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.

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

    Science.gov (United States)

    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 3H- or 125I-labeled cyclosporine ligand. The 3H-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 125I-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 125I-RIA standard curve was linear to 1000 micrograms of cyclosporine per liter. Inter- and intra-assay CVs for 125I-RIA measurements of cyclosporine were less than or equal to 7%. Evidently, the 125I-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.

  14. Low serum zinc is associated with elevated risk of cadmium nephrotoxicity

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    Lin, Yu-Sheng, E-mail: Lin.Yu-Sheng@epa.gov [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States); Ho, Wen-Chao [Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan (China); Caffrey, James L. [Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, TX (United States); Sonawane, Babasaheb [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States)

    2014-10-15

    Background: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. Objective: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans. Methods: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011–2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m{sup 2} and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5 mg/mmol in women. Results: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09–4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13–3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39–8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). Conclusions: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity. - Highlights: • Blood cadmium was associated with increased risk of nephrotoxicity. • Low serum zinc may exacerbate risk of cadmium-mediated renal dysfunction. • Both zinc deficiency and elevated cadmium exposure are global public health issues.

  15. Floral extract of Tecoma stans: a potent inhibitor of gentamicin-induced nephrotoxicity in vivo.

    Science.gov (United States)

    Raju, S; Kavimani, S; Maheshwara Rao, V Uma; Reddy, K Sreeramulu; Kumar, G Vasanth

    2011-09-01

    To highlight the nephroprotective activity of ethyl acetate extract of dried flowers of Tecoma stans for its protective effects on gentamicin-induced nephrotoxicity in albino rats. For studying acute toxicity study, single oral dose of 5,000 mg ethyl acetate floral extract/kg body weight was administered to albino rats (five females, five males). Nephrotoxicity was induced in albino rats by intraperitoneal administration of gentamicin 80 mg/kg/day for eight days. Effect of concurrent administration of ethyl acetate floral extract of Tecoma stans at a dose of 100, 200 and 300 mg/kg/day given by oral route was determined using serum creatinine, serum uric acid, blood urea nitrogen and serum urea as indicators of kidney damage. The study groups contained six rats in each group. As nephrotoxicity of gentamicin is known to involve induction of oxidative stress, in vitro antioxidant activity and free radical-scavenging activity of this extract was also evaluated. For acute toxicity testing both female and male rats administered with the extract at a dose of 5,000 mg/kg. The results showed no toxicity in terms of general behavior change, mortality, or change in gross appearance of internal organs (LD(50) > 5 000 mg/kg). It was observed that the ethyl acetate floral extract of Tecoma stans significantly protected rat kidneys from gentamicin-induced histopathological changes. Gentamicin-induced glomerular congestion, peritubular and blood vessel congestion, epithelial desquamation, accumulation of inflammatory cells and necrosis of the kidney cells were found to be reduced in the groups receiving the ethyl acetate floral extract of Tecoma stans along with gentamicin in a dose dependent manner. The floral extract also reduced the gentamicin-induced increase in serum creatinine, serum uric acid, blood urea nitrogen and serum urea levels (P >0.01). The present study indicates a very important role of reactive oxygen species (ROS) and the relation to renal dysfunction and point

  16. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

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    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  17. [Amniotic membrane transplantation and high-dose systemic cyclosporin A (Sandimmun optoral) for Mooren's ulcer].

    Science.gov (United States)

    Spelsberg, H; Sundmacher, R

    2007-02-01

    Mooren's ulcer is a rare, severe corneal autoimmune inflammation leading to blindness if treated insufficiently. High-dose systemic cyclosporin A (Sandimmun optoral) was shown to markedly reduce inflammation and stop corneal destruction. We report on three cases in which this immunosuppressive regimen required additional AM transplantation for complete healing. One 37-year-old male (M) and two 49- (F1) and 58-year-old females (F2) presented with unilateral Mooren's ulcer in different stages of the disease, which deteriorated despite high-dose systemic cyclosporin A (Sandimmun optoral M, F1) or treatment with topical cyclosporin A 2 % (F2). After surgical removal of all grossly affected corneal stroma, amniotic membrane was made to cover the entire cornea and fixed with episcleral sutures in two patients (M, F2). In one patient (F1) a deep marginal ulcer was covered with a fitted AM glap. All patients were treated postoperatively up to 6 months with high-dose systemic cyclosporin A (Sandimmun optoral). Blood trough levels aimed at 150 to 200 ng/mL. Topical cyclosporin A was administered in addition in two patients (M, F2) postoperatively for at least 6 months. Due to incompatibility, one patient (F1) was treated with topical steroids instead. Follow-up time was 42 months (M), 50 months (F1) and 54 months (F2). All three eyes exhibited clinical healing with stable corneal surfaces thereafter. Depending on the stage of Mooren's ulcer at the time of surgery, visual acuity remained at hand motions in one patient (M) and recovered to 1.0 and 0.6, respectively, in two patients (F1, F2). Due to its anti-inflammatory potential, coverage by AM seems to trigger a therapeutic turnaround in cases of Mooren's ulcer which do not heal with intensive immunosuppressive regimens alone. In order to maintain or restore as much visual function as possible, additional amniotic membrane surgery should be performed early enough in the course of the disease.

  18. Orally co-administrated oleo-gum resin of Commiphora myrrha decreases the bioavailability of cyclosporine A in rats.

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    Al-Jenoobi, F I; Alam, M A; Al-Mohizea, A M; Ahad, A; Raish, M

    2015-08-01

    Cyclosporine A is a narrow therapeutic indexed immunosuppressant used after organ transplantation. Several herbs have been reported to alter its pharmacokinetics. Myrrh, dried oleogum resin obtained from Commiphora myrrha (Burseraceae) has been used for many common ailments. The present study was carried out to investigate the effect of myrrh on the pharmacokinetics of cyclosporine A. The rats of the control group received 60 mg/kg, p.o. cyclosporine A, and blood samples were collected at predetermined time intervals. Rats of the test group were treated with an aqueous suspension of myrrh (380 mg/kg p.o.) for eight days and on 8th day a single dose of cyclosporine A was administered to the treated group after 1 h of myrrh administration. Blood samples were drawn at predetermined time points and the drug was analyzed in whole blood by using H-Class UPLC-TQD. Pharmacokinetic profiles of control and test group were compared. Statistically significant differences were observed between the pharmacokinetic parameters of control and treated groups. In the myrrh treated group, the AUC(0-t) and C(max) of cyclosporine A was decreased by about 45% and 48%, respectively. The time to reach maximum concentration (T(max)) remained almost unchanged in both groups. Results indicated that the bioavailability of cyclosporine A was reduced by about 45% when co-administered with myrrh. This observation suggests that concurrent consumption of myrrh and cyclosporine A should be avoided. To confirm the clinical relevance of these findings, P-gp and CYP3A based molecular investigations can be performed along with a well-planned clinical study.

  19. Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

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    Richdeep S Gill

    Full Text Available 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 (H(2O(2 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 H(2O(2 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 H(2O(2 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 H(2O(2 production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

  20. The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine.

    Science.gov (United States)

    Lim, Wai H; Russ, Graeme R; Wong, Germaine; Pilmore, Helen; Kanellis, John; Chadban, Steven J

    2017-04-01

    Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  1. Hipertrofia gengival em transplantados renais Cyclosporine induced gingival hyperplasia in kidney transplants

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    Paulo Roberto Torrezan

    2005-08-01

    Full Text Available OBJETIVO: Avaliar os fatores associados ao crescimento gengival excessivo em transplantados renais. MÉTODOS: A pesquisa foi realizada no Hospital Cajuru de Curitiba, no período de abril a outubro de 2002, com a participação de 60 transplantados renais, em uso diário de ciclosporina e com pelo menos um segmento dentário. O protocolo de ensaio foi observacional transversal. O exame odontológico dos indivíduos consistiu da avaliação dos segmentos dentários com verificação do grau de crescimento da gengiva e do índice de placa bacteriana. Todos os participantes preencheram questionário com dados relacionados ao transplante renal, realizaram coleta de material para controle do nível sérico de ciclosporina e foram avaliados quanto ao peso e altura. Na comparação dos resultados de amostras categóricas, utilizou-se o teste do Qui-quadrado e a correlação de classes de Spearman. O teste t foi aplicado na comparação das variáveis contínuas. RESULTADOS: Em pacientes tratados somente com ciclosporina, 47,2% não apresentavam alterações da gengiva, enquanto 52,8% cursaram com crescimento gengival, sendo 30,6% com grau > 2. Nos pacientes tratados com ciclosporina e nifedipina, notou-se que 29,2% tinham gengiva normal e 70,8% apresentaram crescimento gengival, sendo que em 45,8% o comprometimento foi grau > 2. Não foi observada diferença significativa dos resultados entre os gêneros masculino e feminino. Foi encontrada correlação positiva entre o índice de placa bacteriana e o volume gengival (r = 0,3295; pOBJECTIVE: Assess the influence of cyclosporine on the gingival growth of 60 patients with kidney transplant through a research carried out at the Hospital Cajuru in Curitiba, (April to October of 2002. METHODS: Regardless of age, gender, ethnic or social condition, all patients received cyclosporine daily and had, at least, one dental segment. They monthly returned to the Hospital for medical control and for several

  2. Radioprotective effect of atorvastatin against ionizing radiation-induced nephrotoxicity in mice.

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    Talebpour Amiri, Fereshteh; Hamzeh, Maedeh; Naeimi, Ramezan Ali; Ghasemi, Arash; Hosseinimehr, Seyed Jalal

    2018-02-01

    Kidneys are exposed to ionizing radiation during radiotherapy in patients with abdominal malignancy. The aim of this study is to investigate the protective effect of atorvastatin (ATV) against ionizing radiation-induced nephrotoxicity in mice. Sixty male BALB/c mice were randomly divided into six groups (10 mice per group); control, irradiation (IR), IR plus ATV (10, 20 and 50 mg/kg) and only ATV (50 mg/kg). ATV groups received ATV for seven days via oral gavage before exposure to IR. Animals were exposed to 2 Gy whole body of X-ray on day 8. After exposure to IR, biochemical, histological and immunohistological assays were performed. ATV significantly decreased the level of oxidative stress biomarkers in irradiated mice in comparison with IR alone. A significant reduction in the urea and creatinine levels was observed in ATV plus IR group compared to IR alone. Tubular degeneration, glomerular atrophy, interstitial expansion and fibrosis were observed in irradiated mice. Tubular degeneration and atrophy in the kidneys of IR plus ATV group were less than IR group. In addition, pre-treated animal with ATV significantly showed reduction in caspase-3 immunoreactivity. ATV has significant protective effect against radiation-induced nephrotoxicity in mice and is a promising medication for protection of patients during radiotherapy.

  3. Moringa oleifera Supplemented Diets Prevented Nickel-Induced Nephrotoxicity in Wistar Rats

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    O. S. Adeyemi

    2014-01-01

    Full Text Available Background. The Moringa oleifera plant has been implicated for several therapeutic potentials. Objective. To evaluate whether addition of M. oleifera to diet has protective effect against nickel-induced nephrotoxicity in rats. Methodology. Male Wistar rats were assigned into six groups of five. The rats were given oral exposure to 20 mg/kg nickel sulphate (NiSO4 in normal saline and sustained on either normal diet or diets supplemented with Moringa oleifera at different concentrations for 21 days. 24 hours after cessation of treatments, all animals were sacrificed under slight anesthesia. The blood and kidney samples were collected for biochemical and histopathology analyses, respectively. Results. NiSO4 exposure reduced the kidney-to-body weight ratio in rats and caused significant elevation in the levels of plasma creatinine, urea, and potassium. Also, the plasma level of sodium was decreased by NiSO4 exposure. However, addition of M. oleifera to diets averted the nickel-induced alteration to the level of creatinine and urea. The histopathology revealed damaged renal tubules and glomerular walls caused by NiSO4 exposure. In contrast, the damages were ameliorated by the M. oleifera supplemented diets. Conclusion. The addition of M. oleifera to diet afforded significant protection against nickel-induced nephrotoxicity.

  4. Antioxidant effect of Arabic gum against mercuric chloride-induced nephrotoxicity

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    Gado AM

    2013-10-01

    Full Text Available Ali M Gado,1 Badr A Aldahmash21Forensic Medicine and Clinical Toxicology Department, College of Medicine, Tanta University, Tanta, Egypt; 2Medical Laboratory Department, College of Health Sciences, King Saud University, Riyadh, Saudi ArabiaAbstract: The effects of Arabic gum (AG against nephrotoxicity of mercury (Hg, an oxidative-stress inducing substance, in rats were investigated. A single dose of mercuric chloride (5 mg/kg intraperitoneal injection induced renal toxicity, manifested biochemically by a significant increase in serum creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite production in kidney tissues. In addition, reduced glutathione, glutathione peroxidase, and catalase enzymes in renal tissues were significantly decreased. Pretreatment of rats with AG (7.5 g/kg/day per oral administration, starting 5 days before mercuric chloride injection and continuing through the experimental period, resulted in a complete reversal of Hg-induced increase in creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite to control values. Histopathologic examination of kidney tissues confirmed the biochemical data; pretreatment of AG prevented Hg-induced degenerative changes of kidney tissues. These results indicate that AG is an efficient cytoprotective agent against Hg-induced nephrotoxicity by a mechanism related at least in part to its ability to decrease oxidative and nitrosative stress and preserve the activity of antioxidant enzymes in kidney tissues.Keywords: mercury, acacia gum, oxidative stress, lipid per oxidation, kidney toxicity

  5. Nephrotoxic effects of mercury exposure and smoking among Egyptian workers in a fluorescent lamp factory.

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    El-Safty, Ibrahim A M; Shouman, Ahmed E; Amin, Nour E

    2003-01-01

    It is known that mercury (Hg) has a nephrotoxic effect in exposed workers. This effect is evident when there is advanced damage of kidney tissue. A random morning urine sample was collected from each participant for measuring urinary concentrations of total protein (UTP), retinol-binding protein (URBP), creatinine (UCr), Hg (UHg), and the activities of leucine-aminopeptidase (ULAP) and glutathione S-transferase (UGST) as well as N-acetyl-beta-D-glucosaminidase (UNAG). Urinary excretion of the measured parameters was significantly increased among Hg-exposed workers who were smokers and among Hg-exposed workers with work duration >or=11 years than those with nephrotoxic effect of Hg exposure and that cigarette smoking has toxic and synergistic effects with Hg exposure on kidney. Present results additionally suggest reduction in recommended biological threshold limit (50 microg Hg/g Ucr) or biological exposure index (35 microg Hg/g Ucr) of urinary mercury levels because elevated levels of measured parameters were observed at urinary Hg levels of 17.3-28.2 microg Hg/g Ucr.

  6. Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.

    Science.gov (United States)

    Humanes, Blanca; Lazaro, Alberto; Camano, Sonia; Moreno-Gordaliza, Estefanía; Lazaro, Jose A; Blanco-Codesido, Montserrat; Lara, Jose M; Ortiz, Alberto; Gomez-Gomez, Maria M; Martín-Vasallo, Pablo; Tejedor, Alberto

    2012-09-01

    Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.

  7. Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Jafarey, Mostafa; Changizi Ashtiyani, Saeed; Najafi, Houshang

    2014-01-01

    Calcium dobesilate is an antioxidant drug and this study is aimed to investigate the effects of calcium dobesilate on gentamicin-induced nephrotoxicity. This experimental study was conducted on 40 male Sprague-Dawley rats. The rats were randomly divided into the following 5 groups: control, sham, gentamicin (100 mg/kg/d, intraperitoneal), gentamicin and calcium dobesilate (50 mg/kg body weight), gentamicin and calcium dobesilate (50 mg/kg body weight). Treatment was provided once a day in a 7-day period. At the end of the 7th day, plasma and urine samples were taken and the concentrations of creatinine, urea nitrogen, sodium, potassium, and osmolarity were measured in both samples. The level of oxidative stress in the left kidney tissue samples was also assessed by measuring malondialdehyde and ferric reducing antioxidant power. Calcium dobesilate intake with both doses led to a significant decrease in the elevated concentration of creatinine, urea nitrogen, and fractional excretion of sodium by gentamicin, and an increase in creatinine clearance and absolute excretion of potassium as compared to the gentamicin group. Furthermore, calcium dobesilate decreased tissue malondialdehyde and increased tissue ferric reducing antioxidant power at both doses, in comparison to those in the gentamicin group. Calcium dobesilate is capable of protecting rats against gentamicin-induced nephrotoxicity. This protective effect of calcium dobesilate is probably dependent on its antioxidant properties.

  8. Renoprotective Effects of Total Glucosides from Paeony against Nephrotoxicity Induced by Total Alkaloids from Semen Strychni

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    Mingming Lv

    2017-01-01

    Full Text Available Semen Strychni have been shown to have therapeutic effect in improving blood circulation, relieving rheumatic pain, and treating cancer. However, Semen Strychni could cause severe nephrotoxicity. The present study was designed to evaluate whether treatment with total glucosides from paeony (TGP has renoprotective effect against nephrotoxicity induced by total alkaloids from Semen Strychni (TAS. The levels of blood urea nitrogen (BUN and creatinine (Cr were determined and histopathological changes were also examined to evaluate renal injury. Moreover, a HPLC-MS method was developed and validated to investigate the comparative toxicokinetics of strychnine and brucine in rats plasma after oral administration of TAS and pretreatment with TGP. Results demonstrated that the levels of BUN and Cr were significantly increased (p<0.05 in TAS group, together with tubule epithelium cloudy swelling, degeneration, and glomerular atrophy in rats’ kidneys. The TAS-induced kidney damage was alleviated after pretreatment with TGP. Besides, Tmax of strychnine and brucine were increased and T1/2 of strychnine and brucine were decreased after pretreatment with TGP. The toxicokinetics study showed that pretreatment with TGP could attenuate the absorption of strychnine and brucine, as well as accelerate their elimination. These results suggest that TGP possesses renoprotective effects.

  9. Epigallocatechin-3-gallate protects against cisplatin nephrotoxicity by inhibiting the apoptosis in mouse.

    Science.gov (United States)

    Zou, Peimei; Song, Jian; Jiang, Bei; Pei, Fei; Chen, Binbin; Yang, Xiangdong; Liu, Guangyi; Hu, Zhao

    2014-01-01

    Cisplatin (CP) is a commonly used anticancer drug, but its notable side effect of nephrotoxicity limits its use in clinic. Epigallocatechin-3-gallate (EGCG), an anti-oxidant, anti-inflammatory, and anti-tumorigenic green tea polyphenol, has been available on the market for its beneficial effects. The aim of this study was to investigate whether EGCG can prevent the nephrotoxic effect of CP and the involved mechanisms. Male C57/BL6 mice were randomly divided into four groups: control group, EGCG group, CP group, and CP+EGCG group. On day 5, mice were sacrificed. Our results showed that EGCG treatment significantly ameliorated the histopathological changes and the increased serum creatinine and blood urea nitrogen (BUN) induced by CP. TUNEL-positive cells significantly reduced in the CP+EGCG group compared with CP group. EGCG also inhibited the expression of the ligand of death receptor Fas (Fas-L), apoptosis regulator BAX (Bax) and tumor-suppressor protein p53, and increased the expression of B-cell lymphoma 2 (Bcl-2). These findings suggest that EGCG can ameliorate CP-induced apoptosis in the kidney by regulating death receptor Fas conducted extrinsic pathway, and the expression of Bax and Bcl-2.

  10. Nephroprotective effect of Murraya koenigii on cyclophosphamide induced nephrotoxicity in rats.

    Science.gov (United States)

    Mahipal, Patel; Pawar, Rajesh Singh

    2017-08-01

    To evaluate the nephroprotective effect of defatted methanolic extract and aqueous extract of Murraya koenigii (M. koenigii) against cyclophosphamide drug. Nephrotoxicity was induced by cyclophosphamide in 7 days at 150 mg/kg body weight through intraperitoneal route in rat model. Nephroprotective activity of M. koenigii extract (100 mg/kg and 200 mg/kg in intraperitoneal route) was measured, including nephrological source, oxidative stress parameters like superoxide dismutase, glutathione, the lipid peroxide and in vivo assay like blood urea nitrogen, creatinine were determined and analyzed by One way analysis of variance followed by Tukey's test. The study result showed that important phytochemicals such as carbohydrates, flavonoids, tannin, alkaloids, glycosides, protein and steroids were found to be present in the extract of M. koenigii. The renal function markers like blood urea nitrogen and creatinine level were found to be decreased significantly by M. koenigii extract treatment. A significant difference was found to be at P koenigii extract against cyclophosphamide induced nephrotoxicity. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  11. Effects of medical ozone therapy on acetaminophen-induced nephrotoxicity in rats.

    Science.gov (United States)

    Demirbag, Suzi; Uysal, Bulent; Guven, Ahmet; Cayci, Tuncer; Ozler, Mehmet; Ozcan, Ayhan; Kaldirim, Umit; Surer, Ilhami; Korkmaz, Ahmet

    2010-05-01

    Acetaminophen (APAP), also known as paracetamol, is the commonest cause of toxic ingestion in the world. Because overdose of APAP has life-threatening effects on kidney, treatment of APAP-induced nephrotoxicity has life-saving importance. Aim of the study was to evaluate the efficacy of medical ozone therapy in experimental model of APAP toxication. Twenty-one male Wistar rats (200-250 g) were randomly assigned into three groups containing seven rats each: Sham, control (only APAP treated), and APAP + ozone therapy groups. Rats were killed 48 hours after administration of APAP. Urea, creatinine levels in the blood, and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity in renal tissue were measured. Kidney tissues were stained with hematoxylin and eosin for histological assessment. APAP administration deteriorated the renal functions and significantly elevated renal MDA levels and depleted SOD and GSH-Px activities. Ozone therapy significantly reduced the MDA level, increased the SOD and GSH-Px activities, and normalized the renal histology. In conclusion, our study results are consistent with encouraging data for ozone therapy on APAP-induced nephrotoxicity in rats by improving antioxidant mechanism and oxidative stress.

  12. Olive oil abrogates acrylamide induced nephrotoxicity by modulating biochemical and histological changes in rats.

    Science.gov (United States)

    Ghorbel, Imen; Elwej, Awatef; Fendri, Nesrine; Mnif, Héla; Jamoussi, Kamel; Boudawara, Tahia; Grati Kamoun, Naziha; Zeghal, Najiba

    2017-11-01

    Acrylamide (ACR) is one of the most important contaminants occurring in foods heated at high temperatures. The aim of this study is to investigate the protective efficacy of extra virgin olive oil (EVOO), a main component of the Mediterranean diet, against nephrotoxicity induced by ACR. Rats have received by gavage during 21 days either ACR (40 mg/kg body weight) or ACR-associated with EVOO (300 μl) or only EVOO (300 μl). Acrylamide induced nephrotoxicity as evidenced by an increase in malondialdehyde (MDA), hydrogen peroxide (H2O2), protein carbonyls (PCOs) and a decrease in glutathione, non-protein thiols (NPSHs), and vitamin C levels. Activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) were also decreased. Lactate dehydrogenase (LDH) activity, creatinine, urea, and uric acid, urinary volume and creatinine clearance levels were modified. EVOO supplementation improved all the parameters indicated above. Kidney histoarchitecture confirmed the biochemical parameters and the beneficial role of EVOO. EVOO, when added to the diet, may have a beneficial role against kidney injury by scavenging free radicals and by its potent antioxidant power.

  13. Moringa oleifera Supplemented Diets Prevented Nickel-Induced Nephrotoxicity in Wistar Rats

    Science.gov (United States)

    Adeyemi, O. S.; Elebiyo, T. C.

    2014-01-01

    Background. The Moringa oleifera plant has been implicated for several therapeutic potentials. Objective. To evaluate whether addition of M. oleifera to diet has protective effect against nickel-induced nephrotoxicity in rats. Methodology. Male Wistar rats were assigned into six groups of five. The rats were given oral exposure to 20 mg/kg nickel sulphate (NiSO4) in normal saline and sustained on either normal diet or diets supplemented with Moringa oleifera at different concentrations for 21 days. 24 hours after cessation of treatments, all animals were sacrificed under slight anesthesia. The blood and kidney samples were collected for biochemical and histopathology analyses, respectively. Results. NiSO4 exposure reduced the kidney-to-body weight ratio in rats and caused significant elevation in the levels of plasma creatinine, urea, and potassium. Also, the plasma level of sodium was decreased by NiSO4 exposure. However, addition of M. oleifera to diets averted the nickel-induced alteration to the level of creatinine and urea. The histopathology revealed damaged renal tubules and glomerular walls caused by NiSO4 exposure. In contrast, the damages were ameliorated by the M. oleifera supplemented diets. Conclusion. The addition of M. oleifera to diet afforded significant protection against nickel-induced nephrotoxicity. PMID:25295181

  14. Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients

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    Aleksandra Semeniuk-Wojtaś

    2016-12-01

    Full Text Available Renal cell carcinoma (RCC is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF signaling pathway inhibitor (anti-VEGF therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents.

  15. The protective effects of Ribes diacanthum Pall on cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Tilyek, Akhtolkhyn; Chai, Chengzhi; Hou, Xiaoli; Zhou, Baoping; Zhang, Chunlei; Cao, Zhengyu; Yu, Boyang

    2016-02-03

    Ribes diacanthum Pall. (Saxifragaceae), a Mongolian folk medicinal plant, was used to treat urinary system diseases. The present work aims to investigate the protective effects of Ribes diacanthum Pall (RDP) against cisplatin-induced nephrotoxicity. The renal injury was modeled by intraperitoneal injection of cisplatin for 5 consecutive days (5 mg/kg). Nephroprotection of RDP was investigated by oral administration of RDP aqueous extract at a daily dose of 40 mg/kg for 14 consecutive days, starting 7 days prior to cisplatin administration. We demonstrated that pretreatment with RDP aqueous extract protected the mice from death induced by cisplatin administration. RDP treatment also significantly reduced blood urea nitrogen (BUN) and serum creatinine (Cr) levels observed in cisplatin-administrated mice. Histopathological analysis demonstrated that RDP administration protected cisplatin-induced renal tubular cell apoptosis. Further western blotting analysis revealed that RDP significantly reversed cisplatin-increased expression levels of cleaved-Caspase-3, Bax and cisplatin-decreased expression level of Bcl-2 in renal tissue. Finally, RDP markedly enhanced enzyme activities of reduced superoxide dismutase (SOD), Heme oxygenase 1 (HO-1) and catalase (CAT), suppressed lipid peroxidation as well as reactive oxygen species (ROS) production. We concluded that RDP displayed nephroprotective effects against cisplatin-induced renal tubular cell apoptosis, possibly associated with both enhanced antioxidase activity and suppressed ROS generation. Given the major nephrotoxicity of cisplatin cancer chemotherapy, RDP might be a potential candidate for neoadjuvant chemotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Effect of aqueous extract of Rheum ribes on cisplatin-induced nephrotoxicity in rat.

    Science.gov (United States)

    Hadjzadeh, Mousa-Al-Reza; Rajaei, Ziba; Keshavarzi, Zakieh; Shirazi, Mohsen Ghasem; Toosi, Vahedeh

    2013-10-01

    The purpose of the present study was to examine whether Rheum ribes extract prevents cisplatin-induced nephrotoxicity. THE ANIMALS WERE DIVIDED INTO THREE GROUPS: Group A considered as control group, group B were treated with cisplatin (3 mg/kg B.W. for 3 alternative days), and group C further to cisplatin received the aqueous extract of Rheum ribes (150 mg/rat). Blood urea nitrogen (BUN) level increased in group B on days 14 and 42 compared to day 0 (P ribes extract decreased the serum BUN level on day 14 compared to group B (P ribes had no effect on blood creatinine level. Serum cholesterol level was increased in group B on days 14 and 42 compared to day 0 (P ribes decreased the blood cholesterol level on day 42 in comparison to group B (P ribes increased the serum glucose level on days 14 and 42 compared to day 0 (P ribes had no effect on the kidney architecture. Cisplatin-induced nephrotoxicity was confirmed in our study. Although Rheum ribes had some effects on biochemical parameters; its effect on renal histology in injured kidney was insignificant.

  17. Hesperidin ameliorates trichloroethylene-induced nephrotoxicity by abrogation of oxidative stress and apoptosis in wistar rats.

    Science.gov (United States)

    Siddiqi, Aisha; Nafees, Sana; Rashid, Summya; Sultana, Sarwat; Saidullah, Bano

    2015-08-01

    Trichloroethylene (TCE), a nephrotoxicant is known to cause severe damage to the kidney. In this study, the nephroprotective potential of hesperidin was evaluated against TCE-induced nephrotoxicity in wistar rats. Oral administration of TCE (1000 mg/kg b.wt) for 15 days enhanced renal lipid peroxidation and reduced antioxidant enzymes armoury viz., reduced renal glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase and superoxide dismutase. It also enhanced the levels of blood urea nitrogen, creatinine and kidney injury molecule (KIM-1). Caspase-3 and bax expression were found to be elevated, while that of bcl-2 reduced suggesting that TCE induces apoptosis. However, pretreatment with hesperidin at a dose of 100 and 200 mg/kg b.wt for 15 days significantly decreased lipid peroxidation, increased the levels of antioxidant enzymes and reduced blood urea, creatinine and KIM-1 levels. Hesperidin also modulated the apoptotic pathways by altering the expressions of caspase-3, bax and bcl-2 to normal. Our results suggest that hesperidin can be used as a nephroprotective agent against TCE-induced nephrotoxicity.

  18. Nephroprotective effect of Kabab chini (Piper cubeba in gentamycin-induced nephrotoxicity

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    Qazi Zaid Ahmad

    2012-01-01

    Full Text Available Kabab chini (KC (Piper cubeba is an important drug in Unani Medicine, widely described to be effective in renal diseases, and physicians are using it as a protective and curative agent in various renal disorders from ancient times. The present study was designed to evaluate the nephroprotective effect of KC against gentamycin-induced nephrotoxicity in Wistar rats. This was studied in two different sets of tests, in which both the protective as well as the curative effects were evaluated in groups of albino rats. The powder of the test drug was administered orally in a dose of 810 mg/kg and 1220 mg/kg, in suspension form, in the pre- and post-treated models. The nephroprotective effect was assessed on the basis of biochemical estimation of serum urea and creatinine levels and histopathological examination of the treated kidney. The effect observed in the pre-treated and post-treated groups was compared with plain as well as negative control groups using one-way ANOVA with Dunnett′s multiple pair comparison test. The findings of the two tests demonstrated that KC produced a significant nephroprotective effect in both pre-treated and post-treated groups. The results of our study indicate that KC possesses significant benefit against gentamycin-induced nephrotoxicity.

  19. Nephroprotective effect of Kabab chini (Piper cubeba) in gentamycin-induced nephrotoxicity.

    Science.gov (United States)

    Ahmad, Qazi Zaid; Jahan, Nasreen; Ahmad, Ghufran

    2012-07-01

    Kabab chini (KC) (Piper cubeba) is an important drug in Unani Medicine, widely described to be effective in renal diseases, and physicians are using it as a protective and curative agent in various renal disorders from ancient times. The present study was designed to evaluate the nephroprotective effect of KC against gentamycin-induced nephrotoxicity in Wistar rats. This was studied in two different sets of tests, in which both the protective as well as the curative effects were evaluated in groups of albino rats. The powder of the test drug was administered orally in a dose of 810 mg/kg and 1220 mg/kg, in suspension form, in the pre- and post-treated models. The nephroprotective effect was assessed on the basis of biochemical estimation of serum urea and creatinine levels and histopathological examination of the treated kidney. The effect observed in the pre-treated and post-treated groups was compared with plain as well as negative control groups using one-way ANOVA with Dunnett's multiple pair comparison test. The findings of the two tests demonstrated that KC produced a significant nephroprotective effect in both pre-treated and post-treated groups. The results of our study indicate that KC possesses significant benefit against gentamycin-induced nephrotoxicity.

  20. Urinary gamma-glutamyl transferase as an indicator of acute nephrotoxicity in rats.

    Science.gov (United States)

    Dierickx, P J

    1981-06-01

    A series of nephrotoxic compounds dissolved in 0.9% NaCl was given to groups of five male Wistar rats in a single i.p. injection. Mercuric acetate and mercuric trifluoroacetate at 1 mg Hg/kg induced a sharp increase in urinary gamma-glutamyl transferase (GGT) activity on day 1, followed by a decrease below control values on day 3. Sodium ethylmercurithiosalicylate induced a relatively small urinary GGT increase, explained by its low Hg-bioavailability. An increased urinary GGT activity was noted after treatment with the aminoglycoside antibiotics kanamycin, neomycin, paramomycin, and streptomycin (100 and 800 mg/kg), ammonium fluoride (18.5 and 37 mg/kg), potassium bichromate (7.5 and 30 mg/kg), sodium tetrathionate (62.5 and 125 mg/kg), and cis-diamminedichloroplatinum (2 and 4 mg/kg). This was lower than for the mercury compounds, but clearly different from the controls. The urinargy GGT increase was an acute phenomenon. It is concluded that the measurement of urinary GGT can be used as an indicator of acute nephrotoxicity.

  1. Influence of Moxifloxacin on Hepatic Redox Status and Plasma Biomarkers of Hepatotoxicity and Nephrotoxicity in Rat

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    Ayokanmi Ore

    2015-01-01

    Full Text Available Moxifloxacin is a broad spectrum fluoroquinolone antibacterial agent. We examined the hepatic redox status and plasma biomarkers of nephrotoxicity and hepatotoxicity in rat following administration of moxifloxacin (MXF. Twenty-four Wistar rats, 180–200 g, were randomized into four groups (I–IV. Animals in group I (control received 1 mL of distilled water, while animals in groups II, III, and IV received 1 mL each of MXF equivalent to 4 mg/kg b.w., 8 mg/kg b.w., and 16 mg/kg b.w., respectively. After seven days, plasma urea, bilirubin, and creatinine were significantly (P<0.05 elevated in the MXF-treated animals. Activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were significantly increased in the plasma of MXF-treated animals compared to control. Also plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides increased significantly in the MXF-treated groups relative to control. Moreover, MXF triggered a significant decrease in hepatic catalase, superoxide dismutase, and glutathione-S transferase activities. Likewise, MXF caused a decrease in the hepatic levels of glutathione and vitamin C. A significant increase in hepatic MDA content was also observed in the MXF-treated animals relative to control. Overall, our data suggest that the half-therapeutic, therapeutic, and twice the therapeutic dose of MXF induced nephrotoxicity, hepatotoxicity, and altered hepatic redox balance in rats.

  2. Evaluation of "Dream Herb," Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells.

    Science.gov (United States)

    Mossoba, Miriam E; Flynn, Thomas J; Vohra, Sanah; Wiesenfeld, Paddy; Sprando, Robert L

    2016-01-01

    A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. "Dream herb," Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement.

  3. The efficacy of theophylline in preventing cisplatin-related nephrotoxicity in patients with cancer.

    Science.gov (United States)

    Karademir, Lutfiye Derya; Dogruel, Fatma; Kocyigit, Ismail; Yazici, Cevat; Unal, Aydin; Sipahioglu, Murat Hayri; Oymak, Oktay; Tokgoz, Bulent

    2016-06-01

    Cisplatin is a potent antineoplastic agent used and its major limiting side effect is nephrotoxicity. The aims of the study are early detection of acute kidney injury (AKI) with biomarkers and investigation of the potential nephron-protective effects of theophylline. Glomerular filtration rates (GFR), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C were measured at 5th day of treatment in all of the patients. In addition, these parameters were measured repeatedly after the administration of cisplatin, at 2nd hour, 5th and 20th days. Sixty patients who are planned to receive cisplatin for the first time were included in the study. Patients were divided into two groups as Group 1 (n = 30) (standard treatment arm) and Group II (n = 30) (theophylline arm). In both groups after the administration of cisplatin, GFR showed a significant decrease within time (p = 0.006). Urine NGAL levels were significantly high after 2 h of cisplatin administration (p theophylline (p = 0.025). After 5 days of cisplatin administration, urine protein levels were significantly higher in both groups (p Theophylline was found not to bring a complete protection for the kidneys, but less nephrotoxicity was developed when compared to the group not receiving theophylline.

  4. Cyclosporine A decreases the fluconazole minimum inhibitory concentration of Candida albicans clinical isolates but not biofilm formation and cell growth.

    Science.gov (United States)

    Wibawa, T; Nurrokhman; Baly, I; Daeli, P R; Kartasasmita, G; Wijayanti, N

    2015-03-01

    Among the genus Candida, Candida albicans is the most abundant species in humans. One of the virulent factors of C. albicans is its ability to develop biofilm. Biofilm forming microbes are characterized by decreasing of its susceptibility to antibiotics and antifungal. The fungicidal effect of fluconazole may be enhanced by cyclosporine A in laboratory engineered C. albicans strains. The aim of this work is to analyze the synergistic effect of cyclosporine A with fluconazole in C. albicans clinical isolates and the effect of cycolsporine A alone in the biofilm formation. Six fluconazole resistant and six sensitive C. albicans clinical isolates were analyzed for its minimum inhibitory concentration (MICs), biofilm formation, and cell growths. A semi-quantitative XTT [2,3-bis(2-methoxy-4-nitro-5- sulfo-phenyl)-2H-tetrazolium-5-carboxanilide] reduction assay was conducted to measure the biofilm formation. Cyclosporine A has synergistic effect with fluconazole that was shown by decreasing MICs of both fluconazole resistant and sensitive C. albicans clinical isolates. However, cyclosporine A alone did not influence the biofilm formation and cell growth of both fluconazole resistant and sensitive C. albicans clinical isolates. These results indicated that cyclosporine A might be a promising candidate of adjuvant therapy for fluconazole against both fluconazole resistant and sensitive C. albicans clinical isolates.

  5. Kiwi fruit (Actinidia deliciosa) ameliorates gentamicin-induced nephrotoxicity in albino mice via the activation of Nrf2 and the inhibition of NF-κB (Kiwi & gentamicin-induced nephrotoxicity).

    Science.gov (United States)

    Mahmoud, Yomna I

    2017-10-01

    Gentamicin is a potent aminoglycoside antibiotic, but the risk of nephrotoxicity limits its prolonged use. The toxicity of gentamicin is believed to result from oxidative stress, a condition that could be counteracted by dietary antioxidants. This study determines the possible renoprotective effects of kiwifruit against the pathophysiological and ultrastructural alterations induced by gentamicin. Mice were intraperitoneally injected with gentamicin (100mg/kg body weight) for eight consecutive days, and kiwi juice was administered for 8days, either concomitant to or after gentamicin injection. Gentamicin caused nephrotoxicity evidenced by the significant elevation of serum creatinine and blood urea nitrogen levels, along with significant reduction of serum sodium and potassium ions, compared to normal controls. This was associated with proximal tubular necrosis, lysosomal accumulation and mitochondrial alterations, together with glomerular atrophy, mesangial hypercellularity, and inflammatory cell infiltration. Moreover, immunohistochemical results pointed to the relevant role of Nrf2 and NF-κB in gentamicin-induced nephrotoxicity. Kiwi administration, especially when given after gentamicin injection, significantly ameliorated gentamicin-induced pathophysiological alterations, increased the nuclear immunoreactivity of Nrf2 and decreased that of NF-κB. In short, kiwi fruit shows a promising role as a nephroprotective agent against gentamicin-induced nephrotoxicity via attenuating oxidative stress, inflammation and cell death. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

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    W. B. Mattes

    2013-01-01

    Full Text Available Addressing safety concerns such as drug-induced kidney injury (DIKI early in the drug pharmaceutical development process ensures both patient safety and efficient clinical development. We describe a unique adjunct to standard safety assessment wherein the metabolite profile of treated animals is compared with the MetaMap Tox metabolomics database in order to predict the potential for a wide variety of adverse events, including DIKI. To examine this approach, a study of five compounds (phenytoin, cyclosporin A, doxorubicin, captopril, and lisinopril was initiated by the Technology Evaluation Consortium under the auspices of the Drug Safety Executive Council (DSEC. The metabolite profiles for rats treated with these compounds matched established reference patterns in the MetaMap Tox metabolomics database indicative of each compound’s well-described clinical toxicities. For example, the DIKI associated with cyclosporine A and doxorubicin was correctly predicted by metabolite profiling, while no evidence for DIKI was found for phenytoin, consistent with its clinical picture. In some cases the clinical toxicity (hepatotoxicity, not generally seen in animal studies, was detected with MetaMap Tox. Thus metabolite profiling coupled with the MetaMap Tox metabolomics database offers a unique and powerful approach for augmenting safety assessment and avoiding clinical adverse events such as DIKI.

  7. FcγRIIb on myeloid cells and intrinsic renal cells rather than B cells protects from nephrotoxic nephritis

    NARCIS (Netherlands)

    P.E.H. Sharp (Phoebe E.); J. Martin-Ramirez (Javier); S.M. Mangsbo (Sara); P. Boross (Peter); C.D. Pusey (Charles); I.P. Touw (Ivo); H.T. Cook (Terence); J.S. Verbeek (Sjef); R.M. Tarzi (Ruth)

    2013-01-01

    textabstractFcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined

  8. Proteomic approaches in understanding a detected relationship between chemotherapy-induced nephrotoxicity and cell respiration in HK-2 cells.

    Science.gov (United States)

    Perez, Juliana Dinéia; Colucci, Juliana Almada; Sakata, Maísa Mayumi; Cunha, Tatiana Sousa; Arita, Danielle Yuri; Casarini, Dulce Elena

    2011-01-01

    Nephrotoxicity is a prominent component of the profile of chemotherapeutic agents and to date proteomics has represented the main technique to identify protein profiles in response to xenobiotic exposure. We made use of two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight analysis to evaluate chemotoxicity effects of cisplatin (CPT) and carboplatin (CB) on proteins from human renal proximal tubule epithelial cells (HK-2). Tandem mass spectrometry analysis showed that ATP synthase subunit α and serine hydroxymethyltransferase were only expressed in HK-2 cells exposed to CPT. Since CPT causes damage in cellular respiration, we suggest that this might be a protective adaptation to CPT-induced nephrotoxicity. Thioredoxin-dependent peroxide reductase disappeared in the CPT group and was upregulated in the CB group, suggesting that CB exposure stimulates preventive apoptotic mechanisms. We suggest a relationship between chemotherapeutic agent-induced nephrotoxicity and cell respiration. The identification of proteins differentially expressed in HK-2 cells, when exposed to CPT and CB, not only supplies important information to understand the molecular action mechanisms, which are triggered by metal-based drugs in cell nephrotoxicity, but also can lead to the design of more effective anticancer drugs. These results provide important insights into the investigation of possible biomarker(s) of toxicity that could eventually reduce the side effects of chemotherapeutic agents. Copyright © 2011 S. Karger AG, Basel.

  9. Reduction of cisplatin nephrotoxicity by sodium selenite. Lack of interaction at the pharmacokinetic level of both compounds

    NARCIS (Netherlands)

    Vermeulen, N P; Baldew, G S; Los, G; McVie, G.J.; De Goeij, J J

    1993-01-01

    Administration of sodium selenite (Na2SeO3) 1 hr before cis-diamminedichloroplatinum(II) (referred to herein as cisplatin) can protect against the nephrotoxicity of cisplatin. The pharmacokinetic aspects of this interaction were studied in rodents with radiolabeled selenite and cisplatin. Total

  10. The influence of low flow anaesthesia on renal function in cancer patients previously treated with nephrotoxic chemotherapeutic agents.

    Science.gov (United States)

    Wujtewicz, Maria; Sawicka, Wioletta; Wenski, Wojciech; Marciniak, Andrzej; Wujtewicz, Magdalena A; Stepnowski, Piotr; Twardowski, Paweł; Dylczyk-Sommer, Anna; Owczuk, Radosław

    2012-08-08

    The aim of this study was to assess renal morbidity, associated with the use of low flow anaesthesia (LFA), in cancer patients previously treated with nephrotoxic chemotherapeutic agents. Seventy-five patients, aged 30-70 years, scheduled for elective surgery, were randomly allocated to three groups: Group A included those patients who had received nephrotoxic chemotherapeutic agents (cisplatin, carboplatin, methotrexate or cyclophosphamide) within 90 days before surgery, and who were anaesthetised with low flow (0.8(-1) L min(-1)) air-oxygen-sevoflurane (1-3 MAC) anaesthesia; Group B included similar patients who received high flow (6 L min-1) anaesthesia. Non-cancer patients receiving low flow anaesthesia served as controls. Blood was sampled for serum creatinine, BUN, cistatin C, and electrolytes (Na(+), K(+), Cl(-), Ca(2+), P(3+), Mg(2+)) before anaesthesia, and one, three and five days after. There were no statistically significant differences between the groups. The use of low flow sevoflurane anaesthesia is not associated with an increased risk of nephrotoxicity in those previously exposed to nephrotoxic chemotherapeutic agents.

  11. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials

    DEFF Research Database (Denmark)

    Penninga, Luit; Møller, Christian H; Gustafsson, Finn

    2010-01-01

    We conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation.......We conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation....

  12. Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

    Science.gov (United States)

    Schewitz-Bowers, Lauren P.; Lait, Philippa J. P.; Copland, David A.; Chen, Ping; Wu, Wenting; Dhanda, Ashwin D.; Vistica, Barbara P.; Williams, Emily L.; Liu, Baoying; Jawad, Shayma; Li, Zhiyu; Tucker, William; Hirani, Sima; Wakabayashi, Yoshiyuki; Zhu, Jun; Sen, Nida; Conway-Campbell, Becky L.; Gery, Igal; Dick, Andrew D.; Wei, Lai; Nussenblatt, Robert B.; Lee, Richard W. J.

    2015-01-01

    Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation. PMID:25775512

  13. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

    Science.gov (United States)

    Meissner, Konrad; Avram, Michael J.; Yermolenka, Viktar; Francis, Amber M.; Blood, Jane; Kharasch, Evan D.

    2013-01-01

    Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p < 0.05). Analgesia testing was confounded by cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects. PMID:23851346

  14. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    El-Naga, Reem N., E-mail: reemelnaga@hotmail.com

    2014-01-01

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  15. Pneumonia associated with Salmonella spp. infection in a cat receiving cyclosporine.

    Science.gov (United States)

    Callegari, C; Palermo, G; Greco, M F; Corrente, M; Piseddu, E; Auriemma, E; Zini, E

    2014-10-01

    Salmonellosis is uncommon in cats, usually affects the gastrointestinal tract or skin, and can be fatal. This report describes a domestic shorthair cat with severe pneumonia caused by Salmonella spp. without accompanying gastrointestinal or skin manifestations, in which previous administration of cyclosporine may have played a permissive role in its development. Clinical and laboratory findings as well as follow-up are described from diagnosis until complete recovery. This unusual presentation serves to alert practitioners to consider Salmonella spp. as a possible cause of lung disease in cats, especially if immunocompromised.

  16. Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Nygaard, M; Hovgaard, D; Schjødt, I M

    2015-01-01

    WHAT IS KNOWN AND OBJECTIVE: The target level and route of administration of cyclosporine A (CsA) differ between transplantation centres. It is unclear whether oral CsA is sufficient to maintain target level of CsA. CASE SUMMARY: We retrospectively analysed data from 48 adult patients, who...... underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of a...

  17. Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient

    Directory of Open Access Journals (Sweden)

    Kyungmin Huh

    2013-06-01

    Full Text Available Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients.

  18. Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis.

    Science.gov (United States)

    Feuerstein, Joseph D; Akbari, Mona; Tapper, Elliot B; Cheifetz, Adam S

    2016-01-01

    In patients with ulcerative colitis who fail corticosteroids and are treated with rescue therapy (e.g. infliximab or cyclosporine) but fail to respond, salvage therapy with infliximab or cyclosporine can be considered. We sought to assess the efficacy and safety of this third-line salvage therapy. We performed a meta-analysis of trials published in PubMed up to January 2015 relating to the use of third-line salvage therapy following failure of intravenous corticosteroids and infliximab or cyclosporine. Pooled outcome rates for each salvage strategy and pooled odds ratio comparing the two strategies were calculated using the random effects model. Heterogeneity was assessed by the Q and I(2) statistics. The search strategy yielded 40 articles of which 4 were eligible for inclusion. Four articles assessed patients who were treated with infliximab after failure of cyclosporine and 2 articles assessed the use of cyclosporine after failure of infliximab. There were 138 patients using infliximab as a third-line salvage therapy and 30 patients using cyclosporine. When comparing these two strategies, there was no significant difference in clinical response (RR 1.03, 95%CI 0.7-1.46 P=0.87), clinical remission (RR 0.69, 95%CI 0.30-1.57 P=0.37), or colectomy at 12 months (RR 1.14, 95%CI 0.79-1.67 P=0.48). Similarly, there was no significant difference in total (RR 1.91, 95% CI0.38-9.64 p=0.43) or serious adverse events (RR 1.18, 95%CI 0.34-4.07 P=0.80). While third-line salvage therapy may be efficacious in achieving short-term clinical response/remission, there remains a significant risk of colectomy and adverse events.

  19. Cyclosporin A inhibits HTLV-I tax expression and shows anti-tumor effects in combination with VP-16.

    Science.gov (United States)

    Ozaki, Atsuo; Arima, Naomichi; Matsushita, Kakushi; Uozumi, Kimiharu; Akimoto, Masaki; Hamada, Heiichiro; Kawada, Hideaki; Horai, Sawako; Tanaka, Yuetsu; Tei, Chuwa

    2007-12-01

    Adult T cell leukemia (ATL) is one of the most refractory malignant hematological diseases. Our previous studies demonstrated HTLV-1Tax protein involvement in clinical manifestation of the aggressive type of ATL and suggested the potential application of agents to inhibit Tax expression for ATL treatment. In the present study, we first examined Tax involvement in the resistance to VP-16-induced apoptosis using four HTLV-1 infected T cell clones and cTax DNA-transfected cells. Next, we examined whether cyclosporin A reduced expression of Tax and its related transfer factors on Western blot and CAT assay. We further investigated whether cyclosporin A in combination with VP-16 can induce apoptosis in HTLV-1 infected T cells. Tax-producing T cells, K3T and F6T, were resistant to VP-16 induced growth inhibition compared with that of the nonproducing cells, S1T and Su9T01. Experiments using S1T and Tax-expressing cDNA-transfected S1T demonstrated Tax-induced resistance to VP-16 induction of apoptosis by DNA ladder formation. Cyclosporin A reduced Tax expression in K3T by Western blot analysis and on CAT assay, showing maximal reduction of 61% and 60% compared to control culture using LTR CAT transfected Jurkat cells and K3T cells, respectively. Cyclosporin A also reduced the nuclear expression of two Tax-related transfer factors, ATF-1 and ATF-2 on Western blot. Cyclosporin A alone did not show any cytotoxicity by itself, but sensitized cells to VP-16 when combined with VP-16. Cyclosporin A may be a useful anti-ATL agent when combined with other anti-cancer agents possibly related to Tax inhibition. (c) 2007 Wiley-Liss, Inc.

  20. Pharmacokinetic-Pharmacodynamic Analysis of Cisplatin with Hydration and Mannitol Diuresis: The Contribution of Urine Cisplatin Concentration to Nephrotoxicity.

    Science.gov (United States)

    Fukushima, Keizo; Okada, Akira; Oe, Hiroyuki; Hirasaki, Mika; Hamori, Mami; Nishimura, Asako; Shibata, Nobuhito; Sugioka, Nobuyuki

    2017-09-14

    Forced diuresis, high-volume hydration with diuresis, is widely used as a prophylactic treatment against cisplatin nephrotoxicity. However, the details of the underlying mechanisms and the optimal protocol of forced diuresis remain unclear. The present study investigated the alterations in pharmacokinetics and pharmacodynamics (nephrotoxicity) of cisplatin with forced diuresis treatment. Cisplatin (5 mg/kg) was intravenously injected to rats (5 rats/group, except for control group in pharmacodynamic study, n = 13) treated with or without forced diuresis 2-h pre- and post-hydration with 10% mannitol at different infusion rates (0.3, 1.0, and 3.0 mL/h). The unbound cisplatin concentrations in plasma and urine, and the platinum amount in the kidney were monitored in the pharmacokinetic studies. The plasma creatinine concentration was evaluated as an index of nephrotoxicity in the pharmacodynamic studies. Forced diuresis treatment did not significantly alter the plasma cisplatin pharmacokinetics but dramatically decreased the urine concentration of unbound cisplatin and its accumulation into the kidneys in a dose-dependent manner, and correspondingly, nephrotoxicity was dose-dependently attenuated by forced diuresis. The pharmacokinetic-pharmacodynamic analysis suggested that the urine cisplatin concentration has a comparable impact on the cisplatin-induced nephrotoxicity to that in plasma, probably owing to the reabsorption of cisplatin from urine, which can be attenuated by forced diuresis. These results indicated that the nephroprotective effect of forced diuresis is a pharmacokinetic-based drug-drug interaction possibly due to the inhibition of cisplatin reabsorption from urine. Monitoring of urine cisplatin concentration may lead to the optimization of a forced diuresis protocol with mannitol.

  1. Antioxidant and anti-inflammatory effects of Nasturtium officinale involved in attenuation of gentamicin-induced nephrotoxicity.

    Science.gov (United States)

    Shahani, Somayeh; Behzadfar, Farzaneh; Jahani, Danial; Ghasemi, Maryam; Shaki, Fatemeh

    2017-02-01

    Gentamicin (GM) is used against bacterial infections. The aim of our investigation was to evaluate the role of inflammation and also oxidative damage in nephrotoxic potential of GM and protective effects of Nasturtium officinale (watercress) against GM-induced nephrotoxicity in Wistar rats. The animals were divided into eight groups: control, solvent, GM (80 mg/kg IP), GM with three doses (50, 100 and 200 mg/kg/d) of hydroalcoholic extract of watercress and one group only received high dose of extract and a group which received GM plus vitamin E for 10 consecutive days. Then, the animals were killed and kidney tissues were separated. Finally reactive oxygen species (ROS), glutathione (GSH) content, lipid peroxidation (LPO), protein carbonyl (PCO), nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, pathological examination and measuring of blood urea nitrogen (BUN) and creatinine (Cr) were done. The administration of GM for 10 d resulted in an increase in kidney markers (BUN and Cr) and pathological changes in kidney tissue. Also, oxidative stress was evident in GM group by increased ROS, LPO and PCO level and GSH oxidation. Increased in inflammation process was shown by increase in NO and TNF-α. Administration of watercress extract was able to protect against deterioration in nephrotoxic markers and suppressed the increase in oxidative stress and inflammation markers. Our study showed the critical role of oxidative damage and inflammation in GM-induced nephrotoxicity that markedly inhibited by administration of watercress. Therefore, watercress can be suggested for prevention of GM-induced nephrotoxicity.

  2. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.

    Science.gov (United States)

    Wang, Bingying; Jia, Haoyuan; Zhang, Bin; Wang, Juanjuan; Ji, Cheng; Zhu, Xueming; Yan, Yongmin; Yin, Lei; Yu, Jing; Qian, Hui; Xu, Wenrong

    2017-04-08

    The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of

  3. Hypertrichosis: the possible side effect of cyclosporin in an infant with hemophagocyticlymphohistiocytosis receiving HLH-2004 chemotherapy protocol

    Directory of Open Access Journals (Sweden)

    Sinem Akgül

    2009-09-01

    Full Text Available Hemophagocyticlymphohistiocytosis is a life-threatening condition of severe hyperinflammation that results from an uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. The immediate treatment strategies include immune suppressive therapy such as corticosteroid, etoposide and cyclosporin A. Herein, we present a 13-month-old infant who developed severe hypertrichosis after the administration of HLH-2004 treatment protocol. We discuss the various hypotheses regarding the causal relationship between cyclosporin A and hypertrichosis, emphasizing the importance of patient follow up.

  4. Gadolinium-based contrast media may be nephrotoxic even at approved doses

    Energy Technology Data Exchange (ETDEWEB)

    Thomsen, Henrik S. [Department of Diagnostic Radiology, Copenhagen University Hospital at Herlev, Herlev Ringvej 75, 2730, Herlev (Denmark)

    2004-09-01

    It is generally believed that gadolinium-based contrast media are not nephrotoxic at the approved doses for MR (<0.3 mmol/kg body weight). Recently, a patient with diabetic nephropathy required dialysis because of anuria 6-7 days after MR angiography with 0.14 mmol/kg body weight gadolinium-DTPA-BMA to assess renal artery stenosis. No special precautions (e.g., hydration) had been taken. The serum creatinine levels had been within 200 and 300 {mu}mol/l for the last 3 years with a very slow increase. This case highlights that gadolinium-based contrast media can cause contrast medium-induced nephropathy even at doses below 0.2 mmol/kg body weight in patients with multiple risk factors. (orig.)

  5. Bioactive traditional plant Cinnamomum zeylanicum successfully combat against nephrotoxic effects of aminoglycosides

    Directory of Open Access Journals (Sweden)

    Naveed Ullah

    2013-03-01

    Full Text Available Cinnamomum zeylanicum is traditionally used for the treatment of bladder and kidney problems; believed to have kidney tonic effects. The prime objective of the current study was to explore the nephroprotective effects of the plant due to its strong antioxidant properties, to provide experimental facts for their traditional use. Daily dose of 200 mg/kg of plant extract was employed alone and in combination with gentamicin for a period of twenty one days in rabbits. Biochemical kidney functioning parameters were assessed thrice throughout study period. Histopathological examination of the kidneys was performed on the last day of experimental period. Present study showed that C. zeylanicum significantly attenuated renal functional and histological changes associated with gentamicin as assessed by urea, creatinine, uric acid, electrolytes, urinary protein, and histopathological examination. The plant extract successfully proved to have strong nephroprotective properties, especially against aminoglycosides induced nephrotoxicities.

  6. Ayurvedic formulations ameliorate cisplatin-induced nephrotoxicity: preclinical studies on Brahma Rasayana and Chyavanaprash.

    Science.gov (United States)

    Menon, Aditya; Krishnan Nair, Cherupally Krishnan

    2013-01-01

    To explore the ability of two Ayurvedic formulations, Brahma Rasayana (BRM) and Chyavanaprash (CHM) in alleviating Cisplatin (Cis-dichlorodiammineplatinum [II] CDDP) induced acute nephrotoxicity. Swiss albino mice were administered with CDDP (12 mg/kg, i.p) and two doses of BRM or CHM (1 and 2 g/kg). Various antioxidant parameters in the kidney as well as release of marker enzymes in the serum were assayed. Histology of the kidney was also performed to check for CDDP induced damages. Administration of either BRM or CHM (1 and 2 g/kg) maintained the antioxidant status in the kidney thereby preventing tissue damage as well as the release of marker enzymes. CDDP induced variation of renal architecture was also prevented by BRM and CHM administration. BRM and CHM administration could prevent CDDP induced acute renal toxicity.

  7. Is chloroxylenol nephrotoxic like phenol? A study of patients with DETTOL poisoning.

    Science.gov (United States)

    Chan, T Y; Critchley, J A

    1994-06-01

    Chloroxylenol, a phenolic derivative commonly used as a household disinfectant, has similar, although lesser, toxic manifestations in comparison to phenol when ingested. The main objective of this study was to determine if chloroxylenol is nephrotoxic like phenol by studying 121 patients with DETTOL (4.8% chloroxylenol, pine oil, isopropyl alcohol) poisoning. Three patients (2.5%) developed renal impairment as evidenced by raised plasma urea and creatinine concentrations following ingestion of 200 to 500 ml of DETTOL. Two of these patients also had serious complications, including aspiration leading to pneumonia and adult respiratory distress syndrome, from which 1 died. The etiology of the renal impairment is likely a direct toxic effect of chloroxylenol on the kidneys and associated transient hypotension. Fortunately, renal impairment only appears to be a problem when relatively large amounts of DETTOL are ingested.

  8. Gingerol Fraction from Zingiber officinale Protects against Gentamicin-Induced Nephrotoxicity

    Science.gov (United States)

    Rodrigues, Francisco A. P.; Prata, Mara M. G.; Oliveira, Iris C. M.; Alves, Natacha T. Q.; Freitas, Rosa E. M.; Monteiro, Helena S. A.; Silva, Jame's A.; Vieira, Paulo C.; Viana, Daniel A.; Libório, Alexandre B.

    2014-01-01

    Nephrotoxicity is the main complication of gentamicin (GM) treatment. GM induces renal damage by overproduction of reactive oxygen species and inflammation in proximal tubular cells. Phenolic compounds from ginger, called gingerols, have been demonstrated to have antioxidant and anti-inflammatory effects. We investigated if oral treatment with an enriched solution of gingerols (GF) would promote a nephroprotective effect in an animal nephropathy model. The following six groups of male Wistar rats were studied: (i) control group (CT group); (ii) gingerol solution control group (GF group); (iii) gentamicin treatment group (GM group), receiving 100 mg/kg of body weight intraperitoneally (i.p.); and (iv to vi) gentamicin groups also receiving GF, at doses of 6.25, 12.5, and 25 mg/kg, respectively (GM+GF groups). Animals from the GM group had a significant decrease in creatinine clearance and higher levels of urinary protein excretion. This was associated with markers of oxidative stress and nitric oxide production. Also, there were increases of the mRNA levels for proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], IL-2, and gamma interferon [IFN-γ]). Histopathological findings of tubular degeneration and inflammatory cell infiltration reinforced GM-induced nephrotoxicity. All these alterations were attenuated by previous oral treatment with GF. Animals from the GM+GF groups showed amelioration in renal function parameters and reduced lipid peroxidation and nitrosative stress, in addition to an increment in the levels of glutathione (GSH) and superoxide dismutase (SOD) activity. Gingerols also promoted significant reductions in mRNA transcription for TNF-α, IL-2, and IFN-γ. These effects were dose dependent. These results demonstrate that GF promotes a nephroprotective effect on GM-mediated nephropathy by oxidative stress, inflammatory processes, and renal dysfunction. PMID:24395230

  9. The Protective Role of Galium Aparine on Cisplatin – Induced Nephrotoxicity in Male Rats

    Directory of Open Access Journals (Sweden)

    SH Zahiri

    2006-04-01

    Full Text Available ABSTRACT: Introduction & Objective: Cisplatin is a potent antineoplastic drug. The beneficial effects of the drug are limited by its nephrotoxicity. The purpose of this study is to introduce sterological meothds (Estimation of mean glomerular volume to determine the toxicity of drug & examine the Galium aparine (a traditional herbal plant as a protective agent. Materials & Methods: This experimental study was done in histology department in Ahwaz University of medical sciences in 1380. 70 Spraque–Dwally male rats were iselected randomly and divided into 7 groups as below: two control groups (one for drug & one for plant, five experimental groups one treated by acute dose of drug (7.5 mg/kg, IP and other groups treated with 4 doses of hydroalcholic extract of plants (4, 8, 16, 32 mg/kg half an hour before receiving drug orally. Animals were sacrified 96 hour after receiving the drugs and their right kidneys were processed for stereological assessment based on cavalier method. Statistical analysis of data from calculation of mean glomerular volume was done by ANOVA and two sided-dunet test, using SPSS software. Results: The results based on cavalier method, showed an increase in mean glomerular volume in all the groups that were treated with drug, whereas lower grade of glomerulomegaly was seen in those groups which received higher doses (16 & 32 mg/kg of plant’s extract (p<0.05. Conclusion: Nephrotoxicity induced by cisplatin was even observed in quantitative parameters of kidney (e.g. increasing the mean glomerular volume but by using Galim apain’s extract this side effect can be reduced significantly. Moreover stereological techniques are valuable tools for studying the drug effects in all organs of the body.

  10. Nephrotoxicity in Patients with or without Cystic Fibrosis Treated with Polymyxin B Compared to Colistin.

    Science.gov (United States)

    Crass, Ryan L; Rutter, W Cliff; Burgess, Donna R; Martin, Craig A; Burgess, David S

    2017-04-01

    Nephrotoxicity is the primary adverse effect of the polymyxins. The relative rates of toxicity of polymyxin B and colistin have not been fully elucidated, especially in patients with cystic fibrosis (CF). A retrospective cohort study of adults treated with polymyxin B or colistin for at least 48 h was conducted. The primary endpoint was the incidence of kidney injury assessed by RIFLE (i.e., risk, injury, failure, loss, end-stage renal disease) criteria. Risk factors for kidney injury were evaluated using multivariate Cox regression. A total of 414 patients were evaluated, 220 of whom had CF. In patients without CF, there was no difference in kidney injury with polymyxin B and colistin (42.9% versus 50.3%, P = 0.46). Loop diuretic exposure was a risk factor for kidney injury (adjusted hazard ratio [aHR], 1.82; 95% confidence interval [CI], 1.16 to 2.83) in this population. In patients with CF, polymyxin B and colistin were associated with similar rates of kidney injury (34.5% versus 29.8%, P = 0.77). Diabetes (aHR, 2.68; 95% CI, 1.01 to 7.11), loop diuretics (aHR, 3.02; 95% CI, 1.36 to 6.73), and progressive care unit admission (aHR, 8.21; 95% CI, 2.55 to 26.46) were risk factors for kidney injury, while higher baseline serum creatinine levels (per 1 mg/dl) were protective (aHR, 0.08; 95% CI, 0.01 to 0.48). Total unadjusted kidney injury in polymyxin-treated patients was less frequent in those who had CF (30.5% versus 48.5%, P colistin are associated with a high incidence of kidney injury; cystic fibrosis may be protective against polymyxin nephrotoxicity, but further investigation is needed to confirm this conjecture. Copyright © 2017 American Society for Microbiology.

  11. Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Saito, Yoshitaka; Kobayashi, Masaki; Yamada, Takehiro; Kasashi, Kumiko; Honma, Rio; Takeuchi, Satoshi; Shimizu, Yasushi; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Iseki, Ken

    2017-02-01

    Magnesium supplementation is an effective protective method against cisplatin-induced nephrotoxicity (CIN); however, there are few reports regarding the mechanism of its nephroprotective effect. The aim of this study was to determine whether premedication with intravenous magnesium prevents CIN and to determine the relationship between its nephroprotective effect and serum magnesium level. Fifty-eight patients with head and neck cancer who received cisplatin, docetaxel, and 5-fluorouracil (DCF) were retrospectively investigated. Grade 2 or more serum creatinine elevation was defined as CIN. The incidence of CIN was compared between a magnesium sulfate (20 mEq, 2.46 g) premedication group and a non-magnesium group during the first cycle and in all cycles. CIN did not occur in any patients receiving magnesium premedication but did occur in 5 of 29 patients during the first cycle and in 6 patients during all subsequent cycles in patients who did not receive magnesium premedication. Furthermore, the variation of creatinine clearance was significantly worse in the non-magnesium group than in the magnesium premedication group from baseline. There was no difference in adverse effects or response rate between the two groups. Univariate analysis suggested that magnesium premedication significantly reduced the risk of CIN. On the other hand, serum magnesium depletion was seen in both groups to equal degrees despite supplementation. Intravenous magnesium premedication has a protective effect on cisplatin-induced nephrotoxicity without the influence on the serum magnesium level. Magnesium premedication is a simple nephroprotective method that does not influence other adverse effects or rate of response to chemotherapy.

  12. Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion.

    Science.gov (United States)

    El Menyiy, Nawal; Al Waili, Noori; Bakour, Meryem; Al-Waili, Hamza; Lyoussi, Badiaa

    2016-10-01

    Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

  13. The protective effects of caffeic acid phenethyl ester against toluene-induced nephrotoxicity in rats.

    Science.gov (United States)

    Meydan, Sedat; Nacar, Ahmet; Oztürk, Hasan Oktay; Tas, Ufuk; Köse, Evren; Zararsiz, Ismail; Yılmaz, Nigar; Kus, Ilter

    2016-01-01

    Caffeic acid phenethyl ester (CAPE) has antioxidant and anti-inflammatory properties. The aim of this study is to examine the negative effects of toluene on kidney tissues and functions and to investigate the protective effects of CAPE against toluene-induced nephrotoxicity in rats. A total of 21 male Wistar rats were divided into three groups of equal number in each. The rats in group I were the controls. Toluene was intraperitoneally injected into the rats in group II with a dose of 500 mg/kg. Rats in group III received CAPE daily while exposed to toluene. After 14 days of experimental period, all rats were killed by decapitation. Enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and malondialdehyde (MDA) levels were studied in the rat kidneys. Blood urea nitrogen (BUN) and serum creatinine levels were measured for renal function. The CAT and SOD enzyme activities and serum creatinine levels were significantly increased in rats treated with toluene when compared with the controls. But GSH-Px activity, MDA, and BUN levels showed statistically nonsignificant changes. However, increased CAT and SOD enzyme activities and decreased serum creatinine levels were detected in the rats that received CAPE while exposed to toluene. The GSH-Px activity and MDA and BUN levels in the same group did not show statistically significant changes. The results of our study demonstrated that toluene damages kidney tissue and is a nephrotoxic substance. CAPE was able to prevent the renal damage as antioxidant, antitoxic, and nephroprotective agent. © The Author(s) 2013.

  14. A retrospective evaluation of furosemide and mannitol for prevention of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Mach, C M; Kha, C; Nguyen, D; Shumway, J; Meaders, K M; Ludwig, M; Williams-Brown, M Y; Anderson, M L

    2017-06-01

    Nephrotoxicity is a recognized side effect of cisplatin chemotherapy. However, the optimal strategy for preventing cisplatin-induced nephrotoxicity, if any, remains unclear. The primary objective for this study was to determine whether mannitol or furosemide provides better nephroprotection when administered with hydration prior to weekly, low-dose cisplatin concurrently with whole pelvic radiotherapy. Clinical data were abstracted from all women who underwent chemoradiation for FIGO IB2-IVA cervical cancer at a regional safety net health system between January 2009 and December 2014. Creatinine clearance was estimated using the IDMS-traceable MDRD Study Equation. Descriptive statistics were used to summarize patient demographics. Cox proportional hazard models were used to identify factors associated with hypomagnesemia and survival. A total of 133 women received 656 weekly doses of single-agent cisplatin (40 mg/m 2 ) concomitant with whole pelvic radiation. Furosemide (20 mg) was administered intravenously prior to 341 cisplatin doses, whereas mannitol (24 g) was administered prior to 315 doses. Significant magnesium wasting was observed after the second weekly cisplatin infusion regardless of whether furosemide or mannitol was utilized. Repetitive low-dose cisplatin infusion had no impact on measured levels of serum creatinine or estimated glomerular filtration rate. Prior history of hypertension, diabetes mellitus, hepatitis C infection and acute gastrointestinal toxicity were each associated with early onset of hypomagnesemia. Repetitive administration of low-dose cisplatin concurrent with whole pelvic radiation is associated with magnesium wasting. However, choice of diuretic with pretreatment hydration had no significant impact on the severity of this adverse effect. © 2017 John Wiley & Sons Ltd.

  15. Protective effect of allicin against gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    El-Kashef, Dalia H; El-Kenawi, Asmaa E; Suddek, Ghada M; Salem, Hatem A

    2015-12-01

    In this study, the modulator effect of allicin on the oxidative nephrotoxicity of gentamicin in the kidneys of rats was investigated by determining indices of lipid peroxidation and the activities of antioxidant enzymes, as well as by histological analyses. Furthermore, the effect of allicin on gentamicin induced hypersensitivity of urinary bladder rings to ACh was estimated. Twenty-four male Wistar albino rats were randomly divided into three groups, control, gentamicin (100mg/kg, i.p.) and gentamicin+allicin (50mg/kg, orally). At the end of the study, all rats were sacrificed and then urine, blood samples and kidneys were taken. Gentamicin administration caused a severe nephrotoxicity as evidenced by an elevated kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), serum lactate dehydrogenase (LDH) and proteinuria with a reduction in serum albumin and creatinine clearance as compared with control group. In addition, a significant increase in renal contents of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx) and tumor necrosis factor-alpha (TNF-α) concomitantly with a significant decrease in renal reduced glutathione (GSH) and superoxide dismutase (SOD) activities was detected upon gentamicin injection. Exposure to gentamicin increased the sensitivity of isolated urinary bladder rings to ACh and induced acute renal tubular epithelial cells necrosis. Administration of allicin significantly decreased kidney/body weight ratio, serum creatinine, LDH, renal MDA, MPO, NOx and TNF-α while it significantly increased creatinine clearance, renal GSH content and renal SOD activity when compared to gentamicin-treated group. Additionally, allicin significantly reduced the responses of isolated bladder rings to ACh and ameliorated tissue morphology as evidenced by histological evaluation. Our study indicates that allicin exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant, anti

  16. The Protective Effects of Sika Deer Antler Protein on Cisplatin-Induced Nephrotoxicity

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    Huihai Yang

    2017-08-01

    Full Text Available Background/Aims: This study measured the effect of Sika deer (Cervus nippon Temminck antler protein (SDAPR, glycoproteins (SDAG, and polysaccharides (SDAPO on cisplatin-induced cytotoxicity in HEK 293 cells, and investigated the effect of SDAPR against cisplatin-induced nephrotoxicity in mice. Methods: Cell viability was measured by MTT assay. ICR mice were randomly divided into five groups: control, cisplatin with vehicle, and cisplatin with SDAPR at three concentrations: 5, 10, or 20 mg/kg, p.o., 10 d. Cisplatin was injected on 7th day (25 mg/kg, i.p.. Renal function, oxidative stress, levels of inflammatory factors, and expression of apoptosis-related proteins were measured in vivo. Renal tissues were stained with TUNEL and H&E to observe renal cell apoptosis and pathological changes. Results: Pretreatment with SDAPR (125-2000 µg/mL significantly improved cell viability, with an EC50 of approximately 1000 µg/mL. SDAPR also ameliorated cisplatin-induced histopatholo- gic changes, and decreased blood urea nitrogen (BUN and creatinine (Cr (P < 0.05. Western blotting analysis showed SDAPR clearly decreased expression levels of cleaved-caspase-3 and Bax, and increased the expression level of Bcl-2 (P < 0.01. Additionally, SDAPR markedly regulated oxidative stress markers and inflammatory cytokines (P<0.05. TUNEL staining showed decreased apoptosis after SDAPR treatment (P < 0.01. Conclusions: These results indicate that SDAPR can be an effective dietary supplement, to relieve cisplatin-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vivo.

  17. Clinical Effectiveness and Nephrotoxicity of Aerosolized Colistin Treatment in Multidrug-Resistant Gram-Negative Pneumonia

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    Seung Yong Park

    2016-08-01

    Full Text Available Background: Colistin (polymyxin E is active against multidrug-resistant Gram-negative bacteria (MDR-GNB. However, the effectiveness of inhaled colistin is unclear. This study was designed to assess the effectiveness and safety of aerosolized colistin for the treatment of ventilator-associated pneumonia (VAP caused by MDR-GNB. Methods: In this retrospective longitudinal study, we evaluated the medical records of 63 patients who received aerosolized colistin treatment for VAP caused by MDR-GNB in the medical intensive care unit (MICU from February 2012 to March 2014. Results: A total of 25 patients with VAP caused by MDR-GNB were included in this study. The negative conversion rate was 84.6% after treatment, and acute kidney injury (AKI occurred in 11 patients (44%, AKI group. The average length of MICU stay and colistin treatment-related factors, such as daily and total cumulative doses and administration period, were not significantly different between groups. In-hospital mortality tended to be higher in the AKI group (p = 0.07. Multivariate analysis showed that a body mass index less than 18 was an independent risk factor of mortality (odds ratio [OR] = 21.95, 95% confidence interval [CI] 1.59-302.23; p = 0.02. Notably, AKI occurrence was closely related to the administration of more than two nephrotoxic drugs combined with aerosolized colistin (OR = 15.03, 95% CI 1.40-161.76; p = 0.025 and septic shock (OR = 8.10, 95% CI 1.40-161.76; p = 0.04. Conclusions: The use of adjunctive aerosolized colistin treatment appears to be a relatively safe and effective option for the treatment of VAP caused by MDR-GNB. However, more research on the concomitant use of nephrotoxic drugs with aerosolized colistin will be necessary, as this can be an important risk factor of development of AKI.

  18. The protective role of saffron petal extracts on gentamicininduced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Arash Omidi

    2016-07-01

    Full Text Available Different potentially therapeutic approaches to prevent or attenuate gentamicin sulfate (GM induced nephrotoxicity have been proposed. The present study was conducted to investigate the effect of the saffron petals extracts (Crocus sativus (SPE on male Wistar rats with kidney failure. Rats (40 were randomly assigned into five groups of 8 animals each: i the control group, that received normal saline (0.5 mL/kg; ii the GM group, that received GM (80 mg/kg by intraperitoneal (i.p. injection on a daily basis; iii the GM+SPE group that received the same dose of GM and SPE (40 mg/kg by i.p. injection on a daily basis; iv the GM+2SPE group, that received the same dose of GM and twofold of SPE (80 mg/kg by i.p. injection on a daily basis; whereas v 2SPE+GM group, that received 80 mg/kg of SPE a week before initiating the treatment with GM (prevention group. Significant differences were seen in the concentration of glucose, blood urea nitrogen (BUN, and creatinine between treatment groups and control in the male Wistar rats. GM was observed to cause nephrotoxicity, which was evidenced by an elevation of serum BUN and creatinine levels. The biochemical findings of the current study are concordant with those of histopathologic findings. The results of this study indicate that SPE especially in dose of 40 mg/kg can ameliorate harmful effects of GM on the kidney. The present results may suggest that the SPE have ameliorative effects on kidney failures induced by GM.

  19. Tiron ameliorates oxidative stress and inflammation in titanium dioxide nanoparticles induced nephrotoxicity of male rats.

    Science.gov (United States)

    Morgan, Ashraf; Galal, Mona K; Ogaly, Hanan A; Ibrahim, Marwa A; Abd-Elsalam, Reham M; Noshy, Peter

    2017-09-01

    Although the widespread use of titanium dioxide nanoparticles (TiO 2 NPs), few studies were conducted on its hazard influence on human health. Tiron a synthetic vitamin E analog was proven to be a mitochondrial targeting antioxidant. The current investigation was performed to assess the efficacy of tiron against TiO 2 NPs induced nephrotoxicity. Eighty adult male rats divided into four different groups were used: group I was the control, group II received TiO2 NPs (100mg\\Kg BW), group III received TiO2 NPs plus tiron (470mg\\kg BW), and group IV received tiron alone. Urea, creatinine and total protein concentrations were measured in serum to assess the renal function. Antioxidant status was estimated by determining the activities of glutathione peroxidase, superoxide dismutase, malondialdehyde (MDA) level and glutathione concentration in renal tissue. As well as Renal fibrosis was evaluated though measuring of transforming growth factor-β1 (TGFβ1) and matrix metalloproteinase 9 (MMP9) expression levels and histopathological examination. TiO 2 NPs treated rats showed marked elevation of renal indices, depletion of renal antioxidant enzymes with marked increase in MDA concentration as well as significant up-regulation in fibrotic biomarkers TGFβ1 and MMP9. Oral administration of tiron to TiO 2 NPs treated rats significantly attenuate the renal dysfunction through decreasing of renal indices, increasing of antioxidant enzymes activities, down-regulate the expression of fibrotic genes and improving the histopathological picture for renal tissue. In conclusion, tiron was proved to attenuate the nephrotoxicity induced by TiO 2 NPs through its radical scavenging and metal chelating potency. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Atrial natriuretic peptide gene delivery attenuates gentamycin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Murakami, H; Yayama, K; Chao, J; Chao, L

    1999-06-01

    Atrial natriuretic peptide (ANP) is a cardiac hormone which exerts potent natriuretic and vasorelaxant activities. The aim of this study is to investigate potential protective effects of ANP gene delivery in gentamycin-induced nephrotoxicity. Adenovirus (Ad.RSV-ANP) carrying the human ANP gene or carrying the LacZ gene (Ad.RSV-LacZ) under the control of the Rous sarcoma virus promoter were delivered intravenously on the first day of gentamycin administration. Sprague Dawley rats were injected subcutaneously with gentamycin daily for 10 days. A single systemic injection of Ad.RSV-ANP at a dose of 1.2x10(10) pfu results in a significant increase in urine excretion, water intake, urinary sodium and potassium excretion. Adenovirus-mediated ANP gene delivery significantly increased renal blood flow, glomerular filtration rates and urine flow as well as attenuated the elevation of blood urea nitrogen levels. Histological evaluations revealed that ANP delivery attenuated gentamycin-induced renal tubular damage, cellular necrosis, and lumenal protein casts. The expression of human ANP mRNA was identified in rat kidney, heart, aorta and liver. Immunoreactive human ANP was detected in the heart and kidney of rats injected with Ad.RSV-ANP but not in rats injected with Ad.RSV-LacZ. Cyclic GMP levels in the kidney were significantly increased in rats receiving ANP gene delivery. This study shows that ANP gene delivery exhibits protection against gentamycin-induced nephrotoxicity and raises the potential to use ANP gene therapy for the treatment of drug-induced renal failure.

  1. Expression of basolateral organic anion and cation transporters in experimental cadmium nephrotoxicity in rat kidney.

    Science.gov (United States)

    Ljubojević, Marija; Breljak, Davorka; Herak-Kramberger, Carol M; Anzai, Naohiko; Sabolić, Ivan

    2016-03-01

    Cadmium (Cd)-intoxicated experimental animals exhibit impaired renal secretion of organic anions (OA) and cations (OC), indicating their transporters (Oats and Octs) in the proximal tubule (PT) basolateral membrane as possible targets of Cd. To correlate transport data from the literature with the expression of relevant transporters, we performed immunochemical and RT-PCR studies of renal Oats and Octs in the subchronic (treatment with CdCl2; 2 mg Cd/kg b.m./day, for 2 weeks) and acute (treatment with Cd-metallothionein (CdMT); 0.4 mg Cd/kg b.m., 6 or 12 h before killing) models of Cd nephrotoxicity. In the subchronic model, PT exhibited a minor loss of basolateral invaginations and overall unchanged expression of Na(+)/K(+)-ATPase and GAPDH proteins and mRNAs, while the expression of Oat and Oct proteins and their mRNAs was strongly downregulated. In the acute model, a time-related redistribution of basolateral transporters to the intracellular vesicular compartment was a major finding. However, 6 h following CdMT treatment, the total abundance of Oat and Oct proteins in the renal tissue remained unchanged, the expression of mRNAs decreased only for Oats, while a limited Oat1 and Na(+)/K(+)-ATPase immunoreactivity in the PT apical membrane indicated loss of cell polarity. As tested in rats treated with colchicine, the observed loss/redistribution of basolateral transporters in both models may be independent on microtubules. Therefore, the diminished renal secretion of OA and OC via PT in Cd nephrotoxicity may result from (a) limited loss of secretory surface (basolateral invaginations), (b) selective loss of Oats and Octs, and (c) loss of cell polarity.

  2. Cyclosporin effect on sodium and potassium transport across erythrocytes in rheumatoid arthritis.

    Science.gov (United States)

    Rabini, R A; Testa, I; Corvetta, A; Lombardello, M; Polenta, M; Danieli, G; Mazzanti, L

    1990-01-01

    The aim of the present work was to evaluate the action of cyclosporin (CsA) both in vivo and in vitro on the active sodium transport across the erythrocyte membrane of rheumatoid arthritis (RA) patients. The in vivo study was performed on 20 patients affected by refractory RA and treated with CsA (5 mg/kg/die) or with azathioprine (2 mg/kg/die) before and after 7 days' therapy. The control group was formed of 25 healthy subjects. RA patients before treatment showed increased intra-erythrocyte Na+ concentration and decreased Na+, K+ ATPase activity in comparison with normal subjects. A rise in the activity of the sodium pump and a reduction in the intra-erythrocyte Na+ concentration were observed after cyclosporin treatment, but not after azathioprine. The in vitro study was performed on intact RBCs and on erythrocyte membranes from 15 healthy subjects and from 12 patients affected by classical RA, in the presence or absence of CsA (0.5-1-2 micrograms/ml). CsA (0.5 micrograms/ml) increased the Na+, K+ ATPase activity in intact RBCs and in erythrocyte membranes from both groups of subjects. Intracellular Na+ was decreased only in erythrocytes from RA patients after addition of 0.5 micrograms/ml CsA. A direct action of CsA on the membrane hydrophobic environment of the Na+, K+ ATPase is hypothesized on the basis of the present results.

  3. Effect of tangerine juice on cyclosporine levels in renal transplant children.

    Science.gov (United States)

    Sorkhi, Hadi; Moghadamnia, Ali Akbar; Oaliaee, Farshid; Pouramir, Mehdi; Firoozjahi, Ali Reza; Pasha, Abazar Akbarzadeh; Goodarzi, Mohammad Rad

    2008-03-01

    The aim of our study was to investigate the effect of tangerine juice on the pharmacokinetics of cyclosporine A (CsA), in children who had received a renal transplant. This placebo-controlled study was done on ten kidney transplant recipients with stable cyclosporine trough levels who received either tangerine (Unshio Satsuma) juice or water. Patients were given their morning doses of CsA and then 250 ml water or the juice, and 12 h, investigations of the pharmacokinetics (PK) were performed. The main outcome measures were peak concentration and time to peak and area under the concentration-time curve. Administration of CsA with tangerine juice compared with water did not increase significantly the area under the whole-blood concentration versus time curve from 0-12 h (AUC(0-12)) of CsA, (tangerine juice 2,797 +/- 1,361 (P = 0.5); water 3,053 +/- 1,532). Co-administration of tangerine juice with CsA compared with water had no significant effects on the AUC(0-12), peak concentration (C(max)) or time to C(max) (t(max)) of the CsA in pediatric renal transplantation.

  4. Experimental and DFT study on complexation of the strontium cation with cyclosporin A

    Science.gov (United States)

    Makrlík, Emanuel; Böhm, Stanislav; Vaňura, Petr

    2015-11-01

    By using extraction experiments and γ-activity measurements, the extraction constant corresponding to the equilibrium Sr2+(aq) + 2A-(aq) + 1(nb) ⇄ 1·Sr2+(nb) + 2A-(nb) occurring in the two-phase water-nitrobenzene system (A- = picrate, 1 = cyclosporin A; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (1·Sr2+,2A-) = 0.1 ± 0.1. Further, the stability constant of the 1·Sr2+ complex in nitrobenzene saturated with water was calculated for a temperature of 25 °C: log βnb (1·Sr2+) = 9.2 ± 0.1. Finally, applying quantum mechanical DFT calculations, the most probable structure of the proven 1·Sr2+ cationic complex was derived. In the resulting complex, the "central" cation Sr2+ is bound by five bonds to the corresponding five oxygen atoms of the parent cyclosporin A ligand. The interaction energy, E(int), of the investigated 1·Sr2+ complex, involving the 7-point correction for the basis set superposition error, was calculated as -894.5 kJ/mol.

  5. Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results

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    Luciano Merlini

    2011-01-01

    Full Text Available Six individuals with Ullrich congenital muscular dystrophy (UCMD and mutations in the genes-encoding collagen VI, aging 5–9, received 3–5 mg/kg of cyclosporine A (CsA daily for 1 to 3.2 years. The primary outcome measure was the muscle strength evaluated with a myometer and expressed as megalimbs. The megalimbs score showed significant improvement (P=0.01 in 5 of the 6 patients. Motor function did not change. Respiratory function deteriorated in all. CsA treatment corrected mitochondrial dysfunction, increased muscle regeneration, and decreased the number of apoptotic nuclei. Results from this study demonstrate that long-term treatment with CsA ameliorates performance in the limbs, but not in the respiratory muscles of UCMD patients, and that it is well tolerated. These results suggest considering a trial of CsA or nonimmunosuppressive cyclosporins, that retains the PTP-desensitizing properties of CsA, as early as possible in UCMD patients when diaphragm is less compromised.

  6. Cyclosporine: A Historical Perspective on Its Role in the Treatment of Noninfectious Uveitis.

    Science.gov (United States)

    Smith, Wendy M

    2017-05-01

    The history of cyclosporine and uveitis is intertwined with the development of experimental autoimmune uveitis (EAU) animal models and the understanding that T lymphocytes play a major role in the pathogenesis of uveitis. The early studies of CsA in uveitis also demonstrated the power of collaborative efforts in translational research. Dr. Robert Nussenblatt and his colleagues were the first to show that CsA can inhibit EAU. Over many years after the initial CsA experiments, Dr. Nussenblatt's group as well as others continued to study CsA under experimental conditions as well as in clinical trials with human patients. The data and observations from these studies significantly advanced our knowledge of uveitis pathophysiology and demonstrated the value of well-designed masked, controlled treatment trials in uveitis. Dr. Nussenblatt and his collaborators delved into the most significant adverse effect of CsA, renal toxicity, and helped elucidate the pathophysiology of renal injury. They explored adjunctive treatments to improve the efficacy and decrease the toxicity of CsA and also studied other members of the cyclosporine family. Among the immunosuppressives used to treat ocular inflammation, CsA was the first, and remains the only medication comprehensively studied under both experimental and clinical conditions.

  7. Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients.

    Science.gov (United States)

    Hamour, Iman M; Lyster, Haifa S; Burke, Margaret M; Rose, Marlene L; Banner, Nicholas R

    2007-03-15

    Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, Pcyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

  8. Results with cyclosporine monotherapy in long-term cardiac transplant recipients.

    Science.gov (United States)

    Sansone, F; Boffini, M; Comoglio, C; Checco, L; Saviolo, R; Centofanti, P; La Torre, M; Rinaldi, M

    2010-05-01

    Triple therapy is the gold standard after heart transplantation while few reports have described experiences with cyclosporine monotherapy (CM). We have analyzed our experience with CM in long-term heart transplant recipients, surviving >5 years. Of the 219 patients transplanted between January 1990 and December 1998, 143 survived >5 years (mean age, 49.6 +/- 10.4). There were 124 (86.7%) male subjects. Matching patients respect to follow-up length, we obtained 2 groups: group A of 41 patients on double therapy (DT; cyclosporine plus Azathioprine) and group B of 41 patients on CM. After a mean follow-up of 119.8 +/- 32.2 months, we did not observe a significant difference in terms of survival and major events: heart failure, malignancy, dialysis, infections, and CAV. We strongly support the use of triple therapy in cardiac transplant recipients because of its known safety and efficacy. However, our experience with CM suggests the utility of this approach. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  9. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study

    NARCIS (Netherlands)

    Mocroft, Amanda; Lundgren, Jens D.; Ross, Michael; Law, Matthew; Reiss, Peter; Kirk, Ole; Smith, Colette; Wentworth, Deborah; Neuhaus, Jacqueline; Fux, Christoph A.; Moranne, Olivier; Morlat, Phillipe; Johnson, Margaret A.; Ryom, Lene; Lundgren, J. D.; Powderly, B.; Shortman, N.; Moecklinghoff, C.; Reilly, G.; Franquet, X.; Sabin, C. A.; Phillips, A.; Kirk, O.; Weber, R.; Pradier, C.; Law, M.; d'Arminio Monforte, A.; Dabis, F.; El-Sadr, W. M.; de Wit, S.; Ryom, L.; Kamara, D.; Smith, C.; Mocroft, A.; Tverland, J.; Mansfeld, M.; Nielsen, J.; Raben, D.; Salbøl Brandt, R.; Rickenbach, M.; Fanti, I.; Krum, E.; Hillebregt, M.; Geffard, S.; Sundström, A.; Delforge, M.; Fontas, E.; Torres, F.; McManus, H.; Wright, S.; Kjær, J.; Sjøl, A.; Meidahl, P.; Helweg-Larsen, J.; Schmidt Iversen, J.; Ross, M.; Fux, C. A.; Morlat, P.; Moranne, O.; Kesselring, A. M.; Kamara, D. A.; Friis-Møller, N.; Kowalska, J.; Sabin, C.; Bruyand, M.; Bower, M.; Fätkenheuer, G.; Donald, A.; Grulich, A.; Prins, J. M.; Kuijpers, T. W.; Scherpbier, H. J.; van der Meer, J. T. M.; Wit, F. W. M. N.; Godfried, M. H.; van der Poll, T.; Nellen, F. J. B.; Geerlings, S. E.; van Vugt, M.; Pajkrt, D.; Bos, J. C.; Wiersinga, W. J.; van der Valk, M.; Goorhuis, A.; Hovius, J. W.; van Eden, J.; Henderiks, A.; van Hes, A. M. H.; Mutschelknauss, M.; Nobel, H. E.; Pijnappel, F. J. J.; Westerman, A. M.; Jurriaans, S.; Back, N. K. T.; Zaaijer, H. L.; Berkhout, B.; Cornelissen, M. T. E.; Schinkel, C. J.; Thomas, X. V.; de Ruyter Ziekenhuis, Admiraal; van den Berge, M.; Stegeman, A.; Baas, S.; Hage de Looff, L.; Versteeg, D.; Pronk, M. J. H.; Ammerlaan, H. S. M.; Korsten-Vorstermans, E. M. H. M.; de Munnik, E. S.; Jansz, A. R.; Tjhie, J.; Wegdam, M. C. A.; Deiman, B.; Scharnhorst, V.; van der Plas, A.; Weijsenfeld, A. M.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; van Gorp, E. C. M.; Schurink, C. A. M.; Nouwen, J. L.; Verbon, A.; Rijnders, B. J. A.; Bax, H. I.; Hassing, R. J.; van der Feltz, M.; Bassant, N.; van Beek, J. E. A.; Vriesde, M.; van Zonneveld, L. M.; de Oude-Lubbers, A.; van den Berg-Cameron, H. J.; Bruinsma-Broekman, F. B.; de Groot, J.; de Zeeuw-de Man, M.; Broekhoven-Kruijne, M. J.; Schutten, M.; Osterhaus, A. D. M. E.; Boucher, C. A. B.; Driessen, G. J. A.; van Rossum, A. M. C.; van der Knaap, L. C.; Visser, E.; Branger, J.; Duijf-van de Ven, C. J. H. M.; Schippers, E. F.; van Nieuwkoop, C.; Brimicombe, R. W.; van Ijperen, J. M.; van der Hut, G.; Franck, P. F. H.; van Eeden, A.; Brokking, W.; Groot, M.; Damen, M.; Kwa, I. S.; Groeneveld, P. H. P.; Bouwhuis, J. W.; van den Berg, J. F.; van Hulzen, A. G. W.; van der Bliek, G. L.; Bor, P. C. J.; Bloembergen, P.; Wolfhagen, M. J. H. M.; Ruijs, G. J. H. M.; Gasthuis, Kennemer; van Lelyveld, S. F. L.; Soetekouw, R.; Hulshoff, N.; van der Prijt, L. M. M.; Schoemaker, M.; Bermon, N.; van der Reijden, W. A.; Jansen, R.; Herpers, B. L.; Veenendaal, D.; Kroon, F. P.; Arend, S. M.; de Boer, M. G. J.; Bauer, M. P.; Jolink, H.; Vollaard, A. M.; Dorama, W.; Moons, C.; Claas, E. C. J.; Kroes, A. C. M.; den Hollander, J. G.; Pogany, K.; Kastelijns, M.; Smit, J. V.; Smit, E.; Bezemer, M.; van Niekerk, T.; Pontesilli, O.; Lowe, S. H.; Oude Lashof, A.; Posthouwer, D.; Ackens, R. P.; Schippers, J.; Vergoossen, R.; Weijenberg Maes, B.; Savelkoul, P. H. M.; Loo, I. H.; Weijer, S.; el Moussaoui, R.; Heitmuller, M.; Kortmann, W.; van Twillert, G.; Cohen Stuart, J. W. T.; Diederen, B. M. W.; Pronk, D.; van Truijen-Oud, F. A.; Leyten, E. M. S.; Gelinck, L. B. S.; van Hartingsveld, A.; Meerkerk, C.; Wildenbeest, G. S.; Mutsaers, J. A. E. M.; Jansen, C. L.; van Vonderen, M. G. A.; van Houte, D. P. F.; Dijkstra, K.; Faber, S.; Weel, J.; Kootstra, G. J.; Delsing, C. E.; van der Burg-van de Plas, M.; Heins, H.; Lucas, E.; Brinkman, K.; Frissen, P. H. J.; Blok, W. L.; Schouten, W. E. M.; Bosma, A. S.; Brouwer, C. J.; Geerders, G. F.; Hoeksema, K.; Kleene, M. J.; van der Meché, I. B.; Toonen, A. J. M.; Wijnands, S.; van Ogtrop, M. L.; Koopmans, P. P.; Keuter, M.; van der Ven, A. J. A. M.; ter Hofstede, H. J. M.; Dofferhoff, A. S. M.; van Crevel, R.; Albers, M.; Bosch, M. E. W.; Grintjes-Huisman, K. J. T.; Zomer, B. J.; Stelma, F. F.; Burger, D.; Richter, C.; van der Berg, J. P.; Gisolf, E. H.; ter Beest, G.; van Bentum, P. H. M.; Langebeek, N.; Tiemessen, R.; Swanink, C. M. A.; Veenstra, J.; Lettinga, K. D.; Spelbrink, M.; Sulman, H.; Witte, E.; Peerbooms, P. G. H.; Mulder, J. W.; Vrouenraets, S. M. E.; Lauw, F. N.; van Broekhuizen, M. C.; Paap, H.; Vlasblom, D. J.; Oudmaijer Sanders, E.; Smits, P. H. M.; Rosingh, A. W.; Verhagen, D. W. M.; Geilings, J.; van Kasteren, M. E. E.; Brouwer, A. E.; de Kruijf-van de Wiel, B. A. F. M.; Kuipers, M.; Santegoets, R. M. W. J.; van der Ven, B.; Marcelis, J. H.; Buiting, A. G. M.; Kabel, P. J.; Bierman, W. F. W.; Sprenger, H. G.; Scholvinck, E. H.; van Assen, S.; Wilting, K. R.; Stienstra, Y.; de Groot-de Jonge, H.; van der Meulen, P. A.; de Weerd, D. A.; Niesters, H. G. M.; Riezebos-Brilman, A.; van Leer-Buter, C. C.; Hoepelman, A. I. M.; Schneider, M. M. E.; Mudrikova, T.; Ellerbroek, P. M.; Oosterheert, J. J.; Arends, J. E.; Barth, R. E.; Wassenberg, M. W. M.; van Elst-Laurijssen, D. H. M.; Laan, L. M.; van Oers-Hazelzet, E. E. B.; Patist, J.; Vervoort, S.; Nieuwenhuis, H. E.; Frauenfelder, R.; Schuurman, R.; Verduyn-Lunel, F.; Wensing, A. M. J.; Peters, E. J. G.; van Agtmael, M. A.; Perenboom, R. M.; Bomers, M.; de Vocht, J.; Elsenburg, L. J. M.; Pettersson, A. M.; Vandenbroucke-Grauls, C. M. J. E.; Ang, C. W.; Geelen, S. P. M.; Wolfs, T. F. W.; Bont, L. J.; Nauta, N.; Bezemer, D. O.; Gras, L.; van Sighem, A. I.; Smit, C.; Zaheri, S.; Kimmel, V.; Tong, Y.; Lascaris, B.; van den Boogaard, R.; Hoekstra, P.; de Lang, A.; Berkhout, M.; Grivell, S.; Jansen, A.; de Groot, L.; van den Akker, M.; Bergsma, D.; Lodewijk, C.; Meijering, R.; Peeck, B.; Raethke, M.; Ree, C.; Regtop, R.; Ruijs, Y.; Schoorl, M.; Tuijn, E.; Veenenberg, L.; Woudstra, T.; Bakker, Y.; de Jong, A.; Broekhoven, M.; Claessen, E.; Rademaker, M. J.; Munjishvili, L.; Kruijne, E.; Tuk, B.; Bonnet, F.; Dupon, M.; Chêne, G.; Breilh, D.; Fleury, H.; Malvy, D.; Mercié, P.; Pellegrin, I.; Neau, D.; Pellegrin, J. L.; Bouchet, S.; Gaborieau, V.; Lacoste, D.; Tchamgoué, S.; Thiébaut, R.; Lawson-Ayayi, S.; Wittkop, L.; Bernard, N.; Hessamfar, M.; Vandenhende, M. A.; Dauchy, F. A.; Dutronc, H.; Longy-Boursier, M.; Duffau, P.; Schmeltz, J. Roger; Pistone, T.; Receveur, M. C.; Cazanave, C.; Ochoa, A.; Vareil, M. O.; Viallard, J. F.; Greib, C.; Lazaro, E.; Lafon, M. E.; Reigadas, S.; Trimoulet, P.; Molimard, M.; Titier, K.; Moreau, J. F.; Haramburu, F.; Miremont-Salamé, G.; Dupont, A.; Gerard, Y.; André, K.; Bonnal, F.; Farbos, S.; Gemain, M. C.; Ceccaldi, J.; de Witte, S.; Courtault, C.; Monlun, E.; Lataste, P.; Meraud, J. P.; Chossat, I.; Blaizeau, M. J.; Conte, V.; Decoin, M.; Delaune, J.; Delveaux, S.; Diarra, F.; D'Ivernois, C.; Frosch, A.; Hannapier, C.; Lenaud, E.; Leleux, O.; Le Marec, F.; Leray, J.; Louis, I.; Palmer, G.; Pougetoux, A.; Sicard, X.; Uwamaliya-Nziyumvira, D. Touchard B.; Petoumenos, K.; Bendall, C.; Moore, R.; Edwards, S.; Hoy, J.; Watson, K.; Roth, N.; Nicholson, J.; Bloch, M.; Franic, T.; Baker, D.; Vale, R.; Carr, A.; Cooper, D.; Chuah, J.; Ngieng, M.; Nolan, D.; Skett, J.; Calvo, G.; Mateu, S.; Domingo, P.; Sambeat, M. A.; Gatell, J.; del Cacho, E.; Cadafalch, J.; Fuster, M.; Codina, C.; Sirera, G.; Vaqué, A.; Clumeck, N.; Necsoi, C.; Gennotte, A. F.; Gerard, M.; Kabeya, K.; Konopnicki, D.; Libois, A.; Martin, C.; Payen, M. C.; Semaille, P.; van Laethem, Y.; Neaton, J.; Bartsch, G.; Thompson, G.; Wentworth, D.; Luskin-Hawk, R.; Telzak, E.; Abrams, D. I.; Cohn, D.; Markowitz, N.; Arduino, R.; Mushatt, D.; Friedland, G.; Perez, G.; Tedaldi, E.; Fisher, E.; Gordin, F.; Crane, L. R.; Sampson, J.; Baxter, J.; Lundgren, J.; Cozzi-Lepri, A.; Grint, D.; Podlekareva, D.; Peters, L.; Reekie, J.; Fischer, A. H.; Losso, M.; Elias, C.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Colebunders, R.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, E.; Skinhøj, P.; Pedersen, C.; Ostergaard, L.; Zilmer, K.; Smidt, J.; Ristola, M.; Katlama, C.; Viard, J. P.; Girard, P.-M.; Livrozet, J. M.; Vanhems, P.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Staszewski, S.; Bickel, M.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Panos, G.; Filandras, A.; Karabatsaki, E.; Sambatakou, H.; Banhegyi, D.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; Hassoun, G.; Maayan, S.; Vella, S.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Chirianni, A.; Montesarchio, E.; Gargiulo, M.; Antonucci, G.; Testa, A.; Narciso, P.; Vlassi, C.; Zaccarelli, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Zeltina, I.; Chaplinskas, S.; Hemmer, R.; Staub, T.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Boron-Kaczmarska, A.; Pynka, M.; Parczewski, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Antunes, F.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Duiculescu, D.; Rakhmanova, A.; Zakharova, N.; Petersburg, Saint; Buzunova, S.; Jevtovic, D.; Mokráš, M.; Staneková, D.; Tomazic, J.; González-Lahoz, J.; Soriano, V.; Labarga, P.; Medrano, J.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miró, J. M.; Gutierrez, M.; Mateo, G.; Karlsson, A.; Flamholc, L.; Ledergerber, B.; Francioli, P.; Cavassini, M.; Hirschel, B.; Boffi, E.; Furrer, H.; Battegay, M.; Elzi, L.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Servitskiy, S.; Krasnov, M.; Barton, S.; Johnson, A. M.; Mercey, D.; Johnson, M. A.; Murphy, M.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Morfeldt, L.; Thulin, G.; Åkerlund, B.; Koppel, K.; Håkangård, C.; Moroni, M.; Angarano, G.; Antinori, A.; Armignacco, O.; Castelli, F.; Cauda, R.; Di Perri, G.; Iardino, R.; Ippolito, G.; Perno, C. F.; von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Puoti, M.; Andreoni, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, R.; Cingolani, A.; Cinque, P.; de Luca, A.; Di Biagio, A.; Gori, A.; Guaraldi, G.; Lapadula, G.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Cicconi, P.; Formenti, T.; Galli, L.; Lorenzini, P.; Giacometti, A.; Costantini, A.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Cassola, G.; Viscoli, G.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Puzzolante, C.; Abrescia, N.; Guida, M. G.; Onofrio, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; d'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Pellizzer, G.; Manfrin, V.; Dollet, K.; Caissotti, C.; Dellamonica, P.; Roger, P. M.; Bernard, E.; Cua, E.; de Salvador-Guillouet, F.; Durant, J.; Ferrando, S.; Dunais, B.; Mondain-Miton, V.; Perbost, I.; Prouvost-Keller, B.; Pugliese, P.; Naqvi, A.; Pillet, S.; Risso, K.; Aubert, V.; Barth, J.; Bernasconi, E.; Böni, J.; Bucher, H. C.; Burton-Jeangros, C.; Calmy, A.; Egger, M.; Fehr, J.; Fellay, J.; Gorgievski, M.; Günthard, H.; Haerry, D.; Hasse, B.; Hirsch, H. H.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kovari, H.; Martinetti, G.; Martinez de Tejada, B.; Metzner, K.; Müller, N.; Nadal, D.; Pantaleo, G.; Rauch, A.; Regenass, A.; Rudin, C.; Schmid, P.; Schultze, D.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Yerly, S.; Bhagani, S.; Burns, F.; Byrne, P.; Carroll, A.; Cropley, I.; Cuthbertson, Z.; Drinkwater, T.; Fernandez, T.; Garusu, E.; Gonzales, A.; Grover, D.; Hutchinson, S.; Killingley, B.; Murphy, G.; Ivens, D.; Johnson, M.; Kinloch de Loes, S.; Lipman, M.; Madge, S.; Marshall, N.; Montgomery, H.; Shah, R.; Swaden, L.; Tyrer, M.; Youle, M.; Webster, D.; Wright, A.; Chaloner, C.; Miah, M.; Tsintas, R.; Burch, L.; Cambiano, V.; Lampe, F.; Nakagawa, F.; O'Connor, J.; Speakman, A.; Connell, M.; Clewley, G.; Martin, S.; Thomas, M.; Aagaard, B.; Aragon, E.; Arnaiz, J.; Borup, L.; Dragsted, U.; Fau, A.; Gey, D.; Grarup, J.; Hengge, U.; Herrero, P.; Jansson, P.; Jensen, B.; Jensen, K.; Juncher, H.; Lopez, P.; Matthews, C.; Mollerup, D.; Pearson, M.; Reilev, S.; Tillmann, K.; Varea, S.; Angus, B.; Babiker, A.; Cordwell, B.; Darbyshire, J.; Dodds, W.; Fleck, S.; Horton, J.; Hudson, F.; Moraes, Y.; Pacciarini, F.; Palfreeman, A.; Paton, N.; Smith, N.; van Hooff, F.; Bebchuk, J.; Collins, G.; Denning, E.; DuChene, A.; Fosdick, L.; Harrison, M.; Herman-Lamin, K.; Larson, G.; Nelson, R.; Quan, K.; Quan, S.; Schultz, T.; Wyman, N.; Carey, C.; Chan, F.; Courtney-Rodgers, D.; Drummond, F.; Emery, S.; Harrod, M.; Jacoby, S.; Kearney, L.; Lin, E.; Pett, S.; Robson, R.; Seneviratne, N.; Stewart, M.; Watts, E.; Finley, E.; Sánchez, A.; Standridge, B.; Vjecha, M.; Belloso, W.; Davey, R.; Duprez, D.; Lifson, A.; Pederson, C.; Price, R.; Prineas, R.; Rhame, F.; Worley, J.; Modlin, J.; Beral, V.; Chaisson, R.; Fleming, T.; Hill, C.; Kim, K.; Murray, B.; Pick, B.; Seligmann, M.; Weller, I.; Cahill, K.; Fox, L.; Luzar, M.; Martinez, A.; McNay, L.; Pierson, J.; Tierney, J.; Vogel, S.; Costas, V.; Eckstrand, J.; Brown, S.; Abusamra, L.; Angel, E.; Aquilia, S.; Benetucci, J.; Bittar, V.; Bogdanowicz, E.; Cahn, P.; Casiro, A.; Contarelli, J.; Corral, J.; Daciuk, L.; David, D.; Dobrzanski, W.; Duran, A.; Ebenrstejin, J.; Ferrari, I.; Fridman, D.; Galache, V.; Guaragna, G.; Ivalo, S.; Krolewiecki, A.; Lanusse, I.; Laplume, H.; Lasala, M.; Lattes, R.; Lazovski, J.; Lopardo, G.; Lourtau, L.; Lupo, S.; Maranzana, A.; Marson, C.; Massera, L.; Moscatello, G.; Olivia, S.; Otegui, I.; Palacios, L.; Parlante, A.; Salomon, H.; Sanchez, M.; Somenzini, C.; Suarez, C.; Tocci, M.; Toibaro, J.; Zala, C.; Agrawal, S.; Ambrose, P.; Anderson, C.; Anderson, J.; Beileiter, K.; Blavius, K.; Boyle, M.; Bradford, D.; Britton, P.; Brown, P.; Busic, T.; Cain, A.; Carrall, L.; Carson, S.; Chenoweth, I.; Clark, F.; Clemons, J.; Clezy, K.; Cortissos, P.; Cunningham, N.; Curry, M.; Daly, L.; D'Arcy-Evans, C.; del Rosario, R.; Dinning, S.; Dobson, P.; Donohue, W.; Doong, N.; Downs, C.; Edwards, E.; Egan, C.; Ferguson, W.; Finlayson, R.; Forsdyke, C.; Foy, L.; Frater, A.; French, M.; Gleeson, D.; Gold, J.; Habel, P.; Haig, K.; Hardy, S.; Holland, R.; Hudson, J.; Hutchison, R.; Hyland, N.; James, R.; Johnston, C.; Kelly, M.; King, M.; Kunkel, K.; Lau, H.; Leamy, J.; Lester, D.; Leung, J.; Lohmeyer, A.; Lowe, K.; MacRae, K.; Magness, C.; Martinez, O.; Maruszak, H.; Medland, N.; Miller, S.; Murray, J.; Negus, P.; Newman, R.; Nowlan, C.; Oddy, J.; Orford, N.; Orth, D.; Patching, J.; Plummer, M.; Price, S.; Primrose, R.; Prone, I.; Ree, H.; Remington, C.; Richardson, R.; Robinson, S.; Rogers, G.; Roney, J.; Russell, D.; Ryan, S.; Sarangapany, J.; Schmidt, T.; Schneider, K.; Shields, C.; Silberberg, C.; Shaw, D.; Smith, D.; Meng Soo, T.; Sowden, D.; Street, A.; Kiem tee, B.; Thomson, J. L.; Topaz, S.; Villella, C.; Walker, A.; Watson, A.; Wendt, N.; Williams, L.; Youds, D.; Aichelburg, A.; Cichon, P.; Gemeinhart, B.; Rieger, A.; Schmied, B.; Touzeau-Romer, V.; DeRoo, A.; O'Doherty, E.; de Salles Amorim, C.; Basso, C.; Flint, S.; Kallas, E.; Levi, G.; Lewi, D.; Pereira, L.; da Silva, M.; Souza, T.; Toscano, A.; Angel, J.; Arsenault, M.; Bast, M.; Beckthold, B.; Bouchard, P.; Chabot, I.; Clarke, R.; Cohen, J.; Coté, P.; Ellis, M.; Gagne, C.; Gill, J.; Houde, M.; Johnston, B.; Jubinville, N.; Kato, C.; Lamoureux, N.; Latendre- Paquette, J.; Lindemulder, A.; McNeil, A.; McFarland, N.; Montaner, J.; Morrisseau, C.; O'Neill, R.; Page, G.; Piche, A.; Pongracz, B.; Preziosi, H.; Puri, L.; Rachlis, A.; Ralph, E.; Raymond, I.; Rouleau, D.; Routy, J. P.; Sandre, R.; Seddon, T.; Shafran, S.; Sikora, C.; Smaill, F.; Stromberg, D.; Trottier, S.; Walmsley, S.; Weiss, K.; Williams, K.; Zarowny, D.; Baadegaard, B.; Bengaard Andersen, Á; Boedker, K.; Collins, P.; Jensen, L.; Moller, H.; Lehm Andersen, P.; Loftheim, I.; Mathiesen, L.; Nielsen, H.; Obel, N.; Petersen, D.; Pors Jensen, L.; Trunk Black, F.; Aboulker, J. P.; Aouba, A.; Bensalem, M.; Berthe, H.; Blanc, C.; Bornarel, D.; Bouchaud, O.; Boue, F.; Bouvet, E.; Brancon, C.; Breaud, S.; Brosseau, D.; Brunet, A.; Capitant, C.; Ceppi, C.; Chakvetadze, C.; Cheneau, C.; Chennebault, J. M.; de Truchis, P.; Delavalle, A. M.; Delfraissy, J. F.; Dumont, C.; Edeb, N.; Fabre, G.; Foltzer, A.; Foubert, V.; Gastaut, J. A.; Gerbe, J.; Girard, P. M.; Goujard, C.; Hoen, B.; Honore, P.; Hue, H.; Hynh, T.; Jung, C.; Kahi, S.; Lang, J. M.; Le Baut, V.; Lefebvre, B.; Leturque, N.; Lévy, Y.; Loison, J.; Maddi, G.; Maignan, A.; Majerholc, C.; de Boever, C.; Meynard, J. L.; Michelet, C.; Michon, C.; Mole, M.; Netzer, E.; Pialoux, G.; Poizot-Martin, I.; Raffi, F.; Ratajczak, M.; Ravaux, I.; Reynes, J.; Salmon-Ceron, D.; Sebire, M.; Simon, A.; Tegna, L.; Tisne-Dessus, D.; Tramoni, C.; Vidal, M.; Viet-Peaucelle, C.; Weiss, L.; Zeng, A.; Zucman, D.; Adam, A.; Arastéh, K.; Behrens, G.; Bergmann, F.; Bittner, D.; Bogner, J.; Brockmeyer, N.; Darrelmann, N.; Deja, M.; Doerler, M.; Esser, S.; Faetkenheuer, G.; Fenske, S.; Gajetzki, S.; Goebel, F.; Gorriahn, D.; Harrer, E.; Harrer, T.; Hartl, H.; Hartmann, M.; Heesch, S.; Jakob, W.; Jäger, H.; Klinker, H.; Kremer, G.; Ludwig, C.; Mantzsch, K.; Mauss, S.; Meurer, A.; Niedermeier, A.; Pittack, N.; Plettenberg, A.; Potthoff, A.; Probst, M.; Rittweger, M.; Ross, B.; Rotty, J.; Rund, E.; Ruzicka, T.; Schmidt, R. T.; Schmutz, G.; Schnaitmann, E.; Schuster, D.; Sehr, T.; Spaeth, B.; Stephan, C.; Stockey, T.; Stoehr, A.; Trein, A.; Vaeth, T.; Vogel, M.; Wasmuth, J.; Wengenroth, C.; Winzer, R.; Wolf, E.; Reidy, D. L.; Cohen, Y.; Drora, G.; Eliezer, I.; Godo, O.; Kedem, E.; Magen, E.; Mamorsky, M.; Sthoeger, Z.; Vered, H.; Aiuti, F.; Bechi, M.; Bergamasco, A.; Bertelli, D.; Bruno, R.; Butini, L.; Cagliuso, M.; Carosi, G.; Casari, S.; Chrysoula, V.; Cologni, G.; Conti, V.; Corpolongo, A.; D'Offizi, G.; Gaiottino, F.; Di Pietro, M.; Filice, G.; Francesco, M.; Gianelli, E.; Graziella, C.; Magenta, L.; Martellotta, F.; Maserati, R.; Murdaca, G.; Nardini, G.; Nozza, S.; Puppo, F.; Pogliaghi, M.; Ripamonti, D.; Ronchetti, C.; Rusconi, V.; Sacchi, P.; Silvia, N.; Suter, F.; Tambussi, G.; Uglietti, A.; Vechi, M.; Vergani, B.; Vichi, F.; Vitiello, P.; Iwamoto, A.; Kikuchi, Y.; Miyazaki, N.; Mori, M.; Nakamura, T.; Odawara, T.; Oka, S.; Shirasaka, T.; Tabata, M.; Takano, M.; Ueta, C.; Watanabe, D.; Yamamoto, Y.; Erradey, I.; Himmich, H.; Marhoum El Filali, K.; Blok, W.; van Boxtel, R.; Brinkman H Doevelaar, K.; Grijsen, M.; Juttmann, J.; Ligthart, S.; van der Meulen, P.; Lange, J.; Schrijnders-Gudde, L.; Septer-Bijleveld, E.; Sprenger, H.; Vermeulen, J.; Kvale, D.; Inglot, M.; Rymer, W.; Szymczak, A.; Aldir, M.; Baptista, C.; da Conceicao Vera, J.; dos Santos, C. Raquel A.; Valadas, E.; Vaz Pinto, I.; Chia, E.; Foo, E.; Karim, F.; Lim, P. L.; Panchalingam, A.; Quek, A.; Alcázar-Caballero, R.; Arribas, J.; Arrizabalaga, J.; de Barron, X.; Blanco, F.; Bouza, E.; Calvo, S.; Carbonero, L.; Carpena, I.; Castro, M.; Cortes, L.; del Toro, M.; Elias, M.; Espinosa, J.; Estrada, V.; Fernandez-Cruz, E.; Fernández, P.; Freud, H.; Garcia, A.; Garcia, G.; Garrido, R.; Gijón, P.; Gonzalez-García, J.; Gil, I.; González, A.; López Grosso, P.; Guzmán, E.; Iribarren, J.; Jiménez, M.; Juega, J.; Lopez, J.; Lozano, F.; Martín-Carbonero, L.; Mata, R.; Menasalvas, A.; Mirelles, C.; de Miguel Prieto, J.; Montes, M.; Moreno, A.; Moreno, J.; Moreno, V.; Muñoz, R.; Ocampo, A.; Ortega, E.; Ortiz, L.; Padilla, B.; Parras, A.; Paster, A.; Pedreira, J.; Peña, J.; Perea, R.; Portas, B.; Pulido, F.; Rebollar, M.; de Rivera, J.; Roca, V.; Rodríguez-Arrondo, F.; Rubio, R.; Santos, J.; Sanz, J.; Sebastian, G.; Segovia, M.; Tamargo, L.; Viciana, P.; von Wichmann, M.; Bratt, G.; Hollander, A.; Olov Pehrson, P.; Petz, I.; Sandstrom, E.; Sönnerborg, A.; Gurtner, V.; Ampunpong, U.; Auchieng, C.; Bowonwatanuwong, C.; Chanchai, P.; Chetchotisakd, P.; Chuenyan, T.; Duncombe, C.; Horsakulthai, M.; Kantipong, P.; Laohajinda, K.; Phanuphak, P.; Pongsurachet, V.; Pradapmook, S.; Ruxruntham, K.; Seekaew, S.; Sonjai, A.; Suwanagool, S.; Techasathit, W.; Ubolyam, S.; Wankoon, J.; Alexander, I.; Dockrell, D.; Easterbrook, P.; Edwards, B.; Evans, E.; Fox, R.; Gazzard, B.; Gilleran, G.; Hand, J.; Heald, L.; Higgs, C.; Jebakumar, S.; Jendrulek, I.; Johnson, S.; Kinghorn, G.; Kuldanek, K.; Maw, R.; McKernan, S.; McLean, L.; Morris, S.; O'Farrell, S.; Ong, E.; Peters, B.; Stroud, C.; Wansbrough-Jones, M.; White, D.; Williams, I.; Wiselka, M.; Yee, T.; Adams, S.; Allegra, D.; Andrews, L.; Aneja, B.; Anstead, G.; Artz, R.; Bailowitz, J.; Banks, S.; Baum, J.; Benator, D.; Black, D.; Boh, D.; Bonam, T.; Brito, M.; Brockelman, J.; Bruzzese, V.; Burnside, A.; Cafaro, V.; Casey, K.; Cason, L.; Childress, G.; Clark, C. L.; Clifford, D.; Climo, M.; Couey, P.; Cuervo, H.; Deeks, S.; Dennis, M.; Diaz-Linares, M.; Dickerson, D.; Diez, M.; Di Puppo, J.; Dodson, P.; Dupre, D.; Elion, R.; Elliott, K.; El-Sadr, W.; Estes, M.; Fabre, J.; Farrough, M.; Flamm, J.; Follansbee, S.; Foster, C.; Frank, C.; Franz, J.; Frechette, G.; Freidland, G.; Frische, J.; Fuentes, L.; Funk, C.; Geisler, C.; Genther, K.; Giles, M.; Goetz, M.; Gonzalez, M.; Graeber, C.; Graziano, F.; Grice, D.; Hahn, B.; Hamilton, C.; Hassler, S.; Henson, A.; Hopper, S.; John, M.; Johnson, L.; Johnson, R.; Jones, R.; Kahn, J.; Klimas, N.; Kolber, M.; Koletar, S.; Labriola, A.; Larsen, R.; Lasseter, F.; Lederman, M.; Ling, T.; Lusch, T.; MacArthur, R.; Machado, C.; Makohon, L.; Mandelke, J.; Mannheimer, S.; Martínez, M.; Martinez, N.; Mass, M.; Masur, H.; McGregor, D.; McIntyre, D.; McKee, J.; McMullen, D.; Mettinger, M.; Middleton, S.; Mieras, J.; Mildvan, D.; Miller, P.; Miller, T.; Mitchell, V.; Mitsuyasu, R.; Moanna, A.; Mogridge, C.; Moran, F.; Murphy, R.; Nahass, R.; Nixon, D.; O'Brien, S.; Ojeda, J.; Okhuysen, P.; Olson, M.; Osterberger, J.; Owen, W.; Pablovich, S.; Patel, S.; Pierone, G.; Poblete, R.; Potter, A.; Preston, E.; Rappoport, C.; Regevik, N.; Reyelt, M.; Riney, L.; Rodriguez-Barradas, M.; Rodriguez, M.; Rodriguez, J.; Roland, R.; Rosmarin-DeStefano, C.; Rossen, W.; Rouff, J.; Saag, M.; Santiago, S.; Sarria, J.; Wirtz, S.; Schmidt, U.; Scott, C.; Sheridan, A.; Shin, A.; Shrader, S.; Simon, G.; Slowinski, D.; Smith, K.; Spotkov, J.; Sprague, C.; States, D.; Suh, C.; Sullivan, J.; Summers, K.; Sweeton, B.; Tan, V.; Tanner, T.; Temesgen, Z.; Thomas, D.; Thompson, M.; Tobin, C.; Toro, N.; Towner, W.; Upton, K.; Uy, J.; Valenti, S.; van der Horst, C.; Vita, J.; Voell, J.; Walker, J.; Walton, T.; Wason, K.; Watson, V.; Wellons, A.; Weise, J.; White, M.; Whitman, T.; Williams, B.; Williams, N.; Windham, J.; Witt, M.; Workowski, K.; Wortmann, G.; Wright, T.; Zelasky, C.; Zwickl, B.; Dietz, D.; Chesson, C.; Schmetter, B.; Grue, L.; Willoughby, M.; Demers, A.; Dragsted, U. B.; Jensen, K. B.; Jansson, P. O.; Jensen, B. G.; Benfield, T. L.; Darbyshire, J. H.; Babiker, A. G.; Palfreeman, A. J.; Fleck, S. L.; Collaco-Moraes, Y.; Wyzydrag, L.; Cooper, D. A.; Drummond, F. M.; Connor, S. A.; Satchell, C. S.; Gunn, S.; Delfino, M. A.; Merlin, K.; McGinley, C.; Neaton, J. D.; George, M.; Grund, B.; Hogan, C.; Miller, C.; Neuhaus, J.; Roediger, M. P.; Thackeray, L.; Campbell, C.; Lahart, C.; Perlman, D.; Rein, M.; DerSimonian, R.; Brody, B. A.; Daar, E. S.; Dubler, N. N.; Fleming, T. R.; Freeman, D. J.; Kahn, J. P.; Kim, K. M.; Medoff, G.; Modlin, J. F.; Moellering, R.; Murray, B. E.; Robb, M. L.; Scharfstein, D. O.; Sugarman, J.; Tsiatis, A.; Tuazon, C.; Zoloth, L.; Klingman, K.; Lehrman, S.; Belloso, W. H.; Losso, M. H.; Benetucci, J. A.; Bogdanowicz, E. P.; Cahn, P. E.; Casiró, A. D.; Cassetti, I.; Contarelli, J. M.; Corral, J. A.; Crinejo, A.; David, D. O.; Ishida, M. T.; Laplume, H. E.; Lasala, M. B.; Lupo, S. H.; Masciottra, F.; Michaan, M.; Ruggieri, L.; Salazar, E.; Sánchez, M.; Hoy, J. F.; Rogers, G. D.; Allworth, A. M.; Anderson, J. S. C.; Armishaw, J.; Barnes, K.; Chiam, A.; Chuah, J. C. P.; Curry, M. C.; Dever, R. L.; Donohue, W. A.; Doong, N. C.; Dwyer, D. E.; Dyer, J.; Eu, B.; Ferguson, V. W.; French, M. A. H.; Garsia, R. J.; Hudson, J. H.; Jeganathan, S.; Konecny, P.; McCormack, C. L.; McMurchie, M.; Moore, R. J.; Moussa, M. B.; Piper, M.; Read, T.; Roney, J. J.; Shaw, D. R.; Silvers, J.; Smith, D. J.; Street, A. C.; Vale, R. J.; Wendt, N. A.; Wood, H.; Youds, D. W.; Zillman, J.; Tozeau, V.; DeWit, S.; de Roo, A.; Leonard, P.; Lynen, L.; Moutschen, M.; Pereira, L. C.; Souza, T. N. L.; Schechter, M.; Zajdenverg, R.; Almeida, M. M. T. B.; Araujo, F.; Bahia, F.; Brites, C.; Caseiro, M. M.; Casseb, J.; Etzel, A.; Falco, G. G.; Filho, E. C. J.; Flint, S. R.; Gonzales, C. R.; Madruga, J. V. R.; Passos, L. N.; Reuter, T.; Sidi, L. C.; Toscano, A. L. C.; Cherban, E.; Conway, B.; Dufour, C.; Foster, A.; Haase, D.; Haldane, H.; Klein, M.; Lessard, B.; Martel, A.; Martel, C.; Paradis, E.; Schlech, W.; Schmidt, S.; Thompson, B.; Vezina, S.; Wolff Reyes, M. J.; Northland, R.; Hergens, L.; Loftheim, I. R.; Raukas, M.; Justinen, J.; Landman, R.; Abel, S.; Abgrall, S.; Amat, K.; Auperin, L.; Barruet, R.; Benalycherif, A.; Benammar, N.; Bentata, M.; Besnier, J. M.; Blanc, M.; Cabié, A.; Chavannet, P.; Dargere, S.; de la Tribonniere, X.; Debord, T.; Decaux, N.; Delgado, J.; Frixon-Marin, V.; Genet, C.; Gérard, L.; Gilquin, J.; Jeantils, V.; Kouadio, H.; Leclercq, P.; Lelièvre, J.-D.; Levy, Y.; Michon, C. P.; Nau, P.; Pacanowski, J.; Piketty, C.; Salmon, D.; Schmit, J. L.; Serini, M. A.; Tassi, S.; Touam, F.; Verdon, R.; Weinbreck, P.; Yazdanpanah, Y.; Yeni, P.; Bitsch, S.; Bogner, J. R.; Goebel, F. D.; Lehmann, C.; Lennemann, T.; Potthof, A.; Wasmuth, J. C.; Wiedemeyer, K.; Hatzakis, A.; Touloumi, G.; Antoniadou, A.; Daikos, G. L.; Dimitrakaki, A.; Gargalianos-Kakolyris, P.; Giannaris, M.; Karafoulidou, A.; Katsambas, A.; Katsarou, O.; Kontos, A. N.; Kordossis, T.; Lazanas, M. K.; Panagopoulos, P.; Paparizos, V.; Papastamopoulos, V.; Petrikkos, G.; Skoutelis, A.; Tsogas, N.; Bergin, C. J.; Mooka, B.; Mamorksy, M. G.; Agmon-Levin, N.; Karplus, R.; Shahar, E.; Biglino, A.; de Gioanni, M.; Montroni, M.; Raise, E.; Honda, M.; Ishisaka, M.; Caplinskas, S.; Uzdaviniene, V.; Schmit, J. C.; Mills, G. D.; Blackmore, T.; Masters, J. A.; Morgan, J.; Pithie, A.; Brunn, J.; Ormasssen, V.; La Rosa, A.; Guerra, O.; Espichan, M.; Gutierrez, L.; Mendo, F.; Salazar, R.; Knytz, B.; Kwiatkowski, J.; Castro, R. S.; Horta, A.; Miranda, A. C.; Pinto, I. V.; Vera, J.; Vinogradova, E.; Yakovlev, A.; Wood, R.; Orrel, C.; Arnaiz, J. A.; Carrillo, R.; Dalmau, D.; Jordano, Q.; Knobel, H.; Larrousse, M.; Moreno, J. S.; Oretaga, E.; Pena, J. N.; Spycher, R.; Bottone, S.; Christen, A.; Franc, C.; Furrer, H. J.; Gayet-Ageron, A.; Genné, D.; Hochstrasser, S.; Moens, C.; Nüesch, R.; Ruxrungtham, K.; Pumpradit, W.; Dangthongdee, S.; Kiertiburanakul, S.; Klinbuayaem, V.; Mootsikapun, P.; Nonenoy, S.; Piyavong, B.; Prasithsirikul, W.; Raksakulkarn, P.; Gazzard, B. G.; Ainsworth, J. G.; Angus, B. J.; Barber, T. J.; Brook, M. G.; Care, C. D.; Chadwick, D. R.; Chikohora, M.; Churchill, D. R.; Cornforth, D.; Dockrell, D. H.; Easterbrook, P. J.; Fox, P. A.; Gomez, P. A.; Gompels, M. M.; Harris, G. M.; Herman, S.; Jackson, A. G. A.; Jebakumar, S. P. R.; Kinghorn, G. R.; Kuldanek, K. A.; Larbalestier, N.; Lumsden, M.; Maher, T.; Mantell, J.; Muromba, L.; Orkin, C. M.; Peters, B. S.; Peto, T. E. A.; Portsmouth, S. D.; Rajamanoharan, S.; Ronan, A.; Schwenk, A.; Slinn, M. A.; Stroud, C. J.; Thomas, R. C.; Wansbrough-Jones, M. H.; Whiles, H. J.; White, D. J.; Williams, E.; Williams, I. G.; Acosta, E. A.; Adamski, A.; Antoniskis, D.; Aragon, D. R.; Barnett, B. J.; Baroni, C.; Barron, M.; Baxter, J. D.; Beers, D.; Beilke, M.; Bemenderfer, D.; Bernard, A.; Besch, C. L.; Bessesen, M. T.; Bethel, J. T.; Blue, S.; Blum, J. D.; Boarden, S.; Bolan, R. K.; Borgman, J. B.; Brar, I.; Braxton, B. K.; Bredeek, U. F.; Brennan, R.; Britt, D. E.; Bulgin-Coleman, D.; Bullock, D. E.; Campbell, B.; Caras, S.; Carroll, J.; Casey, K. K.; Chiang, F.; Cindrich, R. B.; Clark, C.; Cohen, C.; Coley, J.; Condoluci, D. V.; Contreras, R.; Corser, J.; Cozzolino, J.; Daley, L.; Dandridge, D.; D'Antuono, V.; Darcourt Rizo, J. G.; DeHovitz, J. A.; Dejesus, E.; DesJardin, J.; Dietrich, C.; Dolce, E.; Erickson, D.; Faber, L. L.; Falbo, J.; Farrough, M. J.; Farthing, C. F.; Ferrell-Gonzalez, P.; Flynn, H.; Frank, M.; Freeman, K. F.; French, N.; Fujita, N.; Gahagan, L.; Gilson, I.; Goetz, M. B.; Goodwin, E.; Guity, C. K.; Gulick, P.; Gunderson, E. R.; Hale, C. M.; Hannah, K.; Henderson, H.; Hennessey, K.; Henry, W. K.; Higgins, D. T.; Hodder, S. L.; Horowitz, H. W.; Howe-Pittman, M.; Hubbard, J.; Hudson, R.; Hunter, H.; Hutelmyer, C.; Insignares, M. T.; Jackson, L.; Jenny, L.; Johnson, D. L.; Johnson, G.; Johnson, J.; Kaatz, J.; Kaczmarski, J.; Kagan, S.; Kantor, C.; Kempner, T.; Kieckhaus, K.; Kimmel, N.; Klaus, B. M.; Koeppe, J. R.; Koirala, J.; Kopka, J.; Kostman, J. R.; Kozal, M. J.; Kumar, A.; Lampiris, H.; Lamprecht, C.; Lattanzi, K. M.; Lee, J.; Leggett, J.; Long, C.; Loquere, A.; Loveless, K.; Lucasti, C. J.; MacVeigh, M.; Makohon, L. H.; Markowitz, N. P.; Marks, C.; Martorell, C.; McFeaters, E.; McGee, B.; McIntyre, D. M.; McManus, E.; Melecio, L. G.; Melton, D.; Mercado, S.; Merrifield, E.; Mieras, J. A.; Mogyoros, M.; Moran, F. M.; Murphy, K.; Mutic, S.; Nadeem, I.; Nadler, J. P.; Ognjan, A.; O'Hearn, M.; O'Keefe, K.; Okhuysen, P. C.; Oldfield, E.; Olson, D.; Orenstein, R.; Ortiz, R.; Parpart, F.; Pastore-Lange, V.; Paul, S.; Pavlatos, A.; Pearce, D. D.; Pelz, R.; Peterson, S.; Pitrak, D.; Powers, S. L.; Pujet, H. C.; Raaum, J. W.; Ravishankar, J.; Reeder, J.; Reilly, N. A.; Reyelt, C.; Riddell, J.; Rimland, D.; Robinson, M. L.; Rodriguez, A. E.; Rodriguez-Barradas, M. C.; Rodriguez Derouen, V.; Rosmarin, C.; Rossen, W. L.; Rouff, J. R.; Sampson, J. H.; Sands, M.; Savini, C.; Schrader, S.; Schulte, M. M.; Scott, R.; Seedhom, H.; Sension, M.; Sheble-Hall, A.; Shuter, J.; Slater, L. N.; Slotten, R.; Smith, M.; Snap, S.; States, D. M.; Stringer, G.; Summers, K. K.; Swanson, K.; Sweeton, I. B.; Szabo, S.; Tedaldi, E. M.; Telzak, E. E.; Thompson, M. A.; Thompson, S.; Ting Hong Bong, C.; Vaccaro, A.; Vasco, L. M.; Vecino, I.; Verlinghieri, G. K.; Visnegarwala, F.; Wade, B. H.; Weis, S. E.; Weise, J. A.; Weissman, S.; Wilkin, A. M.; Witter, J. H.; Wojtusic, L.; Wright, T. J.; Yeh, V.; Young, B.; Zeana, C.; Zeh, J.; Savio, E.; Vacarezza, M.

    2015-01-01

    Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a

  10. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study

    NARCIS (Netherlands)

    Mocroft, A.; Lundgren, J.D.; Ross, M.; Law, M.; Reiss, P.; Kirk, O.; Smith, C.; Wentworth, D.; Neuhaus, J.; Fux, C.A.; Moranne, O.; Morlat, P.; Johnson, M.A.; Ryom, L.; Burger, D.M.

    2015-01-01

    BACKGROUND: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic

  11. The modulatory effect of Moringa oleifera leaf extract on endogenous antioxidant systems and inflammatory markers in an acetaminophen-induced nephrotoxic mice model

    National Research Council Canada - National Science Library

    Karthivashan, Govindarajan; Kura, Aminu Umar; Arulselvan, Palanisamy; Md Isa, Norhaszalina; Fakurazi, Sharida

    2016-01-01

    ...; numerous scientific reports have focused majorly on APAP hepatotoxicity. Alternatively, not many works approach APAP nephrotoxicity focusing on both its mechanisms of action and therapeutic exploration. Moringa oleifera (MO...

  12. The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight

    Directory of Open Access Journals (Sweden)

    Nguyen Gia Binh

    2015-06-01

    Conclusion: A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.

  13. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with {sup 177}Lu-octreotate

    Energy Technology Data Exchange (ETDEWEB)

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Pape, Ulrich-Frank [Charite, University Medicine Berlin, Campus Virchow Clinic, Department of Hepatology and Gastroenterology, Berlin (Germany); Nagarajah, James [University Hospital, Department of Nuclear Medicine, Essen (Germany)

    2014-03-15

    Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine - allowing only approximate estimates of GFR - the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using {sup 99m}Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with {sup 177}Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by {sup 99m}Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m{sup 2} per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m{sup 2} per year) and 16 patients (22 %) a significant (>10 ml/min/m{sup 2} per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m{sup 2} per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of

  14. Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier

    NARCIS (Netherlands)

    Bellwon, P; Culot, M; Wilmes, A; Schmidt, T.; Zurich, M G; Schultz, L.; Schmal, O; Gramowski-Voss, A; Weiss, D G; Jennings, P; Bal-Price, A; Testai, E; Dekant, W.

    2015-01-01

    There is an increasing need to develop improved systems for predicting the safety of xenobiotics. However, to move beyond hazard identification the available concentration of the test compounds needs to be incorporated. In this study cyclosporine A (CsA) was used as a model compound to assess the

  15. Effects of cyclosporin A and cyclophosphamide on Peyer's patches in rat, exposed in utero and neonatally or during adult age

    NARCIS (Netherlands)

    Kuper, C.F.; Zijverden, M. van; Klaassen, C.; Tegelenbosch-Schouten, M.; Wolterbeek, A.P.M.

    2007-01-01

    The effects of cyclosporin A (CY) and cyclophosphamide (CPS) on Peyer's patches (PP) were studied in Wistar rats, exposed in utero and neonatally or during adult age. In one study, pregnant dams received 5 or 15 mg/kg bw/day CY from gestation day 6 to day 21 of lactation. In two other studies,

  16. Cyclosporine A Drives a Th17‐ and Th2‐Mediated Posttransplant Obliterative Airway Disease

    National Research Council Canada - National Science Library

    Lemaître, P. H; Vokaer, B; Charbo