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

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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.

Reduced bioavailability of cyclosporine A in rats by mung bean seed coat extract

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Xiping Li

2014-09-01

Full Text Available Mung bean seed coat (MBSC is a healthcare product in Asian countries. The aim of this study was to investigate the effect of an MBSC ethanol extract on the bioavailability of cyclosporine A (CsA in rats. Rats were orally dosed with CsA alone or in combination with MBSC ethanol extracts (500 mg/kg, p.o.. The blood levels of CsA were assayed by liquid chromatography with an electrospray ionization source and tandem mass spectrometry (LC-MS/MS. The everted rat intestinal sac technique was used to determine the influence of MBSC on the absorption of CsA. The results reveal that combined CsA intake with MBSC decreased the Cmax, AUC0-t, t1/2z and MRT0-t values of CsA by 24.96%, 47.28%, 34.73% and 23.58%, respectively (P<0.05, and significantly raised the CL/F by 51.97% (P<0.01. The in vitro results demonstrated that significantly less CsA was absorbed (P<0.05. The overall results indicate that after being concomitantly ingested, MBSC reduced the bioavailability of CsA, at least partially, in the absorption phase.

Generalized pustular psoriasis of pregnancy successfully treated with cyclosporine.

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Hazarika, Debeeka

2009-01-01

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.

Cyclosporin safety in a simplified rat brain tumor implantation model

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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.

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

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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.

Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats.

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Caires, A; Fernandes, G S; Leme, A M; Castino, B; Pessoa, E A; Fernandes, S M; Fonseca, C D; Vattimo, M F; Schor, N; Borges, F T

2017-12-11

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

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A. Caires

2017-12-01

Full Text Available Cyclosporin-A (CsA is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1 receptor blockade with bosentan (BOS and macitentan (MAC antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg or MAC (25 mg/kg by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP, RBF and renal vascular resistance (RVR, and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Site-specific immunosuppression using a new formulation of topical cyclosporine A with polyethylene glycol-8 glyceryl caprylate/caprate.

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Tran, H S; Malli, D; Chrzanowski, F A; Puc, M M; Matthews, M S; Hewitt, C W

1999-05-15

Dermal application of immunosuppressants can be an effective means of achieving site-specific immunosuppression (SITE) on skin allografts in burn wound management and in the treatment of various immune skin disorders. We have previously reported success with topical cyclosporine A (tCsA) in the treatment of skin allograft rejection in rats. Using a new tCsA formulation with a penetration enhancer (PE), polyethylene glycol-8 (PEG-8) glyceryl caprylate/caprate (Labrasol, Gattefossé, St. Priest, France), in a trinary drug delivery system, we hypothesized that we would induce SITE and significantly delay rejection of dual skin allografts in rats. Dual rat skin allografts from Lewis x Brown-Norway (LBN) donors were grafted to Lewis (Lew) recipients. Experimental animals (EXP, n = 7) received a 10-day course of systemic cyclosporine (sCsA, 8 mg/kg/day) followed by topical application. One of the two allografts on each experimental animal received tCsA/PE application (5 mg/kg/day) until sacrifice (tCsA/PE-treated). The other allograft received vehicle only (vehicle-treated). Allogeneic controls (ALLO-CON, n = 9) received no sCsA or tCsA. First signs of rejection were determined based on the initial observation of erythema, hair loss, flakiness, and/or scabs. The mean time to rejection for ALLO-CON allografts was 6.3 +/- 0.7 days (t test, P = 0.0013); for vehicle-treated allografts, 12.3 +/- 3.8 days (paired t test, P = 0.0146); and for tCsA/PE-treated allografts, 25.6 +/- 5.4 days. The disparity of days to rejection between dual allografts in the ALLO-CON group was 0.0 +/- 0.0 day and that between the tCsA/PE- and vehicle-treated dual allografts was 13.3 +/- 3.9 days (t test, P = 0.0016). A new formulation of tCsA in a trinary drug delivery system is successful at delaying the onset of rejection in dual skin allografts in rats by SITE, and PEG-8 glyceryl caprylate/caprate may represent a potentially effective transdermal penetration enhancer. Copyright 1999 Academic

TREATMENT OF STEROID DEPENDENT ASTHMATICS WITH LOW DOSES OF CYCLOSPORINE

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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.

Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

International Nuclear Information System (INIS)

Lacan, Goran; Way, Baldwin M.; Plenevaux, Alain; Defraiteur, Caroline; Lemaire, Christian; Aerts, Joel; Luxen, Andre; Rubins, Daniel J.; Cherry, Simon R.; Melega, William P.

2008-01-01

Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-[ 18 F] fluorobenzamido] ethylpiper azine ([ 18 F]MPPF) for binding to hydroxytryptamine 1A (5-HT 1A ) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Each Sprague-Dawley rat (n=4) received a baseline [ 18 F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. MicroPET studies showed that hippocampus uptake of [ 18 F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [ 18 F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [ 18 F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [ 18 F]MPPF binding to 5-HT 1A receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT 1A receptor density when based on tracer uptake sensitive to P-gp modulation. (orig.)

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

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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.

Effect of cyclosporin A administration on the biodistribution and multipinhole {mu}SPECT imaging of [{sup 123}I]R91150 in rodent brain

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Blanckaert, P.; Burvenich, I.; Bruyne, S. de; Moerman, L.; Wyffels, L.; Vos, F. de [Faculty of Pharmaceutical Sciences, Ghent University, Laboratory for Radiopharmacy, Gent (Belgium); Staelens, S. [Ghent University - IBBT, MEDISIP, Faculty of Engineering, Gent (Belgium)

2009-03-15

P-glycoprotein (Pgp) is an efflux protein found amongst other locations in the blood-brain barrier. It is important to investigate the effect of Pgp modulation on clinically used brain tracers, because brain uptake of the tracer can be altered by blocking of the Pgp efflux transporter. The function of Pgp can be blocked with cyclosporin A. We investigated the effect of cyclosporin A administration on the biodistribution of [{sup 123}I]R91150 in rodents, and the effect of Pgp blocking on the quality of multipinhole {mu}SPECT imaging with [{sup 123}I]R91150. The influence of increasing doses of cyclosporin A on the brain uptake of [{sup 123}I]R91150 was investigated in NMRI mice. A biodistribution study with [{sup 123}I]R91150 was performed in male Sprague-Dawley rats pretreated with cyclosporin A and not pretreated. Brain uptake of [{sup 123}I]R91150 after cyclosporin A injection was compared to the brain uptake in untreated animals, and a displacement study with ketanserin was performed in both groups. A multipinhole {mu}SPECT brain imaging study was also performed using a Milabs U-SPECT-II camera in male Sprague-Dawley rats. To exclude the effect of possible metabolites, a metabolite study was also performed. At the highest cyclosporin A dose (50 mg/kg), a sevenfold increase in brain radioactivity concentration was observed in NMRI mice. Also, a dose-response relationship was established between the dose of cyclosporin A and the brain uptake of [{sup 123}I]R91150 in mice. Compared to the control group, a five-fold increase in [{sup 123}I]R91150 radioactivity concentration was observed in the brain of Sprague-Dawley rats after cyclosporin A treatment (50 mg/kg). Radioactivity concentration in the frontal cortex increased from 0.24{+-}0.0092 to 1.58{+-}0.097% injected dose per gram of tissue after treatment with cyclosporin A (at the 1-h time-point). Blood radioactivity concentrations did not increase to the same extent. The cortical activity was displaced by

Protective effects of vitamin E on cyclosporineA-induced toxicity in rat testis

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Hamidreza Sameni

2011-07-01

Full Text Available Introduction: Cyclosporine A (CsA as an immunosuppressive drug which widely used in organ transplantation and autoimmune diseases. This drug is caused many injuries and cell cytotoxic of the body organs such as reproductive organs. The aim of this study was to investigate the possible protective effects of vitamin E (Vit E against CsA-induced damages in rat testis. Material and Methods: 40 adult male wistar rats were divided into 5 groups: control (without any intervention, placebo (received only pure olive oil, test 1 (CsA+olive oil, 30 mg/kg, test 2 (Vit E, 100 mg/kg and test 3 (CsA+Vit E, with the same dose. All animal received drugs for three weeks daily by oral gavages. Following, the testis were fixed and sections stained with Haematoxylin & Eosin and Trichrome Masson. Then with using a microscope equipped with a scaled ocular micrometer and image analysis software were histomorphometry. Results: This study showed that CsA caused severe degenerative changes in testicular tissue include decreased seminiferous tubules diameter, seminiferous epithelium thickness. Also, the number of spermatogonia, primary spermatocyte, spermatozoa, and sertoli and leydig cells significantly decreased throughout the experiment. These changes are lead to turbulence and atrophy seminiferous epithelium and delay in spermatogenesis. Treatment with vitamin E minimized the adverse effects of CsA on testis structure and spermatogenesis. Conclusion: These results suggest that vitamin E has a protective effect against CsA-induced testicular toxicity in male rat.

Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants

NARCIS (Netherlands)

van der Heide, J. J.; Bilo, H. J.; Donker, J. M.; Wilmink, J. M.; Tegzess, A. M.

1993-01-01

Dietary fish oil exerts effects on renal hemodynamics and the immune response that may benefit renal-transplant recipients treated with cyclosporine. To evaluate this possibility, we studied the effect of fish oil on renal function, blood pressure, and the incidence of acute rejection episodes in

Actinic prurigo in Scandinavian adolescent successfully treated with cyclosporine A

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Jan C. Sitek

2017-06-01

Full Text Available Actinic prurigo is a pruritic sun-induced dermatosis classified among the immunologically mediated photodermatoses. The disease is a well-known entity among Native Americans and in Central and South America, however rare in Caucasians with only a few reports from Australia, Britain and France. We report the first case of actinic prurigo in a Scandinavian patient, responding favorably to systemic treatment with cyclosporine A.

Actinic Prurigo in Scandinavian Adolescent Successfully Treated with Cyclosporine A.

Science.gov (United States)

Sitek, Jan C

2017-03-13

Actinic prurigo is a pruritic sun-induced dermatosis classified among the immunologically mediated photodermatoses. The disease is a well-known entity among Native Americans and in Central and South America, however rare in Caucasians with only a few reports from Australia, Britain and France. We report the first case of actinic prurigo in a Scandinavian patient, responding favorably to systemic treatment with cyclosporine A.

Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion.

Science.gov (United States)

Turner, K; Pflugfelder, S C; Ji, Z; Feuer, W J; Stern, M; Reis, B L

2000-07-01

To evaluate interleukin-6 (IL-6) levels in the conjunctival epithelium of patients with moderate to severe dry eye disease before and after treatment with cyclosporin A ophthalmic emulsion (CsA) or its vehicle. Conjunctival cytology specimens were obtained from a subset of patients enrolled in a 6-month randomized, double-masked clinical trial of the efficacy and safety of topical CsA at baseline and after 3 and 6 months of B.I.D. treatment with 0.05% cyclosporine emulsion (n = 13), 0.1% cyclosporine emulsion (n = 8), or vehicle (n = 10). RNA was extracted and a competitive reverse transcriptase polymerase chain reaction (RT-PCR) was used to evaluate the levels of mRNA encoding the inflammatory cytokine IL-6 and a housekeeping gene, G3PDH. Levels of IL-6 and G3PDH were measured and compared. There was no change from baseline in the level of G3PDH after 3 or 6 months in any group. IL-6 normalized for G3PDH (IL-6/G3PDH ratio) was not different from baseline at 3 months but showed a significant decrease from baseline in the group treated with 0.05% CsA (p = 0.048) at 6 months. No significant between-group differences were noted and no correlation was observed between the change in IL-6/G3PDH and corneal fluorescein staining. This preliminary, small-cohort study showed a decrease in IL-6 in the conjunctival epithelium of moderate to severe dry eye patients treated with 0.05% CsA for 6 months. The observed decrease suggests that dry eye disease involves immune-mediated inflammatory processes that may be decreased by treatment with topical ophthalmic cyclosporine.

Cyclosporin A promotes mineralization by human cementoblastoma-derived cells in culture.

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Arzate, Higinio; Alvarez, Marco A; Narayanan, A Sampath

2005-06-01

The immunosuppressive drug cyclosporin A has been shown to induce cementum deposition in vivo in experimental animals. Using cementoblastoma-derived cells, we have studied whether this drug will be useful to study cementum mineralization and differentiation in vitro. Human cementoblastoma cells and gingival fibroblasts (controls) were cultured and treated with 0.5, 1.0 and 5.0 microg/ml of cyclosporin A. Cell proliferation was evaluated by MTT (tetrazolium) assay and cell number, and cell viability was assessed by trypan blue dye exclusion. Induction of mineralization was evaluated by alizarin red S staining to detect mineralized nodules and by reverse transcription-polymerase chain reaction (RT-PCR) to assess the expression of bone differentiation markers alkaline phosphatase, osteocalcin, bone sialoprotein and core-binding factor a1 (Cbfa1). Cyclosporin A at 5.0 microg/ml concentration reduced significantly the increase in the number of cementoblastoma cells. A dose-dependent increase in the number of mineralized nodules occurred in cultures of cementoblastoma-derived cells treated with cyclosporin A, and RT-PCR analyses showed significantly higher levels of expression of alkaline phosphatase, bone sialoprotein, type I collagen, matrix metalloproteinase-1, osteocalcin, osteopontin, and Cbfa1. Human gingival fibroblast proliferation and cell number were not affected. Mineralized nodules were not detected in gingival fibroblasts and bone specific proteins were not expressed. Presence of cyclosporin A during 14-day culture period appears to suppress the proliferation of cementoblastoma cells and induce the formation mineralized-like tissue by these cells.

Cyclosporine therapy in inflammatory bowel disease: short-term and long-term results.

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Gurudu, S R; Griffel, L H; Gialanella, R J; Das, K M

1999-09-01

Intravenous cyclosporine therapy followed by oral cyclosporine therapy reduce the need for urgent surgery in steroid-refractory inflammatory bowel disease (IBD). Our objective is to report short- and long-term results of cyclosporine therapy in IBD patients. Thirteen patients with steroid-refractory IBD, seven patients with ulcerative colitis (UC), and six patients with Crohn's disease (CD) were treated with intravenous cyclosporine (4 mg/kg/day) for a mean period of 11.4+/-2.8 days (range, 4-15 days). Subsequently the patients were started on oral cyclosporine (8 mg/kg/day) and followed for a mean of 10.3+/-10 months (range, 1-30 months). Twelve patients responded to intravenous cyclosporine therapy. One patient with UC developed sepsis on the fourth day of intravenous cyclosporine therapy and needed urgent colectomy. Nine of 12 initial responders (6 patients with UC and 3 patients with CD) relapsed during follow-up despite oral cyclosporine and underwent elective surgery. One patient with CD relapsed 3 months after discontinuation of oral cyclosporine. Only two patients with CD are in long-term remission. There were no long-term side effects in any of the 13 treated patients. In conclusion, intravenous cyclosporine was effective in inducing remission or significant improvement in 12 of 13 patients with steroid-refractory IBD. However, with subsequent oral cyclosporine the remission could be maintained only for a short while. Each of the six patients with UC needed colectomy and three of the five patients with CD had intestinal resection within 12 months despite oral cyclosporine therapy.

Topical cyclosporine a treatment in corneal refractive surgery and patients with dry eye.

Science.gov (United States)

Torricelli, Andre A M; Santhiago, Marcony R; Wilson, Steven E

2014-08-01

To evaluate preoperative and postoperative dry eye and the effect of cyclosporine A treatment in patients screened for corneal refractive surgery and treated with photorefractive keratectomy (PRK) or LASIK. A consecutive case series of 1,056 patients screened for corneal refractive surgery from 2007 to 2012 was retrospectively analyzed. The level of preoperative and postoperative dry eye and the responsiveness to topical cyclosporine A treatment were assessed. One eye of each patient was randomly selected. A total of 642 eyes progressed to surgery: 524 (81.6%) and 118 (18.4%) underwent LASIK and PRK, respectively. Of 81 (7.7%) diagnosed as having dry eye, 55 were deemed potential candidates and optimized for refractive surgery. Thirty-seven patients with moderate dry eye were treated with topical cyclosporine A prior to surgery (mean duration: 3.2 ± 2.1 months; range: 1 to 12 months). After cyclosporine A treatment, 28 (75.7%) eyes underwent LASIK, 4 (10.8%) eyes underwent PRK, and 5 (13.5%) eyes were not operated on due to failed treatment of dry eye. Postoperative refractive surgery-induced neurotrophic epitheliopathy (LINE in LASIK) was noted in 132 (27.3%) and 12 (11.1%) eyes that underwent LASIK and PRK, respectively. Topical cyclosporine A was prescribed in 79 LASIK-induced and 3 PRK-induced dry eyes. After 12 months or more of cyclosporine A treatment, 5 (6.1%) eyes continued to have dry eye symptoms or signs. Topical cyclosporine A treatment is effective therapy for optimizing patients for refractive surgery and treatment of new onset or worsened dry eye after surgery. Copyright 2014, SLACK Incorporated.

Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy.

Science.gov (United States)

Branche, Julien; Cortot, Antoine; Bourreille, Arnaud; Coffin, Benoît; de Vos, Martine; de Saussure, Philippe; Seksik, Philippe; Marteau, Philippe; Lemann, Marc; Colombel, Jean-Frédéric

2009-07-01

Cyclosporine is considered a safe and effective treatment of severe steroid-refractory ulcerative colitis (UC). However, few data are available concerning its safety profile in pregnant women. We report here the experience of 5 GETAID centers. In a retrospective study data on patients with severe UC treated with cyclosporine during pregnancy were extracted from medical records of consecutive patients treated between 2001 and 2007. Eight patients (median age 30.5 years old) were identified. At the time of flare-up the median duration of pregnancy was 11.5 weeks of gestation (range 4-25). Seven patients had pancolitis. All patients had more than 3 commonly used clinical and biological severity criteria. Three patients had severe endoscopic lesions and 5 patients had not. All patients received intravenous corticosteroids for at least 7 days before introduction of cyclosporine. Two patients received azathioprine during treatment with cyclosporine. No severe infections or other complications due to treatment were observed. Treatment was effective in 7/8 patients. One patient received infliximab due to cyclosporine therapy failure with a good outcome. No colectomy was performed during pregnancy. Seven pregnancies were conducted to term, but 1 in utero death occurred due to maternal absence of S-protein. Two newborns were premature, including 1 case of hypotrophy. No malformations were observed. In our experience, treatment with cyclosporine for steroid-refractory UC during pregnancy can be considered safe and effective.

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...

Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats

OpenAIRE

Chung-Ping Yu; Ching-Ya Huang; Shiuan-Pey Lin; Yu-Chi Hou

2018-01-01

Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P-gp) and CYP3A4 in order to investigate the in vivo modulation effect of CR on P-gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repe...

Preclinical evaluation of nephroprotective potential of a probiotic formulation LOBUN on Cyclosporine-A induced renal dysfunction in Wistar rats

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Kambham Venkateswarlu

2017-06-01

Full Text Available ABSTRACT The aim of present study was to evaluate the nephroprotective effect of probiotic formulation LOBUN on Cyclosporine A (CsA induced renal dysfunction in Wistar rats. CsA (20 mg/kg body weight s.c was administered for 15 days to cause renal dysfunction in Wistar rats. The probiotic formulation LOBUN was administered with the dose of 500 mg/kg body weight (p.o for twice (TGI and thrice a day (TGII. The samples were analyzed for the parameters like blood urine nitrogen (BUN, serum creatinine, serum uric acid, total serum protein and urine proteins, urine potassium, urine sodium. The renal functional and histopathological studies revealed that the oral administration of probiotic formulation LOBUN has provided appreciable renoprotection and possibly alleviated the symptoms of Chronic Kidney Disease (CKD at the dose of 500 mg/kg body weight administered thrice a day and also the results were supported by histopathological findings.

High-performance liquid chromatographic analysis of cyclosporin A in rat blood and liver using a commercially available internal standard.

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Chimalakonda, Anjaneya P; Shah, Rakhi B; Mehvar, Reza

2002-05-25

All the available HPLC assays of cyclosporin A (CyA) use internal standards that are not commercially available. Our purpose was to develop an HPLC assay for measurements of CyA in rat blood and liver using a commercially available internal standard (I.S.). After the addition of tamoxifen (I.S.), blood (0.25 ml) or the liver homogenate (1 ml) samples were extracted into a mixture of ether:methanol (95:5). The residue after evaporation of the organic layer was dissolved in 200 microl of an injection solution and washed with 1 ml of hexane before analysis. The separation was achieved using an LC-1 column (70 degrees C) with a mobile phase of methanol-acetonitrile-0.01 M KH(2)PO(4) (50:25:25, v/v) and a flow-rate of 1 ml/min. Detection was at 205 nm. Cyclosporin A and I.S. eluted at 5 and 7 min, respectively, free from endogenous peaks. Linear relationships (r>0.98) were observed between the CyA:I.S. peak area ratios and the CyA concentrations within the range of 0.2-10 microg/ml for blood and 0.1-4 microg/ml for the liver homogenates. The intra- and inter-run C.V.s and errors for both the blood and liver samples were <15%. The extraction efficiency (n=5) was close to 100% for both CyA and I.S. in both blood and liver homogenates. The lower limit of quantitation of the assay was 0.2 or 0.1 microg/ml based on 250 microl of blood or 1 ml of liver homogenate, respectively. The assay was capable of measuring blood and liver concentrations of CyA in a rat injected intravenously with a single 5-mg/kg dose of the drug.

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

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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

The study of teratogenic effect of Cyclosporine in vitro

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Ostad SN

2001-07-01

Full Text Available The use of immunosuppressive medication such as Azathioprine, methoterxate and mercaptopurine in treatment of rheumatic disease in women at childbearing age has some risks of teratogeniesis. Cyclosporine is one of the newer medicines, which has been introduced for this disease but little is known about its teratogenicity. This study was designed to investigate the possible teratogenicity of this drug by using cultured rat limb bud cells, which were obtained from rat embryos 13 days after conception. Cells were incubated in trypsin-EDTA solution for 30 min at 37°C and then filtered through 50 µm nylon filters. The resultant cell suspension was cultivated in 1 ml Dulbecco modified Eagle medium (DMEM containing 10% fetal bovine serum and 445 µg/L L-glutamine at 37°C with 5% CO2. After 8 days of culture the differentiated foci extract were measured by staining with 1% alcian blue. To assess the teratogenic effects of cyclosporine, it was placed in the culture well together with the cells. Results showed that the decrease in the expression of the extracellular matrix at dose of 0.01 molar of cyclosporine is due to limb bud cell toxicity rather than inhibition of cell differentiation.

Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus.

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Campistol, Josep M; Holt, David W; Epstein, Solomon; Gioud-Paquet, Martine; Rutault, Karine; Burke, James T

2005-09-01

Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.

Cyclosporine: a novel therapeutic approach for Burning Mouth Syndrome.

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Saraceno, Rosita; Lorè, Bruno; Pavlidis, Athanasios; Karaiskou, Maria; Arcuri, Claudio; Chimenti, Sergio; Magnato, Roberto

2016-10-01

The aim of this paper was to evaluate the efficacy and safety of topical cyclosporine applied as mouthwash in the treatment of burning mouth syndrome (BMS). This was a prospective and pilot study conducted by the Department of Dermatology of the University of Rome Tor Vergata. Patients were treated with cyclosporine topically applied as mouthwash for 4 weeks. Clinical improvement was assessed using a 5 grade clinical evaluation scale and a visual analogue scale from 0 to 10 was also used to evaluate the burning symptoms. Fifteen patients between 22-85 years (61.1±19.3), 11 female and 4 male, with a mean duration of BMS of 12.5 months, completed the study. Five out of 15 patients presented a marked improvement, 6 patients showed a moderate response, 3 patients had a slight improvement and 1 patient did not show any change. The VAS showed a reduction from 8.7 to 3.5. Adverse events were not reported. Cyclosporine mouthwash appeared to be safe and beneficial for reducing the burning sensation in patients with BMS representing an alternative therapy in this condition.

Cyclosporine treatment of severe Hidradenitis suppurativa

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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...

Cyclosporin A levels in suction-blister fluid of patients with psoriasis treated systemically

NARCIS (Netherlands)

Meinardi, M. M.; van Eendenburg, J. P.; Oosting, J.; van Boxtel, C. J.; de Rie, M. A.; Bos, J. D.

1990-01-01

Oral cyclosporin A (CyA) is highly effective in the treatment of psoriasis. The long-term use is limited by dose-dependent side-effects, and the local concentration of CyA is a determining factor in treatment. The concentration of CyA in suction-blister fluid (SBF) and in whole blood was assessed

Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient

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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.

Diffusion MR findings in cyclosporin-A induced encephalopathy

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Aydin, Kubilay; Minareci, Ozenc; Donmez, Fuldem; Tuzun, Umit; Atamer, Tanju

2004-01-01

Cyclosporin encephalopathy is a well-known entity, which is clinically characterized by altered mental status, vision problems, focal neurological deficits and seizures. The exact pathophysiology of the cyclosporin encephalopathy has not yet been defined. We report the diffusion-weighted MR imaging and proton MR spectroscopy findings in a case of cyclosporin encephalopathy. The white-matter lesions with reversible restricted diffusion supported the hypothesis of reversible vasospasm induced by the cyclosporin. (orig.)

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

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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

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 ...

Production enhancement of Cyclosporin 'A' by Aspergillus terreus ...

African Journals Online (AJOL)

Yomi

2012-01-24

Jan 24, 2012 ... After fermentation, biomass measurement, Cyclosporin 'A' extraction and analysis was carried out as previously mentioned. Estimation of Cyclosporin 'A'. The following equation was used for the estimation of cyclosporin through chromatograms (Minutza et al., 2009). Area of Sample Peak. Weight of Ref ...

Treatment with cyclosporine A in serpiginous choroiditis: A case report

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Kovačević Dragana

2012-03-01

Full Text Available Serpiginous choroiditis is a rare clinical entity. The clinical course of serpiginous choroiditis is very variable, there is no universal marker of treatment success, and even among experts there is debate about what is the most appropriate treatment. The aim of this paper is to describe a case of serpiginous choroiditis treated with Cyclosporine A at a tertiary uveitis referral centre.

Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

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José Sereno

2014-01-01

Full Text Available Protocols of conversion from cyclosporin A (CsA to sirolimus (SRL have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n=6 were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks. Classical and emergent serum, urinary, and kidney tissue (gene and protein expression markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κβ, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions, while NGAL (serum versus urine seems to be a feasible biomarker of CsA replacement to SRL.

Relation of magnesium level to cyclosporine and metabolic complications in renal transplant recipients

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Ahmadi Farrokhlagha

2009-01-01

Full Text Available Cyclosporine is the main immunosuppressive drug used for renal transplant reci-pients in order to prevent transplant rejection. Although the drug has increased the survival of patients and grafted organ, it has some side effects independent of its effect on the immune system. This study was done to evaluate the effect of cyclosporine on serum Mg level and its metabolic side effects in renal allograft patients. 157 (62 female and 95 male renal transplant recipients treated with cyclosporine to prevent transplant rejection were included in the study. Clinical and biochemical data along with cyclosporine levels was documented. Mean serum Mg level was 196 ± 0.31 mg/dL and mean serum cyclosporine level was 371 ± 192 µg/dL. Hypomagnesemia was detected in 16 (10.2% with a negative significant correlation with cyclosporine levels, serum creatinine, plasma LDL, fasting Blood sugar and uric acid. In conclusion according to the results of this study there is a significant correlation between cyclosporine and hypomagnesemia. Therefore, routine measurement of serum Mg and its treatment seems necessary to prevent its complications.

Cyclosporine Neoral: A Local Experience

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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

Cyclosporin A preferentially attenuates skeletal slow-twitch muscle regeneration

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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.

Lipid profile in post renal transplant patients treated with cyclosporine in Sudan

International Nuclear Information System (INIS)

Suleiman, Bahga; Eltahir, Khalid; Eltahir, Ahmed; ElImam, Mohamed; Elsabigh, Mohamed; Miskeen, Elhadi

2009-01-01

Lipid profile abnormality places kidney graft recipients at an increase risk for cardiovascular diseases.This study was undertaken to determine the impact of cyclosporine A (CsA) on lipid profile of transplant patients in Gezira Hospital for Renal Diseases, Medani, Sudan. We studied 78 renal transplant patients with mean age of 42.1 years and mean transplant duration of 3.8 years. Cyclosporine A (CsA), total cholesterol (Tch), triglyceride (TG), HDL cholesterol (HDLch), LDL cholesterol (LDLch), and VLDL cholesterol (VLDLch) were estimated. 62.8% of the patients showed significant lipoprotein abnormalities. Renal allograft recipients showed significantly high levels of TG (p< 0.002), Tch (p< 0.00), LDLch (p< 0.01), and VLDLch (p< 0.05) compared with age and sex matched normal subjects. Increased CsA was reported in females and hypertensive patients. A significant negative correlation was noted between post transplant duration and VLDLch. The study confirms the existence of dyslipidemia in renal transplant patients in our patients. (author)

Lipid profile in post renal transplant patients treated with cyclosporine in Sudan

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Suleiman, Bahga; Eltahir, Khalid; Eltahir, Ahmed [Dept. of Biochemistry, Faculty of Applied Medical Sciences, Univ. of Gezira (Sudan); ElImam, Mohamed [Faculty of Medicine, Univ. of Gezira (Sudan); Elsabigh, Mohamed [Gezira Hospital for Renal Diseases, Univ. of Gezira (Sudan); Miskeen, Elhadi [Educational Development and Research Centre, Univ. of Gezira (Sudan)

2009-07-01

Lipid profile abnormality places kidney graft recipients at an increase risk for cardiovascular diseases.This study was undertaken to determine the impact of cyclosporine A (CsA) on lipid profile of transplant patients in Gezira Hospital for Renal Diseases, Medani, Sudan. We studied 78 renal transplant patients with mean age of 42.1 years and mean transplant duration of 3.8 years. Cyclosporine A (CsA), total cholesterol (Tch), triglyceride (TG), HDL cholesterol (HDLch), LDL cholesterol (LDLch), and VLDL cholesterol (VLDLch) were estimated. 62.8% of the patients showed significant lipoprotein abnormalities. Renal allograft recipients showed significantly high levels of TG (p< 0.002), Tch (p< 0.00), LDLch (p< 0.01), and VLDLch (p< 0.05) compared with age and sex matched normal subjects. Increased CsA was reported in females and hypertensive patients. A significant negative correlation was noted between post transplant duration and VLDLch. The study confirms the existence of dyslipidemia in renal transplant patients in our patients. (author)

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...... at days 1 and 180 were the same for both drugs. Furthermore, we found that patients treated with tacrolimus or cyclosporin displayed different calcineurin activity profiles. We found that cyclosporin displayed greater calcineurin inhibition than tacrolimus. We have demonstrated that the two drugs exert...

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.

Comparison of Semen Analysis Parametes Changes after Priscription of Two Immunosuppresive Drugs, Tacrolimus and Cyclosporine in Men Undergoing Renal Transplantation

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Ali Ramouz

2017-02-01

Full Text Available Background & Objective: The research objective was to investigate the prevalence of infertility in renal transplant patients receiving immunosuppressive agents and compare the impact of tacrolimus (target of Rapamycin inhibitors (TOR-I and Cyclosporine on spermogram parameters after the transplantation. Material & Methods: In this prospective study, from March 2013 to March 2014, all male patient who underwent renal transplantation and were treated with Tacrolimus or Cyclosporine, were included. Patients’ spermogram was analyzed in terms of sperm count and motility. Results: Average sperm count in patients receiving cyclosporine and tacrolimus before the transplantation was 1.73 × 106 and 2.08 × 106 and after the transplantation was 1.2 × 106 and 1.22 × 106, respectively (P=0.008(P=0.002. Average percentage of the motile sperms of patients treated with Cyclosporine, before the transplantation and start of immunosuppressive course was 45.10%, which decreased to 40.50% at the end of the course. The analysis indicated a significant reduction in sperm motility (P=0.001. Average percentage of the motile sperms of patients receiving Tacrolimus, before the transplantation and start of treatment was 46% that decreased to 38% after the transplantation. This finding presents the significantly reduced sperm motility (P=0.002. Finally, the effective sperm motility in patients treated with Cyclosporine was significantly higher than patients treated with Tacrolimus. Conclusion: Tacrolimus reduces sperms’ motility in renal transplant patients significantly higher than Cyclosporine.

Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats

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Chung-Ping Yu

2018-04-01

Full Text Available Coptidis Rhizoma (CR, the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP, an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P-gp and CYP3A4 in order to investigate the in vivo modulation effect of CR on P-gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repeated dosing of CR in a parallel design. Blood samples were collected at specific time points and the blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. The results showed that a single dose (1.0 g/kg and the 7th dose (1.0 g/kg of CR significantly decreased the Cmax of CSP by 56.9% and 70.4%, and reduced the AUC0-540 by 56.4% and 68.7%, respectively. Cell study indicated that CR decoction, berberine, coptisine, palmatine all activated the efflux transport of P-gp. Ex-vivo study showed that the serum metabolites of CR activated CYP 3A4. In conclusion, through using CSP as an in vivo probe substrate, we have verified that oral intake of CR activated the functions of P-gp and CYP3A based on in vivo and in vitro studies. Keywords: Cyclosporine, P-glycoprotein, Cytochrome P450 3A, Herb–drug interactions, Pharmacokinetics

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

International Nuclear Information System (INIS)

El-Mas, Mahmoud M.; Helmy, Maged W.; Ali, Rabab M.; El-Gowelli, Hanan M.

2015-01-01

The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ET A /ET B ) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20 mg kg −1 day −1 , 10 days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renal perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ET A (increases) and ET B (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5 mg kg −1 day −1 ), celecoxib (10 mg kg −1 day −1 ) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ET A /ET B receptor expressions. Selective blockade of ET A receptors by atrasentan (5 mg kg −1 day −1 ) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ET B receptor blocker, 0.1 mg kg −1 day −1 ) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ET A downregulation and ET B upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen. - Highlights: • Chronic CSA causes hypertension and renal perivascular fibrosis in rats. • CSA increased and decreased renal ET A and ET B receptor expression, respectively. • CSA

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

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B.J. Pereira

2010-08-01

Full Text Available Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 ηg/mL; CsA (100 µg/mL; sirolimus (50 and 250 ηg/mL + CsA (100 µg/mL; control; vehicle (20% ethanol. For in vivo studies, 3-week-old Wistar rats (150-250 g were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I in five groups: sham, I, I + SRL (3 mg·kg-1·day-1, po, I + CsA (3 mg·kg-1·day-1, sc, I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 ± 0.1 mL/min but not in rats receiving sirolimus + CsA (0.8 ± 0.1 mL/min despite the reduction in renal blood flow (3.9 ± 0.5 mL/min. Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients

International Nuclear Information System (INIS)

McDiarmid, S.V.; Ettenger, R.B.; Hawkins, R.A.; Senguttvan, P.; Busuttil, R.W.; Vargas, J.; Berquist, W.E.; Ament, M.E.

1990-01-01

We performed indium-111-DTPA plasma clearance studies in 61 pediatric kidney and liver recipients treated with cyclosporine to compare true glomerular filtration rate with calculated GFR (cGFR). The mean true GFR of 61.9 +/- 36.6 ml/min/1.73 m2 indicated renal impairment. The mean cGFR of 85.2 +/- 22.4 ml/min/1.73 m2 was significantly higher (P less than 0.001), and overestimated GFR by 38%. cGFR alone did not accurately reflect the degree of renal dysfunction. A group of 48 pediatric orthotopic liver transplant recipients was studied in more detail: 73% of these patients had a true GFR less than 70 ml/min/1.73 m2, while 85% had a true GFR below 90 ml/min/1.73 m2, the lower limit for normal GFR in children. The mean true GFR for patients treated more than 24 months with CsA was lower (P = 0.02) than patients treated with CsA for 12 to 24 months. OLT patients with normal true GFR (greater than 90 ml/min/1.73 m2) had significantly lower plasma CsA levels, and 50% of patients with a true GFR less than or equal to 50 ml/min/1.73 m2 had hypertension. There was no effect on true GFR of age, liver function, azathioprine use, or peritransplant treatment with other nephrotoxic drugs. We conclude that true GFR is significantly impaired in long-term CsA-treated allograft pediatric recipients. Calculations of GFR underestimate the degree of renal dysfunction. As patients treated greater than 24 months had the lowest true GFRs, the fall in GFR may be progressive

Effect of ultraviolet-B-irradiated donor-specific blood transfusions and peritransplant immunosuppression with cyclosporine on rat cardiac allograft survival

International Nuclear Information System (INIS)

Oluwole, S.F.; Lau, H.T.; Reemtsma, K.; Hardy, M.A.

1988-01-01

We have previously demonstrated that pretreatment of ACI recipients with ultraviolet-irradiated donor-specific blood transfusion (UV-DST) leads to permanent cardiac allograft survival without further host immunosuppression (ACI rats are weak responders to Lewis lymphocytes in mixed-lymphocyte reaction). This study examines the effect of UV-DST and the timing of transfusions on ACI cardiac allograft survival in Lewis recipients with and without the addition of peritransplant cyclosporine (CsA) (20 mg/kg i.m.) given on days 0, +1, and +2 in relation to the time of transplantation. The mean survival time (MST) of ACI cardiac allografts in Lewis recipients was significantly increased to 33.6 +/- 5.7 days (P less than 0.001) by CsA treatment alone as compared to 6.5 +/- 0.5 days survival in control. When DST was given on day -3 combined with CsA, graft survival was increased to 42.0 +/- 9.3 days (P less than 0.01), as compared to 5.8 +/- 1.3 days when DST alone was used. When DST was irradiated with ultraviolet B (UV-DST) and administered on day -3 combined with peritransplant CsA, the MST was increased to 68.83 +/- 16.1 days as compared to an MST of 10.0 +/- 1.0 days in controls treated with UV-DST alone. When UV-DST was given on day -7 and combined with peritransplant CsA immunosuppression, the results were similar. However, when UV-DST was peritransplant CsA course, 4 of 6 recipients maintained their ACI heart allografts indefinitely (greater than 300 days) in contrast to the effect of UV-DST alone (MST of 13.5 days). Third-party (W/F) UV-irradiated blood transfusions were ineffective in prolonging ACI cardiac allografts in Lewis rats, regardless of whether the transfusions were given alone or in combination with peritransplant immunosuppression with CsA

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

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Jang Hoon Lee

2016-01-01

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

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

Combination therapy with cyclosporine and psoralen plus ultraviolet a in the patients with severe alopecia areata: a retrospective study with a self-controlled design.

Science.gov (United States)

Park, Kui Young; Jang, Woo Sun; Son, In Pyeong; Choi, Sun Young; Lee, Moo Yeol; Kim, Beom Joon; Kim, Myeung Nam; Ro, Byung In

2013-02-01

Alopecia areata (AA) is believed to be an organ-specific autoimmune disease in which a mononuclear cell infiltrate develops in and around anagen hair follicles. There is no definitive therapy for AA. We sought to determine whether the combination therapy of cyclosporine and psoralen plus ultraviolet A (PUVA) could be an effective treatment for severe AA. A total of 41 patients with severe AA were treated with oral cyclosporine and topical PUVA. Cyclosporine was given at an initial daily dose of 200 mg for adult and 100 mg for children for periods of up to 16 weeks. Eight-methoxypsoralen (Methoxsalen) was applied topically 20 minutes prior to ultraviolet A (UVA) exposure, and the patients were irradiated with UVA twice a week for 16 weeks. Of the total 41 patients, 2 (7.3%) patients were lost to follow-up, and 1 (2.4%) patient discontinued the treatment due to abdominal discomfort. Six (14.6%) patients were treated for less than 12 weeks. Of remaining 32 patients, 3 (9.4%) showed excellent response, 3 (9.4%) showed good response, 12 (37.5%) showed fair response, and 14 (43.7%) showed poor response. Although limited by its uncontrolled character, this study shows that the combination therapy with cyclosporine and PUVA may be an additional choice for severe and recalcitrant AA.

Outcome of children with severe acquired aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine A

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Marlene Pereira Garanito

2014-09-01

Full Text Available Objective: To evaluate the outcome of children with severe acquired aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine as first-line treatment at this institution. Methods: Retrospective analysis of 26 pediatric patients with aplastic anemia, treated between 1996 and 2011 with rabbit antithymocyte globulin plus cyclosporine. Results: The overall response rate at six months was 34.6% (9/26, and the cumulative incidence of relapse was 26.5% (95% confidence interval [CI]: 1.4%-66% at 5 years. The cumulative incidence of clonal evolution after immunosuppressive therapy was 8.3% (95% CI: 0.001%-53.7% at five years with both clonal evolutions in non -responders who acquired monosomy 7 karyotype. The overall survival at five years was 73.6% (95% CI: 49.2%-87.5%. Conclusions: The present results confirm the poor response rate with rabbit antithymocyte globulin as first therapy in pediatrics patients, similar to what has been reported for patients of all ages. This confirmation is problematic in Brazil, given the lack of horse antithymocyte globulin in many markets outside the United States. Resumo: Objetivo: Avaliar o resultado de crianças com anemia aplástica grave adquirida tratadas com globulina antitimocítica de coelho e ciclosporina como tratamento inicial em nosso instituto. Métodos: Análise retrospectiva de 26 pacientes pediátricos com anemia aplástica tratados entre 1996 e 2011 com globulina antitimocítica de coelho e ciclosporina. Resultados: A taxa de resposta geral em seis meses foi de 34,6% (9/26, e a incidência acumulada de recorrência foi de 26,5% (intervalo de confiança [IC] de 95%,1,4%-66% em cinco anos. A incidência acumulada de evolução clonal após a terapia imunossupressora foi de 8,3% (IC 95%, 0,001%-53,7% em cinco anos, com ambas as evoluções clonais em pacientes sem resposta que adquiriram o cariótipo com monossomia 7. A sobrevida geral em cinco anos foi de 73,6% (IC 95%, 49

Coronary blood flow and thallium 201 uptake in rejecting rat heart transplantations

International Nuclear Information System (INIS)

Bergsland, J.; Hwang, K.; Driscoll, R.; Carr, E.A.; Wright, J.R.; Curran-Everett, D.C.; Carroll, M.; Krasney, E.; Krasney, J.A.

1989-01-01

The effects of rejection on coronary flow (CAF) in heart allografts are unclear, although previous evidence with cardiac imaging agents indicates impaired flow during advanced rejection. The purpose of this study was to measure CAF in heterotopically placed heart grafts. Lewis rats (LEW) received grafts from either syngeneic Lewis rats (LEW/LEW group) or allogeneic ACI rats (ACI/LEW group). CAF was measured in both the transplanted and native hearts with radiolabeled microspheres. Rejection was measured histologically (grades 0 [absent] to 4+ [severe]). In addition systemic blood pressure and cardiac outputs of the native hearts were determined with microspheres. Different animals were studied during relatively early (4 days) and late (6 days) rejection. Among the 4-day animals a cyclosporine-treated group was included (ACI/LEW CyA). In 6-day rats CAF in allografts was lower (0.56 +/- .06 ml/gm/min) compared with syngeneic grafts (1.72 +/- 0.4 ml/gm/min) (p less than 0.05). The CAF in the native hearts did not differ significantly but was higher than in the grafts in both groups. Heart rates were reduced in allografts (p less than 0.05). It is interesting that arterial pressure and cardiac output were significantly lower in animals bearing allogeneic than syngeneic grafts. In rats studied at 4 days graft CAF was lower than in the native heart in both the LEW/LEW and ACI/LEW groups, but there was no significant difference in behavior between groups. The same was true for a cyclosporine-treated group. Graft heart rates were similar in all 4-day rats

Oral cyclosporine therapy for refractory severe vernal keratoconjunctivitis

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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.

Enhancing effect of negative polypropylene electret on in vitro transdermal delivery of cyclosporine A solution and its synergistic effect with ethyl oleate

International Nuclear Information System (INIS)

Cui, L L; Liu, H Y; Ma, L; Liang, Y Y; Guo, X; Jiang, J

2013-01-01

In this study, the corona charged electrets at voltages of −500 V, −1000 V and −2000 V were made from polypropylene (PP) film. The cyclosporine A (CsA) and 10% ethyl oleate were chosen as the model drug and chemical enhancer, respectively. The charge storage stability of the electrets and the in vitro transdermal behaviour of the model drug in solution under different conditions were studied. The results indicate that the external electrostatic field of the negative PP electrets could penetrate through the rat skin and enhance the transdermal delivery of cyclosporine A. A synergistic effect on enhancing the transdermal delivery of cyclosporine A was observed by combining different surface potential negative PP electrets with 10% ethyl oleate, and the amount of transdermal delivery of CsA was greatly increased comparing with only application of electrets. Therefore, the combination application of electret and chemical enhancer could be a feasible strategy in enhancing transdermal delivery of small peptide drugs or some large molecular drugs.

Radioimmunoassay of salivary cyclosporine with use of 125I-labeled cyclosporine

International Nuclear Information System (INIS)

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

1988-01-01

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

Mechanisms of immunologic unresponsiveness induced by ultraviolet-irradiated donor-specific blood transfusions and peritransplant cyclosporine

Energy Technology Data Exchange (ETDEWEB)

Oluwole, S.F.; Chabot, J.; Pepino, P.; Reemtsma, K.; Hardy, M.A.

1988-09-01

Recipient pretreatment with UV-B irradiated donor-specific blood transfusions (UV-DST) combined with peritransplant cyclosporine on days 0, +1, and +2 leads to permanent cardiac allograft survival in the ACI-to-Lewis rat strain combination. This study investigates the mechanisms of immunologic unresponsiveness induced by UV-DST and CsA by examining several in vitro and in vivo parameters in long-term cardiac allograft recipients. The results of the in vitro studies demonstrate that thoracic duct lymphocytes (TDL) of treated and allografted Lewis rats respond less in a mixed lymphocyte reaction to donor splenic lymphocytes (SpL) by 69%, 75%, and 73% (P less than 0.001) at 30, 50, and 100 days after transplantation, respectively, compared with controls, while the response to a third-party (W/F) SpL is unimpaired. In coculture experiments, the TDL from treated recipients specifically suppressed the response of unmodified Lewis TDL to ACI SpL by 59% and 40% (P less than 0.01) at 30 and 50 days after transplantation, respectively, while responses to W/F SpL were suppressed by only 3-6%. The sera obtained from ungrafted rats transfused with UV-DST suppressed the MLR between unmodified Lewis TDL and ACI SpL by 31% (P less than 0.05) while the sera from UV-DST and CsA-treated and allografted rats specifically suppressed the MLR by 75%, 80% (P less than 0.001) and 37% (P less than 0.01) at 10, 30, and 50 days after transplantation, respectively. In vivo adoptive transfer of 10(4) donor-type dendritic cells (DC) into recipients of beating cardiac allografts at 40 or 60 days after transplantation led to rapid and acute allograft rejection, while the adoptive transfer of 10(8) unseparated SpL obtained at 50 days after transplantation from treated Lewis recipients to syngeneic naive hosts led to a modest but significant prolongation of ACI test cardiac allografts.

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

DEFF Research Database (Denmark)

Koefoed-Nielsen, Pernille Bundgaard; Karamperis, Nikolaos; Jørgensen, Kaj Anker

2006-01-01

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.......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...

Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade

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El-Gowelli, Hanan M., E-mail: dr_Hanan_el_gowali@hotmail.com; Saad, Evan I.; Abdel-Galil, Abdel-Galil A.; Ibrahim, Einas R.

2015-11-01

In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5 mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients. - Highlights: • Lipoic acid is more effective than

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

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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.

Cyclosporin A increases recovery after spinal cord injury but does not improve myelination by oligodendrocyte progenitor cell transplantation

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Wang Feng-Chao

2010-10-01

Full Text Available Abstract Background Transplantation of oligodendrocyte precursor cells (OPCs is an attractive therapy for demyelinating diseases. Cyclosporin A (CsA is one of the foremost immunosuppressive agents and has widespread use in tissue and cell transplantation. However, whether CsA affects survival and differentiation of engrafted OPCs in vivo is unknown. In this study, the effect of CsA on morphological, functional and immunological aspects, as well as survival and differentiation of engrafted OPCs in injured spinal cord was explored. Results We transplanted green fluorescent protein (GFP expressed OPCs (GFP-OPCs into injured spinal cords of rats treated with or without CsA (10 mg/kg. Two weeks after cell transplantation, more GFP-positive cells were found in CsA-treated rats than that in vehicle-treated ones. However, the engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes in both groups. In the CsA-treated group, a significant decrease in spinal cord lesion volume along with increase in spared myelin and neurons were found compared to the control group. Such histological improvement correlated well with an increase in behavioral recovery. Further study suggested that CsA treatment could inhibit infiltration of T cells and activation of resident microglia and/or macrophages derived from infiltrating monocytes in injured spinal cords, which contributes to the survival of engrafted OPCs and repair of spinal cord injury (SCI. Conclusions These results collectively indicate that CsA can promote the survival of engrafted OPCs in injured spinal cords, but has no effect on their differentiation. The engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes. The beneficial effect of CsA on SCI and the survival of engrafted cells may be attributed to its neuroprotective effect.

Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats.

Science.gov (United States)

Lopes, Patrícia C; Fuhrmann, Amelia; Sereno, José; Espinoza, Daniel O; Pereira, Maria João; Eriksson, Jan W; Reis, Flávio; Carvalho, Eugenia

2014-05-01

Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new onset diabetes after transplantation and dyslipidemia. We aim to evaluate the molecular effects of CsA (5mg/kg/day) and SRL (1mg/kg/day) treatment for 3 and 9weeks on lipid metabolism, in Wistar rats. Lipolysis was evaluated in isolated adipocytes, while triglycerides (TG) and non-esterified fatty acid (NEFA) were measured in serum. Gene and protein expression involved in lipid metabolism was assessed in adipose tissue and liver. CsA and SRL treatments of rats for 3 and 9weeks increased isoproterenol-stimulated lipolysis by 5-9 fold and 4-6 fold in isolated adipocytes, respectively. While CsA increased adipocyte weight and diameter, as well as NEFA and TG levels in circulation after 9weeks, SRL treatment caused ectopic deposition of TG in the liver after 3weeks. Moreover, ACC1 and FAS protein expression was increased after 3weeks (>100%, p42%, pIAs on expression of lipolytic and lipogenic genes suggest that these agents influence lipid metabolism, thus contributing to the dyslipidemia observed during immunosuppressive therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of 0.5g/L cyclosporine A for symptom and sign scores in patients with moderate to severe dry eye

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Su-Ying Yu

2016-05-01

Full Text Available AIM:To investigate the effect of 0.5g/L cyclosporine A for symptom and sign scores in patients with moderate to severe dry eye.METHODS:Eighty patients(160 eyeswith moderate to severe dry eye were divided into two groups by double-blind and random principles:40 patients(80 eyesin observation group were treated with 10g/L sodium carboxymethyl cellulose and 0.5g/L cyclosporine A eye drops, 40 patients(80 eyesin the control group were treated with 10g/L sodium carboxymethyl cellulose eye drops. The changes of ocular sign and symptom scores were compared between the two groups.RESULTS:The total effective rate of observation group was 95.0%, which was significantly higher than that of control group(85.0%, PPPP>0.05. After treatment, the four parameters of observation group were improved significantly(PPPCONCLUSION:The 0.5g/L cyclosporine A eye drops can effectively relieve the symptoms and signs of moderate to severe dry eye, promote tear secretion, and improve ocular surface environment. The treatment effect is good.

Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET(B) receptor cascade.

Science.gov (United States)

El-Gowelli, Hanan M; Helmy, Maged W; Ali, Rabab M; El-Mas, Mahmoud M

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(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-β₁, TGF-β₁). 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(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(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 ETB 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(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

Cyclosporine Ophthalmic

Science.gov (United States)

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

Dietary supplementation with lish oil modifies renal reserve filtration capacity in postoperative, cyclosporin A-treated renal transplant recipients

NARCIS (Netherlands)

van der Heide, J. J. Homan; Bilo, H. J. G.; Donker, A. J. M.; Wilmink, J. M.; Sluiter, W. J.; Tegzess, Adam M.

The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega-3 = EPA and 20% C22:6 omega-3 = DHA) for 1 month on renal function variables was investigated in a placebo-controlled (6 g coconut oil), prospective, randomized, double-blind study in acute postoperative cyclosporin A

Effects of cyclosporin A on a kidney epithelial cell line (LLC-PK1).

Science.gov (United States)

Becker, G M; Gandolfi, A J; Nagle, R B

1987-05-01

Cyclosporin A (CSA), a potent immunosuppressant with the adverse side effect of nephrotoxicity, inhibited cell growth of pig kidney tubule cells (LLC-PK1) in culture. CSA (10(-5) M) also induced intense cytoplasmic vacuolation and the formation of dense granules. At the same concentration an analogue of CSA, cyclosporin G, had much less effect. This cell line may prove useful for revealing the mechanism of CSA-nephrotoxicity and testing the nephrotoxic potential of new analogues of cyclosporine.

COMPARATIVE ANALYSIS OF SOLUBLE OF CD40 LIGAND LEVELS IN HEART RECIPIENTS TREATED WITH CYCLOSPORINE A AND TACROLIMUS

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O. P. Shevchenko

2012-01-01

Full Text Available Soluble form of CD40L is platelet activating factor, which is a marker of inflammation and thrombosis. Elevated levels of sCD40L before the heart transplantation are associated with the risk of early development of cardiova- scular complications. The study included 54 patients who had received heart transplants. All recipients received a triple heart immu- nosuppressive therapy, including methylprednisolone, mycophenolate mofetil and cyclosporine A (20 recipients or methylprednisolone, mycophenolate mofetil and tacrolimus (34 recipients. Patients were not differed by age, gender, etiology of heart failure before heart transplantation (p > 0,05. In the first group of transplant recipients, the relative risk of cardiovascular events with high sCD40L levels before transplantation was 3 2 (95% CI 1,4; 12,0. In the second group of recipients, respectively, 2.69 (95% CI 1,1; 8,5. SCD40L level after heart transplan- tation was significantly higher for patients receiving cyclosporine (P < 0.05. Increasing concentrations of sCD40L are associated with a higher incidence of cardiovascular complications. 

Cyclosporin A and enterohepatic circulation of bile salts in rats : Decreased cholate synthesis but increased intestinal reabsorption

NARCIS (Netherlands)

Hulzebos, CV; Wolters, H; Plosch, T; Stengelin, S; Stellaard, F; Sauer, PJJ; Verkade, HJ; Kuipers, F

Cyclosporin A (CsA) has been shown to inhibit synthesis and hepatobiliary transport of bile salts. However, effects of CsA on the enterohepatic circulation of bile salts in vivo are largely unknown. We characterized the effects of CsA on the enterohepatic circulation of cholate, with respect to

Cyclosporine in veterinary dermatology.

Science.gov (United States)

Palmeiro, Brian S

2013-01-01

Cyclosporine is an immunomodulatory medication that is efficacious and approved for atopic dermatitis in dogs and allergic dermatitis in cats; it has also been used to successfully manage a variety of immune-mediated dermatoses in dogs and cats. This article reviews the use of cyclosporine in veterinary dermatology including its mechanism of action, pharmacokinetics, drug interactions, side effects, and relevant clinical updates. Dermatologic indications including atopic/allergic dermatitis, perianal fistulas, sebaceous adenitis, and other immune-mediated skin diseases are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

El-Sherbeeny, Nagla A; Nader, Manar A

2016-03-01

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

EFFECT OF CYCLOSPORINE A ON THE KIDNEY OF RABBIT: A LIGHT AND ULTRASTRUCTURAL STUDY

OpenAIRE

Fathy Ahmed Fetouh; Abdelmonem Awad Hegazy

2014-01-01

Background: Nephrotoxicity is a relatively common problem in patients immunosuppressed with cyclosporine A (CsA) with an incidence reaching up to thirty percent. The present work aimed to study the histological and ultrastructural effects of CsA on the kidney of rabbit. Materials and Methods: Two groups of Egyptian adult rabbits were used for this study (5 rabbits for each). One group was used as a control and the other group (experimental) was treated with CsA in a dose of 15 mg/kg of bod...

Hipertrofia gengival em transplantados renais Cyclosporine induced gingival hyperplasia in kidney transplants

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Paulo Roberto Torrezan

2005-08-01

laboratory exams, among them the cyclosporine serum level. This permitted observation of these cases, especially with respect to the reaction of gingival growth. Clinical dental exams of the patients comprised filling out a form on their personal data, height and weight and number of dental segments. Also an observation of the degree of the gingival and bacterial plaque index was recorded. These data were treated statistically. RESULTS: Of the patients treated only with cyclosporine, 47.2% showed no alterations of the gingival structure while 52.8% presented gingival growth, of them 33.3% with a > 2 degree. Of the patients treated with both cyclosporine and nifedipine, 33.3% had a normal gingiva and 66.7% presented gingival growth. In 45.8% of them, the alteration was of > 2 degree, with no significant difference between results of the male and female patients. A positive correlation between excess fat and the corrected cyclosporine dose and serum concentration per unit of Body Mass Index was found, also between excess fat and the bacterial plaque index. A significant association between the extent of increased gingival growth and the bacterial plaque index was also observed. CONCLUSION: Use of cyclosporine when associated with nifedipine brings about an increase of gingival growth.

Evaluation of Danazol, Cyclosporine, and Prednisolone as Single Agent or in Combination for Paroxysmal Nocturnal Hemoglobinuria

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Kanjaksha Ghosh

2013-12-01

Full Text Available OBJECTIVE: The responses of 32 patients with paroxysmal nocturnal hemoglobinuria (PNH were assessed after the patients were put on various combinations of danazol, prednisolone, and cyclosporine. METHODS: Nineteen males and 13 females aged between 14 and 60 years with confirmed diagnosis of PNH were treated with danazol (4, danazol + cyclosporine (7, cyclosporine (1, and prednisolone + danazol (20. Response to these interventions was assessed regularly. Danazol was added to cyclosporine in patients with aplastic bone marrow after 3 months of cyclocporine use only unless the former therapy was successful. Four patients with aplastic marrow received only danazol because they had renal insufficiency at presentation. Patients were evaluated with regular complete blood count and routine liver and renal function tests. RESULTS: One patient responded to cyclosporine only. Thirteen of 32 patients (40% had complete response, 12/32 patients (37% had partial response leading to freedom from red cell transfusion, and 2/32 (7% had no response. Five patients (16% died due to thrombosis or hemorrhage within 3 months of therapy before their response to therapy could be assessed. The median period of review of the cases was 4 years and 6 months. CONCLUSION: Danazol is a useful addition to PNH therapy both in combination with cyclosporine for hypoplastic PNH and with prednisolone for other forms of PNH, and this therapy could be a good alternative where eculizumab and anti-lymphocyte globulin cannot be used for various reasons.

Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates

International Nuclear Information System (INIS)

Wijkstrom, Martin; Kirchhof, Nicole; Graham, Melanie; Ingulli, Elizabeth; Colvin, Robert B.; Christians, Uwe; Hering, Bernhard J.; Schuurman, Henk-Jan

2005-01-01

Streptozotocin (STZ) is widely applied in animal models of insulin-dependent diabetes mellitus. Adverse effects of STZ mainly concern liver and kidney. In nonhuman primates a single 100-150 mg/kg dose invariably induces diabetes with only rare adverse effects. We report one animal with renal failure necessitating sacrifice. Body weight (age) might be a confounding factor, i.e. older animals might be more vulnerable to STZ-related toxicity. We therefore recommended to administer STZ on a mg/m 2 basis and not on a mg/kg basis. In our islet transplantation program nonhuman primates with STZ-induced diabetes received transplants under chronic immunosuppression including calcineurin inhibitors (cyclosporine, tacrolimus), drugs in the rapamycin class affecting growth factor-induced cell proliferation, and the sphingosine 1-phosphate receptor antagonist FTY720. Four animals developed renal failure and had to be sacrificed, most likely caused by cyclosporine. Kidney histology was typical for cyclosporine toxicity including thrombotic microangiopathy in glomeruli and fibrinoid necrosis of arteries, and for STZ toxicity including acute tubular necrosis and accumulations of erythroid precursors. This adverse effect was observed at a pharmacologically active cyclosporine exposure. Additionally, six diabetic animals without major adverse effects during cyclosporine or tacrolimus treatment are presented. We conclude that cyclosporine facilitates renal dysfunction in animals with STZ-induced diabetes, presumably related to an increased vulnerability to a toxic insult after STZ administration

GINGIVAL OVERGROWTH INDUCED BY IMMUNOSUPPRESSIVE TREATMENT WITH CYCLOSPORINE A AND MYCOPHENOLATE MOFETIL IN A PATIENT WITH KIDNEY TRANSPLANT – A CASE REPORT AND LITERATURE REVIEW

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Daniela Trandafir

2013-07-01

Full Text Available Cyclosporine A, a drug that inhibits the immuneresponse, has been widely used for over 30 years in immunosuppressivetherapy protocols for patient‑recipients ofthe transplanted organs. One of the commonly reportedside effects of Cyclosporine A is gingival overgrowth, withvarying degrees of severity, which may interfere with theaesthetics and normal functions of the oral cavity. Combinationwith other drugs that can recognize the gum tissueas a secondary target organ increases the risk ofdrug‑induced gingival overgrowth. In cases where a lowerdose of Cyclosporine A or conversion to another immunosuppressiveagent (a drug not assigned to such a sideeffect are not possible, the management of severe gingivalovergrowth focuses on surgical excision of the excessivelyproliferated gingival tissue. We report the case of a youngadult with moderate drug‑induced gingival overgrowth,the beneficiary of a functional transplanted kidney about9 years ago, treated with two immunosuppressives, whohas undergone gingivectomy with electrocautery, as a necessaryintervention to improve the oral hygiene and toavoid worsening of malfunctions in the oral cavity.

A survey on the effects of Azithromycin in the treatment of gingival overgrowth induced by Cyclosporin in renal transplant patients

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Kadkhoda Z.

2004-07-01

Full Text Available Statement of Problem: Gingival overgrowth is a side effect commonly induced by Cyclosporin treatment. The effects of Azithromycin, a macrolidic antibiotic, has been focused on gingival enlargement treatment induced by cyclosporine in numerous articles. Purpose: The goal of the present study was to survey the effects of systemic Azithromycin in the treatment of gingival overgrowth induced by cyclosporine among renal transplant patients. Materials and Methods: In this clinical trial study, 18 renal transplant patients (6 females and 12 males with gingival overgrowth were studied. Samples were randomly divided into two groups: case group were treated by systemic Azithromycin and controls were treated by systemic placebo. Periodontal parameters including bleeding on probing (BOP, clinical crown length (CL, periodontal pocket depth (PPD, gingival overgrowth (GOI and stent-IDP (vertical distant between a stent or plate with teeth occlusal planes at least from three of the most anterior contact points to mesial papillae before treatment, two and six weeks after treatment were measured. To analyze the data, Wilcoxon and Mann-Whitney tests were used. Results: Most of the measured indices, among case and control groups, were significantly improved, after two weeks (P<0.05. No statistically significant differences were found between two groups except for BOP index (P<0.05. In other words, more BOP improvement was observed in the case group after six weeks comparing to the control group. Conclusion: Considering the findings of this study, one can assume that the reported effects of Azithromycine on gingival overgrowth, induced by cyclosporine is somehow exaggerated and the effects attributed this medicine is probably inflammation reduction.

Tissue and subcellular localizations of 3H-cyclosporine A in mice

International Nuclear Information System (INIS)

Baeckman, L.; Brandt, I.; Appelkvist, E.-L.; Dallner, G.

1988-01-01

The tissue and subcellular localizations of 3 H-cyclosporine A after administration to mice were determined with whole-body autoradiography and scintillation counting of lipid extracts of tissues and subcellular fractions. The radioactivity was widely distributed in the body and the pattern of distribution after oral or parenteral administration was the same, except that tissue levels were generatlly lower after oral administration. Pretreatment of the animals with a diet containing cyclosporine A for 30 days before the injection of radioactive cyclosporine A did not change the pattern of distribution substantially. No significant radioactivity was found in the central nervous system, except for the choroidal plexus and the area postrema region of the brain. In pregnant mice no passage of radioactivity from the placentas to fetuses was observed after a single injection. 3 H-cyclosporine A and/or its metabolites showed a high affinity for the lympho-myeloid tissues, with a marked long-term retention in bone marrow and lymph nodes. There was massive excretion in the intestinal tract after parenteral administration, and the liver, bile, pancreas and salivary glands contained high levels of radioactivity. In the kidney radioactivity was confined to the outer zone of the outer kidney medulla. In liver homogenates no quantitatively significant binding of 3 H-cyclosporine A and/or its metabolites to cellular molecules such as proteins, DNA, phospho- or neutral lipids was found. After lipid extraction with organic solvents, almost all radioactivity was recovered in the organic phase. (author)

Comparison of the efficacy of topical cyclosporine with fluromethalone in treatment of dry eye disease

International Nuclear Information System (INIS)

Erum, N.; Rasul, A.; Yaqub, A.; Malik, A. M.

2017-01-01

Objective: To compare the efficacy of 0.05 percent cyclosporine eye drops with 0.1 percentage fluromethalone eye drops on keratoconjunctivitis sicca (dry eye disease). Study Design: Randomized controlled trial. Place and Duration of Study: Ophthalmology department of HIT Hospital Taxila, from Oct 2014 to May 2015. Material and Methods: The patients with keratoconjunctivitis sicca (KCS) were selected from outpatient and divided in two treatment groups. The dry eye disease was defined according to criteria set by International task force for dry eye disease (ITF). The group I was treated with 0.05 percent cyclosporine drops while group-II was treated with 0.1 percent fluromethalone eye drops three times a day after informed written consent. The patients were followed up after three months and six months. Results: At the start of treatment 94 patients were placed in two treatment groups (n=47 in each group) and all the patients with KCS were graded according to severity following rules set by ITF. There were 46 patients in grade III (severe) KCS and 20 patients in grade IV (very severe) KCS. At the end of study only 24 were in grade II (moderate) KCS and 2 in grade III KCS. Of these only 5 patients in grade II and none in grade III were in treatment group I (cyclosporine). The remaining 19 patients in grade II and 5 patients in grade III KCS belonged to group II (fluromethalone). Conclusion: Cyclosporine eye drops are better than fluromethalone in treatment of keratoconjunctivitis sicca. (author)

Influence of Overt Diabetes Mellitus on Cyclosporine Pharmacokinetics in a Canine Model

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Khalid M. Alkharfy

2009-01-01

Full Text Available Background/Aims. Diabetic patients usually require more medications than their nondiabetic counterparts. This work examined the effect of hyperglycemia on the pharmacokinetic properties of cyclosporine in a diabetic dog model. Main Methods. Diabetes was induced using a streptozotocin/alloxan combination and verified by measuring the serum glucose level. Cyclosporine was administered as a bolus intravenous dose of 5 mg/kg, and blood samples were collected at different time points for determining drug concentrations and biochemical analyses. Results. Diabetic dogs showed a significant increase in total body clearance of cyclosporine compared to healthy controls (0.457 L hr−1Kg−1 versus 0.201 L hr−1Kg−1, =.0019 and a decrease in its biological half-life (9.32 hours versus 22.56 hours, =.0125. In addition, diabetic animals exhibited a higher total cholesterol (7.20±0.62 mmol/L and 5.28±0.36 mmol/L; <.05 as well as more serum low density lipoproteins (4.45±0.72 mmol/L versus 1.06±0.10 mmol/L; <.05. Conclusion. Overt diabetes alters cyclosporine disposition by modulating its clearance. Abnormalities in the lipid profile, among other factors, may contribute to the accelerated metabolic degradation of cyclosporine under hyperglycemic conditions.

Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury

International Nuclear Information System (INIS)

Zhu, Haibo; He, Jie; Ye, Liang; Lin, Fei; Hou, Jian; Zhong, Yan; Jiang, Wanglin

2015-01-01

Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood–brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression. - Highlights: • Curculigoside A induces cell proliferation through Wnt5a/β-catenin pathway. • Curculigoside A induces angiogenesis via VEGF/CREB/Egr-3/VCAM-1 signaling axis. • Curculigoside A promotes blood vessel maturation via Ang1/Tie2 pathway.

Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury

Energy Technology Data Exchange (ETDEWEB)

Zhu, Haibo [School of Public Health and Management, Binzhou Medical University, Yantai (China); Institute of Toxicology, Binzhou Medical University, Yantai (China); He, Jie [State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003 (China); Ye, Liang [School of Public Health and Management, Binzhou Medical University, Yantai (China); Institute of Toxicology, Binzhou Medical University, Yantai (China); Lin, Fei; Hou, Jian; Zhong, Yan [State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003 (China); Jiang, Wanglin, E-mail: jwl518@163.com [School of Pharmaceutical Sciences, Institute of Materia Medica, Binzhou Medical University, Yantai (China)

2015-11-01

Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood–brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression. - Highlights: • Curculigoside A induces cell proliferation through Wnt5a/β-catenin pathway. • Curculigoside A induces angiogenesis via VEGF/CREB/Egr-3/VCAM-1 signaling axis. • Curculigoside A promotes blood vessel maturation via Ang1/Tie2 pathway.

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

Dyslipidaemia among renal transplant recipients: cyclosporine versus tacrolimus.

Science.gov (United States)

Fazal, Muhammad Asim; Idrees, Muhammad Khalid; Akhtar, Syed Fazal

2014-05-01

To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3 mg/kg) and group B was treated with tacrolimus (0.1 mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5 ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. Of the 182 patients, 144 (79.1%) were males and 38 (20.9%) were females. The overall mean age was 30.18 +/- 9.57 years, and the mean weight was 54.41 +/- 11.144 kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54 (59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication.

Generation and characterization of cyclosporine aerosols for administration by inhalation

International Nuclear Information System (INIS)

Hoover, M.D.; Muggenburg, B.A.; Snipes, M.B.; Wolff, R.K.; Yeh, H.C.; Griffith, B.P.; Burckart, G.J.; Mauderly, J.L.

1988-01-01

A method was developed for generating aerosols of the immunosuppressive agent cyclosporine and a gamma-emitting radiolabel ( 99m Tc) for administration by inhalation. Cyclosporine was dissolved in ethyl alcohol (EtOH) and nebulized with a Love- lace nebulizer operated with 50 psi compressed air. For a cyclosporine concentration of 25 mg/mL, the particle size of the aerosol was 0.7 μm activity median aerodynamic diameter (AMAD), with 1.8 geometric standard deviation (GSD). The clear solution of EtOH and cyclosporine became a cloudy suspension when a limited amount of saline solution containing a 99m Tc radiolabel was added. This occurred because cyclosporine is hydrophobic. If saline concentrations as high as 6% in EtOH by volume were used, a gummy residue formed in the nebulizer and the particle aerodynamic diameter became unacceptably large (4.7 μm). When the saline concentration was only 3 % (the minimum radiolabel volume needed for gamma camera studies of lung deposition), the suspensions of cyclosporine could be nebulized to give a particle size of 2.2 μm AMAD with 2.1 GSD. The radiolabel was uniformly distributed with the spherical cyclosporine particles. Concentrations and particle size distributions remained constant over 1-h generation periods. These aerosols have been used in inhalation studies with Beagle dogs. (author)

MR findings of cyclosporine neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Yang, Po Song; Ahn, Kook Jin; Ahn, Bo Young; Jung, Hae An; Kim, Hee Je; Lee, Jae Mun [The Catholic Univ. St Mary' s Hospital, Seoul (Korea, Republic of)

1998-12-01

To analyze the MR findings of cyclosporine-induced neurotoxicity in patients receiving high dose of cyclosporine and to suggest the possible pathogenetic mechanism. The cases of seven patients (2 males, 5 females;18-36 years old) who suffered seizures after receiving high-dose cyclosporine for bone marrow transplantation due to diseases such as aplastic anemia or leukemia were retrospectively reviewed. We evaluated the location and pattern of abnormal signal intensity seen on T2 weighted images, the presence of contrast enhancement, and the changes seen on follow-up MR performed at intervals of 12-30 days after initial MR in five of seven patients. We analyzed levels of blood cyclosporine and magnesium, and investigated the presence of hypertension at the sity of the seizure. Locations of the lesions were bilateral(n=3D5), unilateral(n=3D2), parietal(n=3D6), occipital(n=3D6), temporal(n=3D4), and in the frontal lobe(n=3D3). Frontal lesions showed high signal intensities in the borderline ischemic zone of the frontal lobe between the territory of the anterior and middle cerebral arteries. In six of the seven patients, cortical and subcortical areas including subcortical U-fibers were seen on T2-weighted images to be involved in the parietooccipital lobes. Only one of the seven showed high signal intensity in the left basal ganglia. All lesions showed high signal intensity on T2-weighted images, and iso to low signal intensity on T1-weighted. In five of seven patients there was no definite enhancement, but in the other two, enhancement was slight. In four of seven patients seizures occurred within high therapeutic ranges(250-450ng/ml), while others suffered such attacks at levels below the therapeutic range. After cyclospirine was administered at a reduced dosage or stopped, follow-up MR images showed the complete or near-total disappearance of the abnormal findings previously described. Only two patients had hypertension, and the others normotension. Five of the

MR findings of cyclosporine neurotoxicity

International Nuclear Information System (INIS)

Yang, Po Song; Ahn, Kook Jin; Ahn, Bo Young; Jung, Hae An; Kim, Hee Je; Lee, Jae Mun

1998-01-01

To analyze the MR findings of cyclosporine-induced neurotoxicity in patients receiving high dose of cyclosporine and to suggest the possible pathogenetic mechanism. The cases of seven patients (2 males, 5 females;18-36 years old) who suffered seizures after receiving high-dose cyclosporine for bone marrow transplantation due to diseases such as aplastic anemia or leukemia were retrospectively reviewed. We evaluated the location and pattern of abnormal signal intensity seen on T2 weighted images, the presence of contrast enhancement, and the changes seen on follow-up MR performed at intervals of 12-30 days after initial MR in five of seven patients. We analyzed levels of blood cyclosporine and magnesium, and investigated the presence of hypertension at the sity of the seizure. Locations of the lesions were bilateral(n=3D5), unilateral(n=3D2), parietal(n=3D6), occipital(n=3D6), temporal(n=3D4), and in the frontal lobe(n=3D3). Frontal lesions showed high signal intensities in the borderline ischemic zone of the frontal lobe between the territory of the anterior and middle cerebral arteries. In six of the seven patients, cortical and subcortical areas including subcortical U-fibers were seen on T2-weighted images to be involved in the parietooccipital lobes. Only one of the seven showed high signal intensity in the left basal ganglia. All lesions showed high signal intensity on T2-weighted images, and iso to low signal intensity on T1-weighted. In five of seven patients there was no definite enhancement, but in the other two, enhancement was slight. In four of seven patients seizures occurred within high therapeutic ranges(250-450ng/ml), while others suffered such attacks at levels below the therapeutic range. After cyclospirine was administered at a reduced dosage or stopped, follow-up MR images showed the complete or near-total disappearance of the abnormal findings previously described. Only two patients had hypertension, and the others normotension. Five of the

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

DEFF Research Database (Denmark)

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...

Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study

DEFF Research Database (Denmark)

Parving, H H; Tarnow, L; Nielsen, F S

1999-01-01

OBJECTIVE: To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled Cs...... of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17...... randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. CONCLUSIONS: The results of our 7-year...

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

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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.

Adverse effects of cyclosporine A on HSP25, alpha B-crystallin and myofibrillar cytoskeleton in rat heart

International Nuclear Information System (INIS)

Stacchiotti, Alessandra; Bonomini, Francesca; Lavazza, Antonio; Rodella, Luigi Fabrizio; Rezzani, Rita

2009-01-01

Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.

Elevating bioavailability of cyclosporine a via encapsulation in artificial oil bodies stabilized by caleosin.

Science.gov (United States)

Chen, Miles C M; Wang, Jui-Ling; Tzen, Jason T C

2005-01-01

To elevate its bioavailability via oral administration, cyclosporine A (CsA), a hydrophobic drug, was either incorporated into olive oil directly or encapsulated in artificial oil bodies (AOBs) constituted with olive oil and phospholipid in the presence or absence of recombinant caleosin purified from Escherichia coli. The bioavailabilities of CsA in these formulations were assessed in Wistar rats in comparison with the commercial formulation, Sandimmun Neoral. Among these tests, CsA-loaded AOBs stabilized by the recombinant caleosin exhibited better bioavailability than the commercial formulation and possessed the highest maximum whole blood concentration (C(max)), 1247.4 +/- 106.8 ng/mL, in the experimental animals 4.3 +/- 0.7 h (t(max)) after oral administration. C(max) and the area under the plasma concentration-time curve (AUC(0-24)) were individually increased by 50.8% and 71.3% in the rats fed with caleosin-stabilized AOBs when compared with those fed with the reference Sandimmun Neoral. The results suggest that constitution of AOBs stabilized by caleosin may be a suitable technique to encapsulate hydrophobic drugs for oral administration.

Ectopic Liver Tissue Formation in Rats with Induced Liver Fibrosis

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Bauyrzhan Umbayev

2014-12-01

Full Text Available Introduction: The possible alternative approach to whole-organ transplantation is a cell-based therapy, which can also be used as a "bridge" to liver transplantation.  However, morphological and functional changes in the liver of patients suffering from chronic liver fibrosis and cirrhosis restrict the effectiveness of direct cell transplantation. Therefore, extra hepatic sites for cell transplantation, including the spleen, pancreas, peritoneal cavity, and subrenal capsule, could be a useful therapeutic approach for compensation of liver functions. However, a method of transplantation of hepatocytes into ectopic sites is needed to improve hepatocyte engraftment. Previously published data has demonstrated that mouse lymph nodes can support the engraftment and proliferation of hepatocytes as ES and rescue Fah mice from lethal liver failure. Thus, the aim of the study was to evaluate the engraftment of i.p. injected allogeneic hepatocytes into extra hepatic sites in albino rats with chemically induced liver fibrosis (LF. Materials and methods: Albino rats were randomly divided into 4 groups: (1 intact group (n = 18; (2 rats with induced LF (n = 18; (3 rats with induced LF and transplanted with hepatocytes (n = 18; (4 as a control, rats were treated with cyclosporine A only (n = 18. In order to prevent an immune response, groups 2 and 3 were subjected to immunosuppression by cyclosporine A (25 mg/kg per day. LF was induced using N-nitrosodimethylamine (NDMA, i.p., 10 mg/kg, three times a week for 4 weeks and confirmed by histological analysis of the liver samples. Hepatocytes transplantation (HT was performed two days after NDMA exposure cessation by i.p. injection of 5×106 freshly isolated allogeneic hepatocytes. Liver function was assessed by quantifying blood biochemical parameters (ALT, AST, GGT, total protein, bilirubin, and albumin at 1 week, 1 month, and 2 months after hepatocytes transplantation (HT. To confirm a hepatocytes�

Dyslipidaemia among renal transplant recipients: cyclosporine versus tacrolimus

International Nuclear Information System (INIS)

Fazal, M. A.; Idrees, M. K.; Akhtar, S. F.

2014-01-01

Objectives: To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. Methods: The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3mg/kg) and group B was treated with tacrolimus (0.1mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. Results: Of the 182 patients, 144(79.1%) were males and 38(20.9%) were females. The overall mean age was 30.18+-9.57 years, and the mean weight was 54.41+- 11.144kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54(59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. Conclusions: The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication. (author)

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

International Nuclear Information System (INIS)

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

1987-01-01

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

ATG-Fresenius S combined with cyclosporine a: an effective immunosuppressive therapy for children with aplastic anemia.

Science.gov (United States)

Luo, Cheng-Juan; Gao, Yi-Jin; Tang, Jing-Yan; Zhu, Xiao-Hua; Xue, Hui-Liang; Lu, Feng-Juan; Pan, Ci; Jiang, Hua; Luo, Chang-Ying; Ye, Qi-Dong; Zhou, Min; Chen, Jing

2014-07-01

For the first time, we conducted a 2-center retrospective study to show the efficacy of antithymocyte globulin (ATG)-Fresenius S plus cyclosporine treatment of children with severe aplastic anemia. From March 1997 to May 2011, a total of 124 patients (median age, 7.5 y; range, 1.5 to 16 y) from 2 centers with acquired AA treated with an immunosuppressive therapy (IST) regimen, consisting of ATG-Fresenius S (5 mg/kg per day for 5 d) and cyclosporine, were enrolled. The response rate was 55.6%. The median time between IST and response was 6 (0.5 to 18) months. After a median follow-up time of 29 (6 to 153) months, the rates of relapse and clonal evolution were 3.2% and 0.8%, respectively. Overall, 17 patients (13.7%) died in this study: 14 resulted from sepsis, 1 resulted from intracranial hemorrhage, 1 occurred after hematopoietic stem cell transplantation, and 1 resulted from clonal disease progression. The 5-year overall survival rate for the entire cohort was 74.7%. IST responders had a better survival rate (100%) than nonresponders (70.7%). The use of ATG-Fresenius S plus cyclosporine as a first-line immunosuppressive treatment appeared to be effective for children with severe aplastic anemia in our study. ATG-Fresenius S could be another option in the treatment arsenal, especially in countries where the other ATG products are harder to acquire.

Cyclosporine: A Historical Perspective on Its Role in the Treatment of Noninfectious Uveitis.

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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.

HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension.

Science.gov (United States)

Niehof, Monika; Borlak, Jürgen

2011-01-27

Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear

HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension.

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Monika Niehof

Full Text Available Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS. In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII remain elusive. Notably, angiotensinogen (AGT is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1, angiotensin I converting enzyme (ACE, and angiotensin I converting enzyme 2 (ACE2 as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition

Induced expression of mRNA for IL-5, IL-6, TNF-alpha, MIP-2 and IFN-gamma in immunologically activated rat peritoneal mast cells: inhibition by dexamethasone and cyclosporin A.

Science.gov (United States)

Williams, C M; Coleman, J W

1995-10-01

We examined the capacity of purified rat peritoneal connective tissue-type mast cells (PMC) to express mRNA for several cytokines. Stimulation of PMC with anti-IgE for 4 hr induced the expression of mRNA encoding interleukin-5 (IL-5), IL-6, tumour necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-gamma). Unstimulated PMC expressed detectable mRNA for TNF-alpha but not for the other four cytokines. Incubation of PMC with cyclosporin A (CsA) or dexamethasone (DEX), each at 10(-6) M for 24 hr, significantly inhibited the induced expression of mRNA for each of the five cytokines, and also inhibited release of biologically active TNF-alpha. Throughout these experiments mRNA levels of the housekeeping gene G3PDH were not altered by stimulation with anti-IgE or incubation with CsA or DEX. We conclude that immunological activation of rat PMC induces gene expression of several cytokines and that expression of these genes can be inhibited by immunosuppressive drugs.

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....

The effect of cyclosporin-A on the oral microflora at gingival sulcus of the ferret.

Science.gov (United States)

Fischer, R G; Edwardsson, S; Klinge, B; Attström, R

1996-09-01

The effect of cyclosporin-A (CyA) on the dentogingival flora of ferrets with healthy and experimentally induced periodontal breakdown was studied. Five animals were given 10 mg/kg/d CyA. At the start of the experiments (day 0), ligatures were placed around 4 teeth in the right upper and lower jaws; corresponding contralateral teeth on the left side served as control. On days 0 and 28 (end of the experiment), microbiological samples were collected from the gingival sulcus of the experimental and the control teeth and from closely located gingival mucosa membrane. The samples were subjected to viable counts and to darkfield microscopic analyses. On day 0, facultative anaerobic rods, mainly Pasteurella spp, Alcaligenes spp, Corynebacterium spp. and Rothia spp dominated in the viable counts. No anaerobic bacteria were detected in the viable counts. On day 28 spirochetes increased in the experimental gingival sulcus samples and anaerobic bacteria appeared in most of the samples and constituted 40-60% of the total cultivable flora; Fusobacterium necrophorum and Eubacterium spp. predominated in the samples from the experimental sites. The results of the present study were compared with those of our previous investigation of ferrets not medicated with cyclosporin but also subject to experimental ligature periodontitis. Eubacterium spp. were absent in the animals not treated with cyclosporin, while this species was frequently present in the immunosuppressed ferrets. The results indicate that the presence of the large numbers of gram negative rods and of anaerobic bacteria may have enhanced the inflammatory process and further provoked the gingival overgrowth observed.

Relationship of serum magnesium levels and other metabolic indices in renal transplant recipients receiving cyclosporine

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Ahmadi F

2008-10-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Cyclosporine is one of the main immunosuppressors used for renal transplant recipients, and is given to prevent transplant rejection. Although the drug increases the survival of patients and grafted organs, it has some side effects independent of its effect on the immune system that are usually ignored. In this study, we evaluate the effect of cyclosporine on serum Mg levels and metabolic side effects in renal graft patients."n"n Methods: In this study, we followed 157 renal transplant recipients (62 females and 95 males who were being treated with cyclosporine at a private clinic to prevent transplant rejection. The patients were first physically examined and then blood samples were obtained in order to measure levels of cyclosporine, Mg, creatinine, fasting blood sugar, lipids, calcium, phosphorus, and uric acid levels. We then analyzed the data for correlations between serum Mg levels, cyclosporine and other metabolic complications."n"n Results: The mean levels of Mg and cyclosporine were 196±0.31mg/dl and 371±192 μg/dl, respectively. Hypomagnesemia was detected in 16 patients (10.2%.There was a significant negative correlation (p<0.05 between levels of Mg and cyclosporine levels (r=-0.53, serum

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

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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.

Chronic pyelonephritis: Modulation of host defenses by cyclosporin A

International Nuclear Information System (INIS)

Findon, G.; Miller, T.E.

1989-01-01

Chronic experimental pyelonephritis is characterized by a stable level of infection, which persists for many months. Administration of cyclosporin A (CsA) reactivated previously healed renal lesions and caused a marked increase in bacterial numbers in the kidney. Studies were then carried out to compare the effects of CsA, and the nonselective cytodepletive agents irradiation and cyclophosphamide, on both host defenses and the bacteriologic status of chronically infected kidneys. Two different responses were observed. In animals treated with CsA, bacterial numbers increased markedly, although circulating neutrophil numbers were relatively unaffected. This observation was in contrast to the severe ablation of leukocyte numbers and competence needed to achieve an equivalent effect when irradiation and cyclophosphamide were used. One possible explanation for the adverse effect of CsA on the host-parasite balance in chronic pyelonephritis is that CsA affects mediators that control the inflammatory response or induces a qualitative change in a critical cellular defense compartment

Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion.

Science.gov (United States)

Karn, Pankaj Ranjan; Kim, Hyun Do; Kang, Han; Sun, Bo Kyung; Jin, Su-Eon; Hwang, Sung-Joo

2014-01-01

The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the commercially available CsA emulsion (Restasis) for the treatment of dry eye syndrome in rabbits. Liposomes containing CsA were prepared by the supercritical fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF-EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis-treated, EPCS, and S100-treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the determination of CsA concentration in rabbit tears. After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis-treated group. The AUC₀₋₂₄ h for rabbit's tear film after the administration of SCF-S100 was 32.75±9.21 μg·h/mg which was significantly higher than that of 24.59±8.69 μg·h/mg reported with Restasis. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis. These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges associated with the treatment of dry eyes.

Hypomagnesemia and mild rhabdomyolysis in living related donor renal transplant recipient treated with cyclosporine A.

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Cavdar, C; Sifil, A; Sanli, E; Gülay, H; Camsari, T

1998-12-01

Since cyclosporine A (CsA) had been used in renal transplant recipients, important improvements in short-term and long-term graft survivals have been detected. In spite of these improvements CsA seems to have several adverse effects. First, CsA leads to nephrotoxicity. Moreover, CsA affects the other organs and systems (skin, liver, nervous system, etc.) and causes, increased risks of infections and malignancies. Hypomagnesemia is one of the side effects of CsA therapy, but it is a rare condition in living related donor renal transplant recipients. It may also cause multi-system dysfunction, especially hypocalcemia and hypokalemia, which cannot be corrected without magnesium therapy. In addition, rhabdomyolysis was detected in animals, but it has not been reported in living related donor renal transplant recipients. In this case report, a living related donor renal transplant recipient who suffered from hypomagnesemia and mild rhabdomyolysis due to CsA therapy will be described and discussed.

Protective Effect of Edaravone Against Cyclosporine-Induced Chronic Nephropathy Through Antioxidant and Nitric Oxide Modulating Pathways in Rats

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Elahe Sattarinezhad

2017-03-01

Full Text Available Background: Cyclosporine A (CsA is an immunosuppressant with therapeutic indications in various immunological diseases; however, its use is associated with chronic nephropathy. Oxidative stress has a crucial role in CsA-induced nephrotoxicity. The present study evaluates the protective effect of edaravone on CsA-induced chronic nephropathy and investigates its antioxidant and nitric oxide modulating property. Methods: Male Sprague-Dawley rats (n=66 were distributed into nine groups, including a control (group 1 (n=7. Eight groups received CsA (15 mg/kg for 28 days while being treated. The groups were categorized as: •\tGroup 2: Vehicle (n=10 •\tGroups 3, 4, and 5: Edaravone (1, 5, and 10 mg/kg (n=7 each •\tGroup 6: Diphenyliodonium chloride, a specific endothelial nitric oxide synthase (eNOS inhibitor (n=7 •\tGroup 7: Aminoguanidine, a specific inducible nitric oxide synthase (iNOS inhibitor (n=7 •\tGroup 8: Edaravone (10 mg/kg plus diphenyliodonium chloride (n=7 •\tGroup 9: Edaravone (10 mg/kg plus aminoguanidine (n=7 Blood urea nitrogen and serum creatinine levels, malondialdehyde, superoxide dismutase, and glutathione reductase enzyme activities were measured using standard kits. Renal histopathological evaluations and measurements of eNOS and iNOS gene expressions by RT-PCR were also performed. Data were analyzed using one-way analysis of variance (ANOVA followed by Tukey’s test (SPSS software version 18.0. Results: Edaravone (10 mg/kg significantly attenuated CsA-induced oxidative stress, renal dysfunction, and kidney tissue injury. Aminoguanidine improved the renoprotective effect of edaravone. Edaravone reduced the elevated mRNA level of iNOS, but could not alter the level of eNOS mRNA significantly. Conclusion: Edaravone protects against CsA-induced chronic nephropathy using antioxidant property and probably through inhibiting iNOS gene expression.

Effect of topical 0.05% cyclosporine A on corneal endothelium in patients with dry eye disease

OpenAIRE

Pérez-Rico, Consuelo; Germain, Francisco; Castro-Rebollo, María; Moreno-Salgueiro, Agustín; Teus, Miguel Ángel

2013-01-01

AIM:To determine the effect of topical 0.05% cyclosporine A (CsA) on corneal endothelium in patients with dry eye disease.METHODS: Observational, prospective, case series study. Fifty-five eyes of 29 consecutive patients (9 males and 20 females; median age:66.8 years, interquartile range:61-73.2 years) with moderate-severe dry eye disease were evaluated. All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day. The follow...

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

International Nuclear Information System (INIS)

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

1986-01-01

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

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

Science.gov (United States)

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

2013-01-01

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

Effect of pregnancy on cadmium-treated rats

Energy Technology Data Exchange (ETDEWEB)

Takizama, Y. (Akita Univ. School of Medicine, Japan); Nakamura, I.; Kurayama, R.; Hirasawa, F.; Kawai, K.

1982-01-01

It is well known that itai-itai disease with the osteopathy is broken out among multiparas, 40 years of age and up Japanese residents. In this paper we described an experimental study of effect of pregnancy on cadmium treated rats. Female mature rats were administered drinking water containing 50 and 200 ppm cadmium as CdCl/sub 2/. During 180 days of the experiment, three times of pregnancy were succesful, though slight depression of body weight gain was noticed in the 200 ppm group. The cadmium was accumulated in the kidneys, liver and bone proportionally to the amount of cadmium administered. No significant change was recognized in serum calcium, phosphorus and alkaline phosphatase levels after 180 days. Though cadmium 200 ppm treated rats showed slight histological lesions in the proximal convoluted tubules of the kidney, there appeared to be no osteomalacia including excess formation of osteoid tissue.

Clinical efficiency of cyclosporine in chronic idiopathic urticaria in adults

Directory of Open Access Journals (Sweden)

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

Uncaria rhynchophylla (miq) Jack plays a role in neuronal protection in kainic acid-treated rats.

Science.gov (United States)

Tang, Nou-Ying; Liu, Chung-Hsiang; Su, Shan-Yu; Jan, Ya-Min; Hsieh, Ching-Tou; Cheng, Chin-Yi; Shyu, Woei-Cherng; Hsieh, Ching-Liang

2010-01-01

Uncaria rhynchophylla (Miq) Jack (UR) is one of many Chinese herbs. Our previous studies have shown that UR has both anticonvulsive and free radical-scavenging activities in kainic acid (KA)-treated rats. The aim of the present study was to use the effect of UR on activated microglia, nitric oxide synthase, and apoptotic cells to investigate its function in neuroproction in KA-treated rats. UR of 1.0 or 0.5 g/kg was orally administered for 3 days (first day, second day, and 30 min prior to KA administration on the third day), or 10 mg/kg (intraperitoneal injection, i.p.) N-nitro-L-arginine methyl ester (L-NAME) 30 min prior to KA (2 microg/2 microl) was injected into the right hippocampus region of Sprague-Dawly rats. ED1 (mouse anti rat CD68), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) immunoreactive cells and apoptotic cells were observed in the hippocampus region. The results indicated that 1.0 g/kg, 0.5 g/kg of UR and 10 mg/kg of L-NAME reduced the counts of ED1, nNOS, iNOS immunoreactive cells and apoptotic cells in KA-treated rats. This study demonstrates that UR can reduce microglia activation, nNOS, iNOS and apoptosis, suggesting that UR plays a neuro-protective role against neuronal damage in KA-treated rats.

Biological response of rats fed with tofu treated with high hydrostatic pressure.

Science.gov (United States)

Préstamo, G; Arroyo, G

2000-10-01

Emerging technologies for food preservation have arisen in recent years, such as high-pressure (HP) hydrostatic treatment, and the biological response for this kind of food preservation is not well-known. Forty female rats (six weeks old) were used in the experiment to evaluate the biological effects of HP treatment of tofu. The animals were divided into groups that were fed with tofu (untreated), tofu treated with HP, and conventional food (as control) for 28 days. The glucose level, mineral content (calcium, potassium, zinc, and magnesium), shinbone maximum shear force, weight of the body, and weight of organs (heart, liver, spleen, and kidneys) were analyzed. The biological response for the rats was that significant differences were found in the calcium amount determined on the serum of the rats fed with untreated tofu and those fed with tofu treated with HP, and the calcium amount was lower on the rats fed with tofu treated with HP. Also, there were significant differences in the weight of the liver, and it was lower in the rats fed with tofu treated with HP. It was quite remarkable how the weight of the body and organs were smaller in the rats fed with tofu in comparison to the weight of the control rats. In the other components assayed no significant differences were found. HP produces a potential effect on tofu as it is observed in the rats response to the tofu treated with HP.

Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats.

Science.gov (United States)

Yu, Chung-Ping; Huang, Ching-Ya; Lin, Shiuan-Pey; Hou, Yu-Chi

2018-04-01

Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P-gp) and CYP3A4 in order to investigate the in vivo modulation effect of CR on P-gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repeated dosing of CR in a parallel design. Blood samples were collected at specific time points and the blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. The results showed that a single dose (1.0 g/kg) and the 7th dose (1.0 g/kg) of CR significantly decreased the C max of CSP by 56.9% and 70.4%, and reduced the AUC 0-540 by 56.4% and 68.7%, respectively. Cell study indicated that CR decoction, berberine, coptisine, palmatine all activated the efflux transport of P-gp. Ex-vivo study showed that the serum metabolites of CR activated CYP 3A4. In conclusion, through using CSP as an in vivo probe substrate, we have verified that oral intake of CR activated the functions of P-gp and CYP3A based on in vivo and in vitro studies. Copyright © 2017. Published by Elsevier B.V.

Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation.

Science.gov (United States)

Boynton, Grace E; Raoof, Duna; Niziol, Leslie M; Hussain, Munira; Mian, Shahzad I

2015-07-01

To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT). Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT. There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure. Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.

Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine.

Science.gov (United States)

Paine, Mary F; Widmer, Wilbur W; Pusek, Susan N; Beavers, Kimberly L; Criss, Anne B; Snyder, Jennifer; Watkins, Paul B

2008-04-01

We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by > or = 1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [3H]cyclosporine translocation in Caco-2 cells were then compared. The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P or = 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) x 10(-3) h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL(-1), respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7-8 h, respectively; P > or = 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [3H]cyclosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein.

CT and MRI findings of cyclosporine-related encephalopathy and hypertensive encephalopathy

International Nuclear Information System (INIS)

Yamamoto, Akira; Hayakawa, Katsumi; Houjyou, Makoto

2002-01-01

We present the MRI and CT findings of one child with cyclosporine-related encephalopathy, and one child with hypertensive encephalopathy following cyclosporine-related encephalopathy. The imaging findings were shown well on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images. Cyclosporine-related encephalopathy was distributed predominantly in the posterior white matter. Hypertensive encephalopathy showed similar changes of CT attenuation, but with wider distribution. These two disorders seem to have the same pathogenesis. (orig.)

Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence

Science.gov (United States)

Ames, Philip; Galor, Anat

2015-01-01

Dry eye has gained recognition as a public health problem given its high prevalence, morbidity and cost implications. Although dry eye is common and affects patients’ quality of life, only one medication, cyclosporine 0.05% emulsion, has been approved by the US FDA for its treatment. In this review, we summarize the basic science and clinical data regarding the use of cyclosporine in the treatment of dry eye. Randomized controlled trials showed that cyclosporine emulsion outperformed vehicles in the majority of trials, consistently decreasing corneal staining and increasing Schirmer scores. Symptom improvement was more variable, however, with ocular dryness shown to be the most consistently improved symptom over vehicle. PMID:25960865

Cyclosporine A induces senescence in renal tubular epithelial cells

NARCIS (Netherlands)

Jennings, Paul; Koppelstaetter, Christian; Aydin, Sonia; Abberger, Thomas; Wolf, Anna Maria; Mayer, Gert; Pfaller, Walter

The nephrotoxic potential of the widely used immunosuppressive agent cyclosporine A (CsA) is well recognized. However, the mechanism of renal tubular toxicity is not yet fully elucidated. Chronic CsA nephropathy and renal organ aging share some clinical features, such as renal fibrosis and tubular

Heart dysfunction and fibrosis in rat treated with myocardial ...

African Journals Online (AJOL)

Because cardiovascular disease remains a serious problem in modern human society, the aim of this study was to establish the rat model animal and to compare the heart dysfunction and fibrosis with SD and LE rats when treated with myocardial ischemia and reperfusion operation. A 20-minute thoracotomy was performed ...

76 FR 78815 - Oral Dosage Form New Animal Drugs; Cyclosporine

Science.gov (United States)

2011-12-20

..., Inc. The NADA provides for the veterinary prescription use of cyclosporine oral solution, USP.... FOR FURTHER INFORMATION CONTACT: Angela K.S. Clarke, Center for Veterinary Medicine (HFV-112), Food... (cyclosporine oral solution, USP (MODIFIED)) by veterinary prescription for the control of feline allergic...

Bioavailability in rats of bound residues from radishes treated with either radiolabeled dieldrin or carbofuran

International Nuclear Information System (INIS)

Khan, S.U.; Kacew, S.; Dupont, S.; Stratton, G.D. Jr.; Wheeler, W.B.

1987-01-01

The bioavailability of bound residues from radishes treated with [ 14 C]dieldrin and [ 14 C]carbofuran was investigated by feeding the rats 14 C material obtained after exhaustive solvent extraction. For comparison, nonextracted radishes were also fed to rats. The 14 C residues were predominantly excreted in feces. Urinary excretion of 14 C from rats fed nonextracted material was relatively greater than from those fed extracted radishes. The excreted material from rats fed dieldrin-treated radishes contained mainly parent compounds as residue. However, carbofuran and two of its metabolites, 3-hydroxycarbofuran and 3-ketocarbofuran, were present in feces and urine samples of rats fed carbofuran-treated radishes. These data demonstrated that bound residues in radishes treated with dieldrin and carbofuran have a low degree of bioavailability in rats. The results also show that bound residues in dieldrin-treated radishes would be more bioavailable than in the carbofuran-treated samples

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

International Nuclear Information System (INIS)

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 3 H- or 125 I-labeled cyclosporine ligand. The 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 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 125 I-RIA standard curve was linear to 1000 micrograms of cyclosporine per liter. Inter- and intra-assay CVs for 125 I-RIA measurements of cyclosporine were less than or equal to 7%. Evidently, the 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

Determination of rat vertebral bone compressive fatigue properties in untreated intact rats and zoledronic-acid-treated, ovariectomized rats

NARCIS (Netherlands)

Brouwers, J.E.M.; Ruchselman, M.; Rietbergen, van B.; Bouxsein, M.L.

2009-01-01

Summary Compressive fatigue properties of whole vertebrae, which may be clinically relevant for osteoporotic vertebral fractures, were determined in untreated, intact rats and zoledronic-acid-treated, ovariectomized rats. Typical fatigue behavior was found and was similar to that seen in other

Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double

DEFF Research Database (Denmark)

Møller-Bisgaard, S.; Ejbjerg, B. J.; Eshed, I.

2017-01-01

Objectives: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to i......Objectives: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients......, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect.Method: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated...

Effect of cyclosporine, tacrolimus and sirolimus on cellular senescence in renal epithelial cells.

Science.gov (United States)

Koppelstaetter, Christian; Kern, Georg; Leierer, Gisela; Mair, Sabine Maria; Mayer, Gert; Leierer, Johannes

2018-04-01

In transplantation medicine calcineurin inhibitors (CNI) still represent the backbone of immunosuppressive therapy. The nephrotoxic potential of the CNI Cyclosporine A (CsA) and Tacrolimus (FK506) is well recognized and CNI not only have been linked with toxicity, but also with cellular senescence which hinders parenchymal tissue regeneration and thus may prime kidneys for subsequent insults. To minimize pathological effects on kidney grafts, alternative immunosuppressive agents like mTOR inhibitors or the T-cell co-stimulation blocker Belatacept have been introduced. We compared the effects of CsA, FK506 and Sirolimus on the process of cellular senescence in different human renal tubule cell types (HK2, RPTEC). Telomere length (by real time PCR), DNA synthesis (by BrdU incorporation), cell viability (by Resazurin conversion), gene expression (by RT-PCR), protein (by western blotting), Immuncytochemistry and H 2 O 2 production (by Amplex Red® conversion) were evaluated. DNA synthesis was significantly reduced when cells were treated with cyclosporine but not with tacrolimus and sirolimus. Resazurin conversion was not altered by all three immunosuppressive agents. The gene expression as well as protein production of the cell cycle inhibitor p21 (CDKN1A) but not p16 (CDKN2A) was significantly induced by cyclosporine compared to the other two immunosuppressive agents when determined by western blotting an immuncytochemistry. Relative telomere length was reduced and hydrogen peroxide production increased after treatment with CsA but not with FK506 or sirolimus. In summary, renal tubule cells exposed to CsA show clear signs of cellular senescence where on the contrary the second calcineurin inhibitor FK506 and the mTOR inhibitor sirolimus are not involved in such mechanisms. Chronic renal allograft dysfunction could be in part triggered by cellular senescence induced by immunosuppressive medication and the choice of drug could therefore influence long term outcome

Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

International Nuclear Information System (INIS)

Nakajima, Y.; Lie, T.S.; Nakauo, H.; Nakagawa, K.; Segawa, M.

1984-01-01

Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by 51 Cr release assay

Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

Energy Technology Data Exchange (ETDEWEB)

Nakajima, Y; Lie, T S [Bonn Univ. (Germany, F.R.). Chirurgische Klinik und Poliklinik; Nakauo, H; Nakagawa, K; Segawa, M [Nara Women' s Univ. (Japan). Dept. of Physics

1984-01-01

Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by /sup 51/Cr release assay.

An analytical method for cyclosporine using liquid chromatography-mass spectrometry.

Science.gov (United States)

Kanduru, Srividya V; Somayaji, Vishwa; Lavasanifar, Afsaneh; Brocks, Dion R

2010-02-01

A liquid chromatographic mass spectrometric (LC-MS) assay has been developed for cyclosporine A (CyA) in rat plasma using amiodarone as internal standard (IS). Rat plasma (100 microL) containing drug and IS were extracted using liquid-liquid extraction with 4 mL of 95:5 ether:methanol. After evaporation of the organic layer the residue was reconstituted with 500 microL of water. Then the aqueous layer was transferred to LC-MS sample vials. A 10 microL volume was injected. The analysis was performed on a C(8) column 3.5 microm (2.1 x 50 mm) heated to 60 degrees C with a mobile phase consisting of acetonitrile:methanol:0.2% NH(4)OH (60:20:20) at an isocratic flow-rate of 0.2 mL/min. The ions used for quantitation of CyA and IS were m/z 1202.8 and 645.9, with retention times of 3.35 and 4.72 min, respectively. Linear relationships (r(2) > 0.99) were achieved between plasma or blood concentration and peak height ratios (drug:IS) over the concentration range 50-5000 ng/mL. The CV% and mean error were <19%. Based on validation data, the lower limit of quantification for the assay was 50 ng/mL. The reported assay method displayed high measures of linearity, sensitivity, reliability and precision, allowing its applicability in pharmacokinetic studies in rat. (c) 2009 John Wiley & Sons, Ltd.

Embryotoxicity of benzalkonium chloride in vaginally treated rats.

Science.gov (United States)

Buttar, H S

1985-12-01

The effects of the spermicide benzalkonium chloride (BKC) were studied on the conceptus of rat. Single doses (0, 25, 50, 100 or 200 mg kg-1) of aqueous solutions of BKC were administered intravaginally (1 ml kg-1) on gestational day 1. The vulval metallic clips, used to prevent leakage of the solution, were removed 24 h post-treatment. Fetuses were obtained and examined for malformations on day 21 of gestation. slight to copious amounts of vaginal discharge and vaginitis were noticed in rats treated with the two largest doses of BKC. A dose-related increase in resorptions and fetal death, reduction in litter size and weight were observed in BKC-treated dams. The conceptus loss seemed to occur both before and after implantation. BKC did not cause any discernible visceral malformations, although minor sternal defects occurred in fetuses exposed to 100 and 200 mg kg-1 of the spermicide. These results suggest that single vaginal application of BKC is embryo- and fetocidal in the rat at a dose about 143 times higher than that recommended for controlling conception in women.

Efeito imunossupressor da ciclosporina intra-muscular administrada em diferentes períodos pós-operatórios em um modelo de transplante penetrante de córnea em ratos Immunosuppressive effect of intramuscular cyclosporine used at different post-operative period on a penetrating keratoplasty model in the rat

Directory of Open Access Journals (Sweden)

Roberto von Hertwig

1999-12-01

Full Text Available Objetivo: Avaliar o efeito imunossupressor da ciclosporina intramuscular (I.M., administrada por tempo limitado em diferentes períodos do pós-operatório, no transplante penetrante de córnea em um modelo experimental em rato, por meio de avaliação clínica e anátomo-patológica do enxerto corneano. Método: Foram utilizados ratos isogênicos Fischer como doadores e Lewis como receptores, em um modelo ortotópico de transplante de córnea. A administração de ciclosporina I.M. 10 mg/kg/dia foi iniciada em diferentes períodos nos grupos estudados: no pós-operatório imediato, no 7º dia pós-operatório e no 9º dia pós-operatório. A ciclosporina quando iniciada foi administrada até o 30º dia pós-operatório. Um grupo controle não recebeu a ciclosporina I.M. Os enxertos corneanos foram avaliadas clínica e histologicamente. Resultados: Rejeição foi observada nas primeiras três semanas do pós-operatório em 100% dos casos no grupo controle (n = 5 que não recebeu a ciclosporina. Os ratos tratados com ciclosporina (n = 15 apresentaram rejeição em apenas um caso, que teve curta evolução e poucos sinais clínicos. Os estudos histológicos confirmaram as avaliações clínicas. O grupo controle apresentou infiltrado no enxerto corneal com predomínio de linfócitos sobre neutrófilos com mais neovasos, com mais fibrose e com infiltrado inflamatório mais intenso do que os grupos tratados com ciclosporina. Conclusão: Os dados obtidos indicam que a ciclosporina I.M., pode ter efeito benéfico sobre o controle da rejeição do transplante de córnea, mesmo na sua fase ativa.Purpose: Corneal graft rejection suppression after intramus-cular cyclosporine administration at different periods of time was studied on a penetrating keratoplasty rejection model in the rat. Methods: Inbred Lewis rats were used as recipients and Fischer rats were used as donors in a orthotopic rejection model of corneal transplantation. Intramuscular injection

Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging.

Science.gov (United States)

van Vliet, Erwin A; Otte, Willem M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

2016-01-01

The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced magnetic resonance imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis. Imaging was repeatedly performed until 6 weeks after kainic acid-induced status epilepticus in rapamycin (6 mg/kg for 6 weeks starting 4 h after SE) and vehicle-treated rats, using gadobutrol as contrast agent. Seizures were detected using video monitoring in the week following the last imaging session. Gadobutrol leakage was widespread and extensive in both rapamycin and vehicle-treated epileptic rats during the acute phase, with the piriform cortex and amygdala as the most affected regions. Gadobutrol leakage was higher in rapamycin-treated rats 4 and 8 days after status epilepticus compared to vehicle-treated rats. However, during the chronic epileptic phase, gadobutrol leakage was lower in rapamycin-treated epileptic rats along with a decreased seizure frequency. This was confirmed by local fluorescein staining in the brains of the same rats. Total brain volume was reduced by this rapamycin treatment regimen. The initial slow recovery of BBB function in rapamycin-treated epileptic rats indicates that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. The reduced BBB leakage during the chronic phase, however, could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Management of steroid resistant nephrotic syndrome in children with cyclosporine - a tertiary care centre experience

International Nuclear Information System (INIS)

Shah, S.S.H.; Akhtar, N.; Sunbleen, F.

2015-01-01

Objective: To observe the response and adverse effects of cyclosporine in combination with oral steroids for management of idiopathic steroid resistant nephrotic syndrome in pediatric patients. Methodology: It was an observational study conducted at Children Hospital, Lahore, Pakistan from March 2014 to June 2015. Forty normotensive patients of idiopathic steroid resistant nephrotic syndrome between one and twelve years of age with normal renal function were included in the study. Patients were prescribed cyclosporine with prednisolone and were followed to see the response and adverse effects of drugs. Results: Out of 40 patients, 20(50%) were males and 20(50%) females. Mesangioproliferative glomerulonephritis was found in 27(67.5%) patients followed by Focal segmental glomerulosclerosis in 9(22.5%) patients. Complete response was observed in 32(80%) children while partial response in 8(20%) patients at the end of six months. The most common adverse effects were cushingoid features seen in 26(65%) and cyclosporine related hypertrichosis in 34(85%). Conclusion: Management of idiopathic steroid resistant nephrotic syndrome in children with a combination of cyclosporine and prednisolone provided good results as response to treatment was seen in 80% patients. (author)

Cyclosporin in steroid- resistant nephrotic syndrome

African Journals Online (AJOL)

1994-11-11

Nov 11, 1994 ... steroid-unresponsive and alternative therapies therefore need to be assessed. ..... glomerular sclerosis. No vascular or tubular epithelial lesions ... acute tubular necrosis, and probable cyclosporin toxicity. No renal biopsy ...

Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results

Directory of Open Access Journals (Sweden)

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.

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

Reduced gluconeogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats

Energy Technology Data Exchange (ETDEWEB)

Gorski, J.R. (Kansas Univ., Kansas City, KS (USA). Dept. of Pharmacology, Toxicology and Therapeutics); Weber, L.W.D.; Rozman, K. (Kansas Univ., Kansas City, KS (USA). Dept. of Pharmacology, Toxicology and Therapeutics Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen (GSF), Neuherberg (Germany, F.R.). Inst. fuer Toxikologie)

1990-01-01

The effect of a usually lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 {mu}g/kg) was studied on the conversion of {sup 14}C-alanine into {sup 14}C-glucose in male Sprague-Dawley rats by established procedures (determination of plasma alanine and blood glucose by enzymatic assays and isolation of {sup 14}C-alanine and {sup 14}C-glucose from whole blood by column chromatography). TCDD-treated rats converted significantly (p < 0.05) less {sup 14}C-alanine into {sup 14}C-glucose than did their pair-fed or ad libitum-fed counterparts, indicating reduced gluconeogenesis as a result of TCDD treatment. This finding suggests that reduced gluconeogenesis in TCDD-treated rats contributed to the progressively developing, severe hypoglycemia observed in these animals. Corticosterone, a key hormone in gluconeogenesis, provides partial protection from TCDD-induced toxicity in hypophysectomized rats. Therefore, the conversion of {sup 14}C-alanine into {sup 14}C-glucose was also determined in hypophysectomized rats dosed with TCDD (125 {mu}g/kg) and given corticosterone (25 {mu}g/ml in drinking water). These rats also converted significantly (p < 0.05) less {sup 14}C-alanine into {sup 14}C-glucose than did their pair-fed counterparts. However, in contrast to non-hypophysectomized TCDD-treated rats, these rats maintained marginal normoglycemia even at 64 days after dosing with TCDD, which suggests that the partial protective effect of corticosterone in hypophysectomized, TCDD-treated rats is unrelated to its efffect on gluconeogenesis. The protection provided by corticosterone supplementation in TCDD toxicity is more likely due to reduced peripheral utilization of glucose enabling the animals to maintain marginal normoglycemia. (orig.).

Contribution to the study of calcium metabolism in rats treated with tetracycline

International Nuclear Information System (INIS)

Goncalves, M.R.B.

1980-01-01

The tetracycline is one of the most used antibiotics. The interferences in the rats calcium metabolism were studied. Sixteen rats, R dutch type were treated with a 1 mg/100 g of corporal weight, of tetracycline twice a day, for 23 days. In the twentieth day of the treatment, a dose of Calcium 45 was administrated to verify thhe decay curve of the radionuclide plasmatic concentration. A control group of 16 rats was studied to compare the results. A significative decrease of the calcemy and of bone reabsorption in the group treated with tetracycline were observed. (L.M.J.)

Altered Cyclosporine Absorption in a Patient with Ulcerative Colitis, Sclerosing Cholangitis and Pancreatic Insufficiency

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Mark G Swain

1991-01-01

Full Text Available Pancreatic insufficiency leading to altered cyclosporine absorption is reported in a 37-year-old man with ulcerative colitis and sclerosing cholangitis. Asymptomatic chronic pancreatitis occurs frequently in patients with ulcerative colitis, and even more commonly when there is coexistent sclerosing cholangitis. However, pancreatic insufficiency has been documented in only one patient previously with ulcerative colitis and sclerosing cholangitis. Pancreatic function testing can help to identify the complex etiology of malabsorption in these patients and is recommended in patients when liver transplantation is contemplated, as pancreatic insufficiency may alter the absorption of cyclosporine.

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study.

Science.gov (United States)

Schachtner, Thomas; Otto, Natalie M; Reinke, Petra

2018-06-03

Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side.

Serum testosterone concentration in chloroquine- treated rats ...

African Journals Online (AJOL)

ONOS

2010-07-05

Jul 5, 2010 ... The effects of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) were studied on serum testosterone ... chloroquine are probably mediated via the generation of free radicals. ... Effects of ascorbic acid and alpha-tocopherol on serum testosterone concentration in chloroquine-treated rats. Groups.

Working memory in bisphenol-A treated middle-aged ovariectomized rats.

Science.gov (United States)

Neese, Steven L; Bandara, Suren B; Schantz, Susan L

2013-01-01

Over 90% of the U.S. population has detectable bisphenol-A (BPA) in their urine according to recent biomonitoring data. BPA is best known for its estrogenic properties, and most rodent research on the nervous system effects of BPA has focused on determining if chronic exposures during pre- and perinatal development have organizational effects on brain development and behavior. Estrogens also have important impacts on brain and behavior during adulthood, particularly in females during aging, but the impact of BPA on the adult brain is less studied. We have published a series of studies documenting that chronic exposure to various estrogens including 17β-estradiol, ERβ selective SERMs and soy phytoestrogens impairs performance of middle-aged female rats on an operant working memory task. The purpose of this study was to determine if chronic oral exposure to BPA would alter working memory on this same task. Ovariectomized (OVX) middle-aged Long Evans rats were tested on an operant delayed spatial alternation (DSA) task. Rats were treated for 8-10 weeks with either a 0 (vehicle control), 5 or 50 μg/kg bw/day oral bolus of BPA. A subset of the vehicle control rats was implanted with a Silastic implant containing 17β-estradiol (low physiological range) to serve as a positive control. All rats were tested for 25 sessions on the DSA task. BPA treatment did not influence performance accuracy on the DSA task, whereas 17β-estradiol significantly impaired performance, as previously reported. The results of this study suggest that chronic oral exposure to BPA does not alter working memory processes of middle-aged OVX rats assessed by this operant DSA task. Copyright © 2013. Published by Elsevier Inc.

CYCLOSPORIN A IN THERAPY FOR JUVENILE ARTHRITIS

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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

Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway.

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Jin, Meihua; Lv, Pengfei; Chen, Guanyu; Wang, Peng; Zuo, Zhongfu; Ren, Lili; Bi, Jing; Yang, Chul-Woo; Mei, Xifan; Han, Donghe

2017-04-29

Klotho, an antiaging protein, can extend the lifespan and modulate cellular responses to inflammation and oxidative stress which can ameliorate chronic kidney diseases (CKD). To investigate the molecular mechanism of Klotho on inflammation in cyclosporine A (CsA) induced nephropathy, the mice were transfected with adenovirus mediated Klotho gene and treated with cyclosporine A (CsA; 30 mg/kg/day) for 4 weeks. Also, primary human renal proximal tubule epithelial cells (RPTECs) were treated with soluble Klotho protein and LPS. The results showed that Ad-klotho significantly reduced serum creatinine (Scr) and blood urea nitrogen (BUN) caused by CsA, and significantly increased creatinine clearance. Tubule interstitial fibrosis score (TIF), renal 8-OHdG excretion, macrophage infiltration and MCP-1 were decreased after Ad-klotho gene transfer. In addition, the overexpression of Klotho led to increase in the expression of PDLIM2, decreased in the amount of NF-kB p65, and inhibited the production of inflammatory cytokines (TNFα, IL-6, IL-12) and iNOS. Accordingly, in vitro results showed, Klotho enhanced PDLIM2 expression and reduced NF-kB p65 expression, while PDLIM2 siRNA could block the inhibitory effects of Klotho on expression of NF-kB p65. Secretion of inflammatory cytokines was also inhibited by Klotho treatment, and PDLIM2 siRNA hindered regulatory effects of Klotho on the cytokines. Real-time PCR and Luciferase assay showed that Klotho markedly increased expression of PDLIM2 mRNA and PDLIM2 reporter activity in a dose-dependent manner. These findings suggest that Klotho can modulate inflammation via PDLIM2/NF-kB p65 pathway in CsA-induced nephropathy. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term Morphine-treated Rats are more Sensitive to Antinociceptive Effect of Diclofenac than the Morphine-naive rats

OpenAIRE

Akbari, Esmaeil; Mirzaei, Ebrahim; Shahabi Majd, Naghi

2013-01-01

This study investigates the effectiveness of the antinociceptive effects of diclofenac, an NSAID, on the nociceptive behavior of morphine-treated rats on formalin test. Rats were treated with morphine-containing drinking water for twenty one days, which induced morphine dependence. The antinociceptive effects of 8, 16, and 32 mg/kg doses of diclofenac were then evaluated and compared with distilled water in a formalin-based model of pain. Diclofenac potentiated pain suppression in morphine-de...

Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study.

Science.gov (United States)

Kopylov, Uri; Papamichael, Konstantinos; Katsanos, Konstantinos; Waterman, Matti; Bar-Gil Shitrit, Ariella; Boysen, Trine; Portela, Francisco; Peixoto, Armando; Szilagyi, Andrew; Silva, Marco; Maconi, Giovanni; Har-Noy, Ofir; Bossuyt, Peter; Mantzaris, Gerassimos; Barreiro de Acosta, Manuel; Chaparro, Maria; Christodoulou, Dimitrios K; Eliakim, Rami; Rahier, Jean-Francois; Magro, Fernando; Drobne, David; Ferrante, Marc; Sonnenberg, Elena; Siegmund, Britte; Muls, Vinciane; Thurm, Tamara; Yanai, Henit; Dotan, Iris; Raine, Tim; Levin, Avi; Israeli, Eran; Ghalim, Fahd; Carbonnel, Franck; Vermeire, Severine; Ben-Horin, Shomron; Roblin, Xavier

2017-09-01

Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.

Efficacy of fish liver oil and propolis as neuroprotective agents in pilocarpine epileptic rats treated with valproate.

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Mannaa, Fathia; El-Shamy, Karima A; El-Shaikh, Kamal A; El-Kassaby, Mahitab

2011-09-01

To evaluate the action of fish liver oil and propolis in pilocarpine epileptic rats treated with the anticonvulsant drug valproate. Seven groups of rats were treated daily for six months: control; fish liver oil (0.4ml/kg b.w); propolis (50mg/kg b.w); pilocarpine-treated rats (epileptic control); epileptic rats treated with valproate (400mg/kg b.w); groups 6 and 7, epileptic rats treated with valproate plus fish liver oil or propolis. Pilocarpine administration caused a significant increase in hippocampal dopamine and serotonin levels accompanied with a significant decrease in their levels in serum. Lipid peroxidation level and LDH activity in hippocampus were significantly increased after pilocarpine treatment whereas Na(+)/K(+)-ATPase activity and total antioxidant capacity were significantly decreased compared to the controls. Animals treated with the combined treatments showed a significant improvement in tested parameters towards the normal values of the control. Fish liver oil and propolis when given in combination with valproate, neuroprotected against the neurophysiological disorders induced by pilocarpine epilepsy in rats. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Cyclosporine in the Management of Esophageal Lichen Planus

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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.

Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis

NARCIS (Netherlands)

Dijkmans, B. A.; Landewé, R. B.; van den Borne, B. E.; Breedveld, F. C.

1999-01-01

Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial

Efeitos da ciclosporina A e betametasona na toxocaríase murina experimental Effects of cyclosporin A or betamethasone on experimental murine toxocariasis

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Susana A. Zevallos Lescano

2004-02-01

Full Text Available Estudou-se o efeito de ciclosporina A ou betametasona em camundongos experimentalmente infectados por larvas de Toxocara canis administrados 15 dias antes ou 45 dias após infecção por esse ascarídeo. Nos animais infectados determinou-se a cinética da resposta humoral por IgG 60 e 90 dias após infecção por meio de pesquisa de anticorpos anti-Toxocara, utilizando teste imunoenzimático, em amostras de sangue obtidas por punção do plexo orbitário. No 90º dia após a infecção todos os animais sobreviventes foram sacrificados e submetidos a digestão ácida da carcaça, pulmões, fígado e cérebro para recuperação de larvas de Toxocara canis encistadas nesses órgãos. Observou-se retardo na produção de anticorpos IgG anti-Toxocara nos animais tratados com ciclosporina A ou betametasona 15 dias antes da infecção, além de aumento significativo na quantidade de larvas de Toxocara canis recuperadas no grupo de animais que foi tratado com ciclosporina A 15 dias antes da infecção pelo ascarídeo.The effects of administration of either cyclosporin A or betamethasone 15 days before or 45 days after experimental infection with Toxocara canis on mice had been studied. The dynamics of IgG antibody production, employing an enzyme-linked immunosorbent assay, was studied 60 and 90 days after mice infection by Toxocara canis. In the 90th day after infection all surviving mice were sacrificed and the tissue trapped larvae recovered by acid digestion in the muscles, lungs, liver and brain. A significative delay in the production of IgG antibodies anti-Toxocara was observed in all the mice treated with cyclosporin A or betamethasone 15 days before infection. On the other side, mice treated with cyclosporine 15 days before infection, but not with betamethasone, showed a significative higher number of trapped Toxocara canis larvae in the examined tissues.

Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension.

Science.gov (United States)

Bravo González, Roberto Carlos; Huwyler, Jörg; Walter, Isabelle; Mountfield, Richard; Bittner, Beate

2002-10-01

Oral bioavailability of the highly lipophilic and poorly water-soluble immunosuppressive agent cyclosporin A (CyA) in two different formulations was investigated in male Wistar rats. An aqueous microsuspension and a self-dispersing formulation composed of the surface-active ingredients Solutol HS 15:Labrafil M2125CS:oleic acid=7:2:1 (v/v/v) were administered to the animals at a dose level of 20 mg/kg. In order to calculate the absolute oral bioavailability, CyA was additionally administered intravenously at 10 mg/kg as microsuspension. It was found that the oral bioavailability of CyA in the Solutol HS 15-based formulation was twofold higher as compared to the microsuspension (69.9+/-2.8 vs. 35.7+/-3.3%, P=0.001). By contrast, the time to reach maximum plasma concentration (t(max)) and the terminal half-life (t(1/2)) did not differ significantly with the different formulations (t(max): 7.0+/-1.0 vs. 6.3+/-1.7 h; t(1/2): 20.5+/-2.9 vs. 16.7+/-4.7 h). In vitro solubility experiments demonstrated a marked increase in the aqueous solubility of CyA in the presence of the self-dispersing formulation as compared to the micronized powder alone (solubility after 120 min at 37 degrees C: 136 vs. 23.2 microg/ml in human gastric juice; 133 vs. 10.8 microg/ml in simulated intestinal juice). Most likely, the enhanced systemic exposure of CyA in the self-dispersing formulation was caused by improved solubility of CyA in the gastrointestinal fluids in the presence of the surface-active ingredients. Additional factors that may have contributed to increased oral bioavailability are inhibition of metabolism and/or transport processes as well as permeability enhancement by the co-administered excipients.

Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

Science.gov (United States)

Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

2014-01-01

Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

Cyclosporine Amicellar delivery system for dry eyes.

Science.gov (United States)

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

2016-01-01

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

Cyclosporine-A therapy-induced multiple bilateral breast and accessory axillary breast fibroadenomas: a case report

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Darwish Ahmed

2010-08-01

Full Text Available Abstract Introduction Breast adenoma is common. However, in the setting of post-transplantation immune suppression it may be expressed differently. Case presentation A 35-year-old Sudanese woman, with a history of renal transplantation two and half years prior to presentation, was on a single immune suppression therapy in the form of cyclosporine-A since the transplantation. During a regular follow-up visit, she was noticed to have gingival hypertrophy and bilateral breast and axillary swellings. She underwent successful surgical resection of the bilateral fibroadenomas. Conclusions Cyclosporine-A therapy post renal transplantation is associated with an increased incidence of benign breast changes as fibroadenoma. Regular follow-up and appropriate selection of immunosuppressant therapy are essential in the post transplantation management of these patients.

Management of a Dog with Poorly Regulated Diabetes Mellitus, Chronic Pancreatitis, and Suspected Atopy with Cyclosporine

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Jörg M. Steiner

2012-01-01

Full Text Available A 3-year-and-9-months old male neutered Bichon Frise was presented for a second opinion for diabetes mellitus, weight loss, pruritus, and loss of hair. During further work-up, the dog was diagnosed with uncontrolled diabetes mellitus and concurrent diagnoses of pancreatitis and atopy were also suspected. Multiple adjustments of insulin therapy did not improve control of diabetes mellitus. Also, a variety of different treatments failed to improve pruritus. The dog was seen by a veterinary dermatologist who further suspected atopy and started treatment with cyclosporine. Pruritus improved and coincidentally serum Spec cPL and fructosamine concentrations normalized after therapy, suggesting the possibility that cyclosporine may have controlled pancreatic inflammation and improved control of diabetes mellitus. This case report would suggest that further research into autoimmunity in dogs with chronic pancreatitis is warranted. Also, a controlled study is needed and in progress before the use of cyclosporine in dogs with chronic pancreatitis or a subgroup thereof can be advocated.

Curcumin administration suppress acetylcholinesterase gene expression in cadmium treated rats.

Science.gov (United States)

Akinyemi, Ayodele Jacob; Oboh, Ganiyu; Fadaka, Adewale Oluwaseun; Olatunji, Babawale Peter; Akomolafe, Seun

2017-09-01

Curcumin, the main polyphenolic component of turmeric (Curcuma longa) rhizomes have been reported to exert anticholinesterase potential with limited information on how they regulate acetylcholinesterase (AChE) gene expression. Hence, this study sought to evaluate the effect of curcumin on cerebral cortex acetylcholinesterase (AChE) activity and their mRNA gene expression level in cadmium (Cd)-treated rats. Furthermore, in vitro effect of different concentrations of curcumin (1-5μg/mL) on rat cerebral cortex AChE activity was assessed. Animals were divided into six groups (n=6): group 1 serve as control (without Cd) and receive saline/vehicle, group 2 receive saline plus curcumin at 25mg/kg, group 3 receive saline plus curcumin 50mg/kg, group 4 receive Cd plus vehicle, group 5 receive Cd plus curcumin at 25mg/kg and group 6 receive Cd plus curcumin at 50mg/kg. Rats received Cd (2.5mg/kg) and curcumin (25 and 50mg/kg, respectively) by oral gavage for 7days. Acetylcholinesterase activity was measured by Ellman's method and AChE expression was carried out by a quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) assay. We observed that acute administration of Cd increased acetylcholinesterase activity and in addition caused a significant (Pcurcumin inhibited AChE activity and alters AChE mRNA levels when compared to Cd-treated group. In addition, curcumin inhibits rat cerebral cortex AChE activity in vitro. In conclusion, curcumin exhibit anti-acetylcholinesterase activity and suppressed AChE mRNA gene expression level in Cd exposed rats, thus providing some biochemical and molecular evidence on the therapeutic effect of this turmeric-derived compound in treating neurological disorders including Alzheimer's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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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

Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats.

Science.gov (United States)

Kawaura, Kazuaki; Ogata, Yukino; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

2016-04-01

We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline α2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats. Copyright © 2016. Published by Elsevier B.V.

Administration of cyclosporine a (CyA) to rats from birth: increased mortality and NK activity

International Nuclear Information System (INIS)

Clancy, J. Jr.; Tseng, G.; Kodali, S.; Love, S.

1986-01-01

Neonatal DA and LEW rats received 15, 7.5, and 3.75 mg/Kg of CyA or saline subcutaneously 3x each week for 1-12 weeks. In animals receiving 15 and 7.5 mg/Kg a significant (p 51 Cr release from YAC-1 target cells. Also, SPL cells stained with propidium iodide from the 3.75 mg/Kg group demonstrated a 1.5-2x increase in cells within the S phase of their cell cycle by flow cytometry. Thus, prolonged administration of CyA may have selective enhancing effects on certain lymphoid compartments and subpopulations of neonatal rats as well as a selective toxic effects on neonatal rat development

Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression

DEFF Research Database (Denmark)

Hansen, Henning Piilgaard; Witgen, Brent Marvin; Rasmussen, Peter

2011-01-01

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca(2+), and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis...... and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO(2......), and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD...

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.

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

Science.gov (United States)

Stonecipher, Karl G; Chia, Jenny; Onyenwenyi, Ahunna; Villanueva, Linda; Hollander, David A

2013-01-01

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. 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. 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. 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.

Data on administration of cyclosporine, nicorandil, metoprolol on reperfusion related outcomes in ST-segment Elevation Myocardial Infarction treated with percutaneous coronary intervention

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Gianluca Campo

2017-10-01

Full Text Available Mortality and morbidity in patients with ST elevation myocardial infarction (STEMI treated with primary percutaneous coronary intervention (PCI are still high [1]. A huge amount of the myocardial damage is related to the mitochondrial events happening during reperfusion [2]. Several drugs directly and indirectly targeting mitochondria have been administered at the time of the PCI and their effect on fatal (all-cause mortality, cardiovascular (CV death and non fatal (hospital readmission for heart failure (HF outcomes have been tested showing conflicting results [3–16]. Data from 15 trials have been pooled with the aim to analyze the effect of drug administration versus placebo on outcome [17]. Subgroup analysis are here analyzed: considering only randomized clinical trial (RCT on cyclosporine or nicorandil [3–5,9–11], excluding a trial on metoprolol [12] and comparing trial with follow-up length <12 months versus those with longer follow-up [3–16]. This article describes data related article titled “Clinical Benefit of Drugs Targeting Mitochondrial Function as an Adjunct to Reperfusion in ST-segment Elevation Myocardial Infarction: a Meta-Analysis of Randomized Clinical Trials” [17].

Biodegradable in situ gelling system for subcutaneous administration of ellagic acid and ellagic acid loaded nanoparticles: evaluation of their antioxidant potential against cyclosporine induced nephrotoxicity in rats.

Science.gov (United States)

Sharma, G; Italia, J L; Sonaje, K; Tikoo, K; Ravi Kumar, M N V

2007-03-12

Ellagic acid (EA) is a potent antioxidant marketed as a nutritional supplement. Its pharmacological activity has been reported in wide variety of disease models; however its use has been limited owing to its poor biopharmaceutical properties, thereby poor bioavailability. The objective of the current study was to develop chitosan-glycerol phosphate (C-GP) in situ gelling system for sustained delivery of ellagic acid (EA) via subcutaneous route. EA was incorporated in the system employing propylene glycol (PG) and triethanolamine (TEA) as co-solvents; on the other hand EA loaded PLGA nanoparticles (np) were dispersed in the gelling system using water. These in situ gelling systems were thoroughly characterized for mechanical, rheological and swelling properties. These systems are liquid at room temperature and gels at 37 degrees C. The EA C-GP system showed an initial burst release in vitro with about 85% drug released in 12 h followed by a steady release till 160 h, on the other hand EA nanoparticles entrapped in the C-GP system displayed sustained release till 360 h. The histopathological analysis indicates the absence of inflammation on administration, suggesting that these formulations are safe during the studied period. Furthermore, the antioxidant potential of EA C-GP and EA np C-GP gels has been evaluated against cyclosporine induced nephrotoxicity in rats. The data indicates that formulations were effective against cyclosporine induced nephrotoxicity, where the EA C-GP gels showed activity at 10 times lower dose and the EA np C-GP gels at 150 times lower dose when compared to orally given EA. Formulating nanoparticles of EA and incorporating them in C-GP system results in 15 times lowering of dose in comparison EA C-GP gels which is quite significant. Together, these results indicate that the bioavailability of ellagic acid can be improved by subcutaneous formulations administered as simple EA or EA nps.

Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy.

Science.gov (United States)

Leruez, Stéphanie; Verny, Christophe; Bonneau, Dominique; Procaccio, Vincent; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Scherer, Clarisse; Prundean, Adriana; Orssaud, Christophe; Zanlonghi, Xavier; Rougier, Marie-Bénédicte; Tilikete, Caroline; Miléa, Dan

2018-02-17

Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes. Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected. Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy

Circumvention of cisplatin resistance in ovarian cancer by combination of cyclosporin A and low-intensity ultrasound.

Science.gov (United States)

Yu, Tinghe; Yang, Yan; Zhang, Jiao; He, Haining; Ren, Xueyi

2015-04-01

Cisplatin resistance is a challenge in the treatment of ovarian cancer. The aim of this study was to explore if ultrasound can overcome chemoresistance and enhance chemosensitization due to cyclosporin A. Ultrasound and/or cyclosporin A were employed to overcome cisplatin resistance in human ovarian cancer cell line COC1/DDP. Mechanisms were explored from the perspective of: DNA damage, intracellular platinum level, detoxification, and genes related to drug efflux and DNA repair. In vivo therapeutic efficacy was validated in a short-term model (subrenal cell-clot transplantation) in mice and the survival benefit was investigated in an orthotopic cancer model in mice using HO-8910PM cells. The findings were: (i) ultrasound enhanced the effect of cisplatin leading to a lower cell-survival rate (IC50 decreased from 3.19 to 0.35 μg/ml); (ii) ultrasound enhanced cisplatin via direct (increasing the intercellular level of active platinum) and indirect (decreasing the glutathione level, and expression of LRP and ERCC1 genes) mechanisms that intensified cisplatin-induced DNA damage, thus enhancing cell apoptosis and necrosis; (iii) cisplatin followed by ultrasound led to small tumor sizes in the short-term model without exacerbation of the systemic toxicity, and prolonged the survival times in the orthotopic model; and (iv) ultrasound synergized the sensitization due to cyclosporin A in vitro and in vivo. These data demonstrated that ultrasound combined with cyclosporin A overcame cisplatin resistance in ovarian cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

Kinetics and dynamics of cyclosporine A in three hepatic cell culture systems

NARCIS (Netherlands)

Bellwon, P; Truisi, G L; Bois, Frederic Y; Wilmes, A; Schmidt, T.; Savary, C C; Parmentier, C.C.; Hewitt, P.G.; Schmal, O; Josse, R.; Richert, L.; Guillouzo, A; Mueller, S O; Jennings, P; Testai, E; Dekant, W.

2015-01-01

In vitro experiments have a high potential to improve current chemical safety assessment and reduce the number of animals used. However, most studies conduct hazard assessment alone, largely ignoring exposure and kinetic parameters. Therefore, in this study the kinetics of cyclosporine A (CsA) and

CYCLOSPORINE A IN RHEUMATOID ARTHRITIS: CURRENT DATA

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Elena Lvovna Luchikhina

2009-01-01

Full Text Available Despite the advent of the new class of medications, such as gene engineering biologicals, the use of traditional essential anti-inflammatory drugs (EAID remains the most important method of pathogenetic therapy for rheumatoid arthritis (RA. Apart from methotrexate (MT that is the gold standard of treatment for RA, there are a number of other effective EAIDs, including cyclosporine A (CsA, Sandimmun. The review deals with the practical aspects of using CsA in RA. Particular emphasis is laid on the capacities of combined basic therapy with CsA and MT in early RA and on the use of CsA in patients with concomitant chronic viral diseases (including viral hepatitis C.

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

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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.

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

Science.gov (United States)

Stonecipher, Karl G; Chia, Jenny; Onyenwenyi, Ahunna; Villanueva, Linda; Hollander, David A

2013-01-01

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. PMID:24179335

Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study

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Jaehyun Bae

2016-03-01

Full Text Available BackgroundThe use of dipeptidyl peptidase-4 (DPP-4 inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes.MethodsSixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor.ResultsHbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin –0.38%±1.03%, sitagliptin –0.53%±0.95%, and linagliptin –1.40±1.34; P=0.016. Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62±81.70 ng/mL vs. –24.22±53.54 ng/mL, P=0.036. Cyclosporine trough levels were minimally changed in patients with linagliptin.ConclusionLinagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes.

Hydrophilic interaction chromatography-mass spectrometry for anionic metabolic profiling of urine from antibiotic-treated rats

NARCIS (Netherlands)

Kok, Miranda G M; Swann, Jonathan R; Wilson, Ian D; Somsen, Govert W; de Jong, Gerhardus J

Hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) was used for anionic metabolic profiling of urine from antibiotic-treated rats to study microbial-host co-metabolism. Rats were treated with the antibiotics penicillin G and streptomycin sulfate for four or eight days and compared

Hydrophilic interaction chromatography-mass spectrometry for anionic metabolic profiling of urine from antibiotic-treated rats

NARCIS (Netherlands)

Kok, Miranda G M; Swann, Jonathan R.; Wilson, Ian D.; Somsen, Govert W.; de Jong, Gerhardus J.

2014-01-01

Hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) was used for anionic metabolic profiling of urine from antibiotic-treated rats to study microbial-host co-metabolism. Rats were treated with the antibiotics penicillin G and streptomycin sulfate for four or eight days and compared

Glutamate co-transmission from developing medial nucleus of the trapezoid body - Lateral superior olive synapses is cochlear dependent in kanamycin-treated rats

Energy Technology Data Exchange (ETDEWEB)

Lee, Jae Ho [Institute of Tissue Regeneration Engineering (ITREN), Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Pradhan, Jonu [Department of Nanobio Medical Science, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Maskey, Dhiraj; Park, Ki Sup [Department of Anatomy, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Hong, Sung Hwa [Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul 135-710 (Korea, Republic of); Suh, Myung-Whan [Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Kim, Myeung Ju, E-mail: mjukim99@dankook.ac.kr [Department of Anatomy, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Ahn, Seung Cheol, E-mail: ansil67@hanmail.net [Department of Physiology, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of)

2011-02-11

Research highlights: {yields} Glutamate co-transmission is enhanced in kanamycin-treated rats. {yields} VGLUT3 expression is increased in kanamycin-treated rats. {yields} GlyR expression is decreased in kanamycin-treated rats. {yields} GlyR, VGLUT3 expression patterns are asymmetric in unilaterally cochlear ablated rat. -- Abstract: Cochlear dependency of glutamate co-transmission at the medial nucleus of the trapezoid body (MNTB) - the lateral superior olive (LSO) synapses was investigated using developing rats treated with high dose kanamycin. Rats were treated with kanamycin from postnatal day (P) 3 to P8. A scanning electron microscopic study on P9 demonstrated partial cochlear hair cell damage. A whole cell voltage clamp experiment demonstrated the increased glutamatergic portion of postsynaptic currents (PSCs) elicited by MNTB stimulation in P9-P11 kanamycin-treated rats. The enhanced VGLUT3 immunoreactivities (IRs) in kanamycin-treated rats and asymmetric VGLUT3 IRs in the LSO of unilaterally cochlear ablated rats supported the electrophysiologic data. Taken together, it is concluded that glutamate co-transmission is cochlear-dependent and enhanced glutamate co-transmission in kanamycin-treated rats is induced by partial cochlear damage.

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

Science.gov (United States)

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

2013-01-01

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

Characterization and in vitro release of cyclosporine-A from poly(D,L-lactide-co-glycolide implants obtained by solvent/extraction evaporation

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Juliana Barbosa Saliba

2012-01-01

Full Text Available Cyclosporine-A-loaded PLGA implants were developed intended for ocular route. Implants were prepared using solvent extraction/evaporation technique followed by casting of the cake into rods in a heated surface. XRD patterns showed that cyclosporine-A was completely incorporated into PLGA. FTIR and DSC results indicated alterations on drug molecular conformation aiming to reach the most stable thermodynamic conformation at polymer/drug interface. Implants provided controlled/sustained in vitro release of the drug. During the first 7 weeks, the drug release was controlled by the diffusion of the cyclosporine-A; and between 7-23 week period, the drug diffusion and degradation of PLGA controlled the drug release.

Effects of Gallic Acid and Cyclosporine A on Antioxidant Capacity and Cardiac Markers of Rat Isolated Heart After Ischemia/Reperfusion

Science.gov (United States)

Badavi, Mohammad; Sadeghi, Najmeh; Dianat, Mahin; Samarbafzadeh, Alireza

2014-01-01

Background: Myocardial infarction is one of the important causes of death during old ages. Gallic acid as an antioxidant or cyclosporine A (CsA) as inhibitor of mitochondrial permeability transition pore (mPTP) alone could prevent these complications to some extent, but their combination effect has not been investigated. Objectives: The aim of this study was to determine the combined effect of gallic acid and CsA on antioxidant capacity of isolated heart tissues during ischemia reperfusion. Materials and Methods: Eighty male Wistar rats were randomly assigned to different groups: sham, control (Ca, received saline, 1 mL/kg); 3 groups were pretreated with gallic acid (G1a: 7.5, G2a: 15, G3a: 30 mg/kg) for 10 days, and the other 3 groups were pretreated with gallic acid and received CsA (0.2 µM) for 10 minutes before induction of ischemia and during the first 10 minutes of reperfusion (G1b, G2b and G3b) and the last group received CsA alone (Cb). After 10 days of pretreatment, the heart was isolated and transferred to the Langendorff apparatus and exposed to 30 minutes ischemia followed by 60 minutes of reperfusion. After that cardiac markers and antioxidant enzymes were assessed in cardiac tissues. Results: Lactate dehydrogenase (LDH), Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activity increased and malondialdehyde (MDA) decreased in animals pretreated with gallic acid significantly. However, pretreatment with gallic acid followed by CsA during reperfusion improved the antioxidant capacity and cardiac marker enzymes and restored the lipid peroxidation more effective than gallic acid or CsA alone. Nevertheless, CsA did not change the cardiac marker enzymes significantly. Conclusions: Gallic acid and CsA combination improved antioxidant capacity and cell membrane integrity more than each one alone. Therefore, it can be a therapeutic approach to reduce the I/R injury. PMID:25068044

Effects of altered platelet number on pulmonary hypertension and platelet sequestration in monocrotaline pyrrole-treated rats

International Nuclear Information System (INIS)

White, S.M.; Wagner, J.G.; Roth, R.A.

1989-01-01

To study the role of platelets in monocrotaline pyrrole (MCTP)-induced pulmonary hypertension, pulmonary sequestration of 111In-labeled platelets in rats treated with MCTP and anti-rat platelet serum (PAS) was examined. Lung injury from a single, intravenous injection of MCTP (3.5 mg/kg) at Day 8 was evident as elevated lung weight and lavage fluid protein and lactate dehydrogenase activity. Additionally, right ventricular hypertrophy and elevated pulmonary arterial pressures (PAP) occurred. Treatment with PAS on Days 6-8 did not affect the lung injury but resulted in an attenuation of the pulmonary hypertensive response. Pulmonary platelet sequestration was also decreased in PAS-treated rats, yet the sequestration in the lungs of MCTP-treated rats that received PAS was significantly higher than that in the lungs of N,N-dimethylformamide (DMF) controls. MCTP-treated rats receiving control serum (CS) tended to sequester more 111In-labeled platelets than respective DMF controls, but this was not statistically significant. Blood platelet half-life was unaltered in rats receiving CS. When rats were treated similarly with MCTP and PAS and were killed at 18 days, the attenuation of the pulmonary hypertensive response previously described was not observed, and lung injury was more extensive than when CS was given. Apparently, platelet depletion delayed the development of the pulmonary hypertensive response. Supranormal platelet numbers produced by splenectomy did not affect MCTP-induced lung injury or the elevation in PAP. These results support the hypothesis that the development of MCTP-induced pulmonary hypertension is mediated in part by platelets

Evaluation of cyclosporine-sparing effects of polyunsaturated fatty acids in the treatment of canine atopic dermatitis.

Science.gov (United States)

Müller, M R; Linek, M; Löwenstein, C; Röthig, A; Doucette, K; Thorstensen, K; Mueller, R S

2016-04-01

A randomised, double-blinded, placebo-controlled multicentre trial was conducted in 36 dogs with atopic dermatitis to evaluate the cyclosporine-sparing effect of polyunsaturated fatty acids. Dogs were stable on their individual cyclosporine dosage and received either a mainly omega-3 fatty acid product with a minor omega-6 fatty acid fraction or placebo, orally for 12 weeks. Dogs were examined every 4 weeks and the Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) was determined by a clinician. Pruritus, quality of life, global condition and coat quality were scored by the owner. If the dog's CADESI-03 and/or pruritus score improved by at least 25% compared with the previous visit, the cyclosporine dosage was decreased by approximately 25%. If the scores deteriorated by at least 25%, the cyclosporine dosage was increased by the same percentage. The median daily cyclosporine dosage/kg bodyweight decreased in the active group from 4.1 mg to 2.6 mg and in the placebo group from 3.5 mg to 3.3 mg over the study period. The difference between the two groups was significant (P = 0.009). The improvement in median pruritus score from inclusion to completion was significantly greater in the active group than in the placebo group (P = 0.04). There was no significant difference in CADESI-03 changes between groups (P = 0.38). The results of this study indicate a cyclosporine-sparing effect of a mainly omega-3 fatty acid supplement in dogs with atopic dermatitis. Copyright © 2016. Published by Elsevier Ltd.

The clinical value of enzyme-multiplied immunoassay technique monitoring the plasma concentrations of cyclosporine A after renal transplantation

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Xiao-Hui Luo

2011-05-01

Full Text Available The feasibility and the clinical value of the enzyme-multiplied immunoassay technique (EMIT monitoring of blood concentrations of cyclosporine A (CsA in patients treated with CsA were investigated after kidney transplantation. The validation method was performed to the EMIT determination of CsA blood concentration, the CsA whole blood ‘trough concentrations (C0 of patients in different time periods after renal transplantation were monitored, and combined with the clinical complications, the statistical results were analyzed and compared. EMIT was precise, accurate and stable, also with a high quality control. The mean postoperative blood concentration of CsA was as follows: 12 months, (185.6 ± 28.1ng/mL. The toxic reaction rate of CsA blood concentration within the recommended therapeutic concentration was 14. 1%, significantly lower than that of the none-recommended dose group (37.2% (P < 0.05; the transplantation rejection rate was 4.4%, significantly lower than that of the none-recommended dose group (22.5% (P < 0.05. Using EMIT to monitor the blood concentration of CsA as the routine laboratory method is feasible, and is able to reduce the CsA toxicity and rejection significantly, leading to achieving the desired therapeutic effect. Keywords: enzyme-multiplied immunoassay technique, renal transplantation, cyclosporin A, blood concentration monitoring

Resistance to cyclosporin A derives from mutations in hepatitis C virus nonstructural proteins.

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Arai, Masaaki; Tsukiyama-Kohara, Kyoko; Takagi, Asako; Tobita, Yoshimi; Inoue, Kazuaki; Kohara, Michinori

2014-05-23

Cyclosporine A (CsA) is an immunosuppressive drug that targets cyclophilins, cellular cofactors that regulate the immune system. Replication of hepatitis C virus (HCV) is suppressed by CsA, but the molecular basis of this suppression is still not fully understood. To investigate this suppression, we cultured HCV replicon cells (Con1, HCV genotype 1b, FLR-N cell) in the presence of CsA and obtained nine CsA-resistant FLR-N cell lines. We determined full-length HCV sequences for all nine clones, and chose two (clones #6 and #7) of the nine clones that have high replication activity in the presence of CsA for further analysis. Both clones showed two consensus mutations, one in NS3 (T1280V) and the other in NS5A (D2292E). Characterization of various mutants indicated that the D2292E mutation conferred resistance to high concentrations of CsA (up to 2 μM). In addition, the missense mutation T1280V contributed to the recovery of colony formation activity. The effects of these mutations are also evident in two established HCV replicon cell lines-HCV-RMT ([1], genotype 1a) and JFH1 (genotype 2a). Moreover, three other missense mutations in NS5A-D2303H, S2362G, and E2414K-enhanced the resistance to CsA conferred by D2292E; these double or all quadruple mutants could resist approximately 8- to 25-fold higher concentrations of CsA than could wild-type Con1. These four mutations, either as single or combinations, also made Con1 strain resistant to two other cyclophilin inhibitors, N-methyl-4-isoleucine-cyclosporin (NIM811) or Debio-025. Interestingly, the changes in IC50 values that resulted from each of these mutations were the lowest in the Debio-025-treated cells, indicating its highest resistant activity against the adaptive mutation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Cyclosporine Amicellar delivery system for dry eyes

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

2016-01-01

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

Microarray analysis of thioacetamide-treated type 1 diabetic rats

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Devi, Sachin S.; Mehendale, Harihara M.

2006-01-01

It is well known that diabetes imparts high sensitivity to numerous hepatotoxicants. Previously, we have shown that a normally non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats due to inhibited tissue repair allowing progression of liver injury. On the other hand, DB rats exposed to 30 mg TA/kg exhibit delayed tissue repair and delayed recovery from injury. The objective of this study was to investigate the mechanism of impaired tissue repair and progression of liver injury in TA-treated DB rats by using cDNA microarray. Gene expression pattern was examined at 0, 6, and 12 h after TA challenge, and selected mechanistic leads from microarray experiments were confirmed by real-time RT-PCR and further investigated at protein level over the time course of 0 to 36 h after TA treatment. Diabetic condition itself increased gene expression of proteases and decreased gene expression of protease inhibitors. Administration of 300 mg TA/kg to DB rats further elevated gene expression of proteases and suppressed gene expression of protease inhibitors, explaining progression of liver injury in DB rats after TA treatment. Inhibited expression of genes involved in cell division cycle (cyclin D1, IGFBP-1, ras, E2F) was observed after exposure of DB rats to 300 mg TA/kg, explaining inhibited tissue repair in these rats. On the other hand, DB rats receiving 30 mg TA/kg exhibit delayed expression of genes involved in cell division cycle, explaining delayed tissue repair in these rats. In conclusion, impaired cyclin D1 signaling along with increased proteases and decreased protease inhibitors may explain impaired tissue repair that leads to progression of liver injury initiated by TA in DB rats

Evaluation of cyclosporine A eye penetration after administration of liposomal or conventional forms in animal model

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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.

Cyclosporine in the Management of Impetigo Herpetiformis: A Case Report and Review of the Literature

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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.

Novel function of glutathione transferase in rat liver mitochondrial membrane: Role for cytochrome c release from mitochondria

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Lee, Kang Kwang; Shimoji, Manami; Hossain, Quazi Sohel; Sunakawa, Hajime; Aniya, Yoko

2008-01-01

Microsomal glutathione transferase (MGST1) is activated by oxidative stress. Although MGST1 is found in mitochondrial membranes (mtMGST1), there is no information about the oxidative activation of mtMGST1. In the present study, we aimed to determine whether mtMGST1 also undergoes activation and about its function. When rats were treated with galactosamine/lipopolysaccharide (GalN/LPS), mtMGST1 activity was significantly increased, and the increased activity was reduced by the disulfide reducing agent dithiothreitol. In mitochondria from GalN/LPS-treated rats, disulfide-linked mtMGST1 dimer and mixed protein glutathione disulfides (glutathionylation) were detected. In addition, cytochrome c release from mitochondria isolated from GalN/LPS-treated rats was observed, and the release was inhibited by anti-MGST1 antibodies. Incubation of mitochondria from control rats with diamide and diamide plus GSH in vitro resulted in dimer- and mixed disulfide bond-mediated activation of mtMGST1, respectively. The activation of mtMGST1 by diamide plus GSH caused cytochrome c release from the mitochondria, and the release was prevented by treatment with anti-MGST1 antibodies. In addition, diamide plus GSH treatment caused mitochondrial swelling accompanied by cytochrome c release, which was inhibited by cyclosporin A (CsA) and bongkrekic acid (BKA), inhibitors of the mitochondrial permeability transition (MPT) pore. Furthermore, mtMGST1 activity was also inhibited by CsA and BKA. These results indicate that mtMGST1 is activated through mixed disulfide bond formation that contributes to cytochrome c release from mitochondria through the MPT pore

Mitochondrial Ca2+ influx and efflux rates in guinea pig cardiac mitochondria: low and high affinity effects of cyclosporine A.

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Wei, An-Chi; Liu, Ting; Cortassa, Sonia; Winslow, Raimond L; O'Rourke, Brian

2011-07-01

Ca(2+) plays a central role in energy supply and demand matching in cardiomyocytes by transmitting changes in excitation-contraction coupling to mitochondrial oxidative phosphorylation. Matrix Ca(2+) is controlled primarily by the mitochondrial Ca(2+) uniporter and the mitochondrial Na(+)/Ca(2+) exchanger, influencing NADH production through Ca(2+)-sensitive dehydrogenases in the Krebs cycle. In addition to the well-accepted role of the Ca(2+)-triggered mitochondrial permeability transition pore in cell death, it has been proposed that the permeability transition pore might also contribute to physiological mitochondrial Ca(2+) release. Here we selectively measure Ca(2+) influx rate through the mitochondrial Ca(2+) uniporter and Ca(2+) efflux rates through Na(+)-dependent and Na(+)-independent pathways in isolated guinea pig heart mitochondria in the presence or absence of inhibitors of mitochondrial Na(+)/Ca(2+) exchanger (CGP 37157) or the permeability transition pore (cyclosporine A). cyclosporine A suppressed the negative bioenergetic consequences (ΔΨ(m) loss, Ca(2+) release, NADH oxidation, swelling) of high extramitochondrial Ca(2+) additions, allowing mitochondria to tolerate total mitochondrial Ca(2+) loads of >400nmol/mg protein. For Ca(2+) pulses up to 15μM, Na(+)-independent Ca(2+) efflux through the permeability transition pore accounted for ~5% of the total Ca(2+) efflux rate compared to that mediated by the mitochondrial Na(+)/Ca(2+) exchanger (in 5mM Na(+)). Unexpectedly, we also observed that cyclosporine A inhibited mitochondrial Na(+)/Ca(2+) exchanger-mediated Ca(2+) efflux at higher concentrations (IC(50)=2μM) than those required to inhibit the permeability transition pore, with a maximal inhibition of ~40% at 10μM cyclosporine A, while having no effect on the mitochondrial Ca(2+) uniporter. The results suggest a possible alternative mechanism by which cyclosporine A could affect mitochondrial Ca(2+) load in cardiomyocytes, potentially

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

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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

Influence of Gamma Aminobutyric Acid on Some Biochemical Alterations in Irradiated and Streptozotocin Treated Rats

International Nuclear Information System (INIS)

Mohamed, A.S.M.

2015-01-01

The objective of this study was to evaluate the role of GABA on some metabolic complications in STZ-treated, γ- irradiated and STZ-treated-γ-irradiated rats. Animals sacrificed 3 weeks after the different treatments showed that the intraperitoneal administration of STZ (60 mg/Kg) to male albino Sprague Dawley rats induced hyperglycemia and insulin deficiency (DM type 1). While whole body γ-irradiation with 6 Gy using Cs-137 source provoked hyperglycemia, hyperinsulinaemia and insulin resistance (DM type 2) and whole body γ-irradiation of STZ-treated rats induced hyperglycemia, insulin deficiency and insulin resistance. Dyslipidemia (elevated triglycerides, total cholesterol and LDL-C and decreased HDL-C) was recorded in STZ-treated, γ-irradiated and STZ-treated-γ-irradiated rats. Oxidative stress evidenced by significant decreases of SOD, catalase and GSH-Px activities and significant increases of MDA and AOPP was recorded in pancreas, liver and kidney tissues. Oxidative stress in pancreatic tissues was associated with damage of islets of Langerhans and significant decreases of GABA level and GAD activity. Oxidative stress in liver was accompanied by significant elevation of serum ALT and AST activities. Oxidative stress in kidney tissues was associated with significant increases of urea and creatinine levels. The administration of GABA daily via gavages (200 mg/Kg/day) during 3 weeks to STZ-treated, γ-irradiated and STZ-treated-γ-irradiated rats rectified insulin, glucose and lipid levels, reduced oxidative stress in pancreatic tissues accompanied by regenerating pancreatic islets of Langerhans and elevation of GABA level and GAD activity. GABA reduced also oxidative stress in liver and kidney tissues accompanied by lower serum ALT and AST activities and urea and creatinine levels

Effects of Storage Temperature and Time on Stability of Serum Tacrolimus and Cyclosporine A Levels in Whole Blood by LC-MS/MS

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İbrahim Kaplan

2015-01-01

Full Text Available Tacrolimus and cyclosporine A are immunosuppressant drugs with narrow therapeutic windows. The aim of this study was to investigate the stability of tacrolimus and cyclosporin A levels in whole blood samples under different storage conditions. Whole blood samples were obtained from 15 patients receiving tacrolimus and 15 patients receiving cyclosporine A. Samples were immediately analyzed and then stored at different conditions (room temperature (24°C−26°C for 24 hours, +4°C for 24 and 48 hours, and −20°C for one month and then analyzed again. For tacrolimus, there was a significant difference between samples analyzed immediately and those kept 24 hours at room temperature (P=0.005 (percent change 32.89%. However, there were no significant differences between the other groups. For cyclosporine A, there was a significant difference between samples analyzed immediately and those kept 24 hours (P=0.003 (percent change 19.47% and 48 hours (P=0.002 (percent change 15.38% at +4°C and those kept 24 hours at room temperature (P=0.011 (percent change 9.71%. Samples of tacrolimus should be analyzed immediately or stored at either +4°C or −20°C, while samples of cyclosporine A should be analyzed immediately or stored at −20°C.

Influence of zinc on the biokinetics of Zn-65 and hepatic trace elements of ethanol treated rats

International Nuclear Information System (INIS)

Dhawan, D.K.; Pathak, A.; Pathak, R.; Mahmood, A.

2002-01-01

Influence of zinc on the biokinetics of 65 Zn and hepatic trace elements of ethanol treated rats. The effect of zinc on the biokinetics of 65 Zn in liver and whole body and its relation to the hepatic levels of different elements was evaluated in male wistar rats under alcoholic conditions. The rats were segregated into four treatment groups viz., normal control, ethanol treated, zinc treated and combined zinc+ethanol treated. Animals were fed 3ml of 30% ethanol orally daily and zinc in the form of zinc sulfate (ZnSo 4 7H 2 O) was administrated to rats at a dose level of 227mg/L mixed in their drinking water for a total duration of 2 months. Whole body counting studies indicated that the Tb 1 i.e., the faster elimination of the radiotracer. On the contrary, Tb 2 i.e., the slower component was increased significantly following ethanol treatment. Percent uptake values of 65 Zn were found to be increased in liver, intestine, muscle and kidney and decreased in bone under alcoholic conditions. A significant elevation was noticed in in vitro uptake 65 Zn in ethanol treated animals. In the above said conditions, the values were reverted back to within normal limits upon zinc supplementation to these ethanol intoxicated animals, except in the case of in vitro 65 Zn uptake in liver where the uptake was further increased upon combined treatment. A significant decrease in zinc contents was noticed in ethanol treated rats, which however were raised to normal levels upon zinc supplementation. Copper levels, on the other hand, were found to be significantly enhanced in both ethanol fed and combined ethanol+zinc supplemented animals. Calcium levels were found to e significantly decreased in both ethanol and zinc treated rats, which however were further reduced upon zinc supplementation to ethanol fed rats. However, no significant change was observed in the concentrations of sodium and potassium in any of the treatment groups. Therefore, zinc appears to play a protective role by

Effect of Ankaferd Blood Stopper on Skin Superoxide Dismutase and Catalase Activities in Warfarin-Treated Rats.

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Aktop, Sertaç; Emekli-Alturfan, Ebru; Gönül, Onur; Göçmen, Gökhan; Garip, Hasan; Yarat, Ayşen; Göker, Kamil

2017-03-01

Ankaferd Blood Stopper (ABS) is a new promising local hemostatic agent, and its mechanism on hemostasis has been shown by many studies. However, the effects of ABS on skin superoxide dismutase (SOD) and catalase (CAT) activities have not been investigated before. The aim of this study was to evaluate the effects of this new generation local hemostatic agent on warfarin-treated rats focusing on its the antioxidant potential in short-term soft tissue healing. Twelve systemically warfarin treated (warfarin group) and 12 none treated Wistar Albino rats (control group) were selected for the trial. Rats in the warfarin group were treated intraperitonally with 0.1 mg/kg warfarin, and rats in the control group were given 1 mL/kg saline 3 days earlier to surgical procedure and continued until killing. All rats had incisions on dorsal dermal tissue, which was applied ABS or no hemostatic agent before suturing. Six of each group were killed on day 4, and the other 6 were killed on day 8. Blood and skin samples were taken. Prothrombin time (PT) in blood samples, CAT, and SOD activities in skin samples were determined. Warfarin treatment dose was found to be convenient and warfarin treatment increased the PT levels as expected. Warfarin treatment decreased CAT activity significantly compared to the control group. The ABS treatment significantly increased SOD activities in the warfarin group at the end of the eighth day. Ankaferd Blood Stopper acted positively in short-term tissue healing by increasing SOD activity in warfarin-treated rats. Therefore, ABS may be suggeted as a promoting factor in tissue healing.

CD48-deficient T-lymphocytes from DMBA-treated rats have de novo mutations in the endogenous Pig-a gene.

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Dobrovolsky, Vasily N; Revollo, Javier; Pearce, Mason G; Pacheco-Martinez, M Monserrat; Lin, Haixia

2015-10-01

A major question concerning the scientific and regulatory acceptance of the rodent red blood cell-based Pig-a gene mutation assay is the extent to which mutants identified by their phenotype in the assay are caused by mutations in the Pig-a gene. In this study, we identified T-lymphocytes deficient for the glycosylphosphatidylinositol-anchored surface marker, CD48, in control and 7,12-dimethylbenz[a]anthracene (DMBA)-treated rats using a flow cytometric assay and determined the spectra of mutations in the endogenous Pig-a gene in these cells. CD48-deficient T-cells were seeded by sorting at one cell per well into 96-well plates, expanded into clones, and exons of their genomic Pig-a were sequenced. The majority (78%) of CD48-deficient T-cell clones from DMBA-treated rats had mutations in the Pig-a gene. The spectrum of DMBA-induced Pig-a mutations was dominated by mutations at A:T, with the mutated A being on the nontranscribed strand and A → T transversion being the most frequent change. The spectrum of Pig-a mutations in DMBA-treated rats was different from the spectrum of Pig-a mutations in N-ethyl-N-nitrosourea (ENU)-treated rats, but similar to the spectrum of DMBA mutations for another endogenous X-linked gene, Hprt. Only 15% of CD48-deficient mutants from control animals contained Pig-a mutations; T-cell biology may be responsible for a relatively large fraction of false Pig-a mutant lymphocytes in control animals. Among the verified mutants from control rats, the most common were frameshifts and deletions. The differences in the spectra of spontaneous, DMBA-, and ENU-induced Pig-a mutations suggest that the flow cytometric Pig-a assay detects de novo mutation in the endogenous Pig-a gene. © 2015 Wiley Periodicals, Inc.

Cyclosporine-related reversible posterior leukoencephalopathy: MRI

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Jarosz, J.M.; Howlett, D.C.; Cox, T.C.S.; Bingham, J.B.

1997-01-01

Three patients aged 48, 11 and 40 years, two of whom were recent recipients of renal transplants and one of a bone marrow transplant, developed seizures, with cortical blindness in two cases. All were immunosuppressed with cyclosporine and were hypertensive at the onset of symptoms. MRI showed predominantly posterior signal changes in all three cases. The abnormalities were more conspicuous on fast FLAIR images than on conventional T2-weighted spin-echo images. (orig.). With 4 figs

Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin

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Camerino, Giulia Maria; De Bellis, Michela; Conte, Elena; Liantonio, Antonella; Musaraj, Kejla; Cannone, Maria; Fonzino, Adriano; Giustino, Arcangela; De Luca, Annamaria; Romano, Rossella; Camerino, Claudia; Laghezza, Antonio; Loiodice, Fulvio; Desaphy, Jean-Francois; Conte Camerino, Diana; Pierno, Sabata

2016-01-01

Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4–5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly. - Highlights: • This work characterizes the causes of atorvastatin related myotoxicity in aged rats. • Skeletal muscle chloride channel ClC-1 is a target of statin-induced side effects. • ClC-1 dysfunction is worsened by aging process. • Age

Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin

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Camerino, Giulia Maria; De Bellis, Michela; Conte, Elena; Liantonio, Antonella; Musaraj, Kejla; Cannone, Maria; Fonzino, Adriano [Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari (Italy); Giustino, Arcangela [Department of Biomedical Sciences and Human Oncology, University of Bari - Aldo Moro, Medical School, Bari (Italy); De Luca, Annamaria; Romano, Rossella [Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari (Italy); Camerino, Claudia [Department of Medical Sciences, Neurosciences and Sense Organs, University of Bari - Aldo Moro, Bari (Italy); Laghezza, Antonio; Loiodice, Fulvio [Section of Medicinal Chemistry, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari (Italy); Desaphy, Jean-Francois [Department of Biomedical Sciences and Human Oncology, University of Bari - Aldo Moro, Medical School, Bari (Italy); Conte Camerino, Diana [Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari (Italy); Pierno, Sabata, E-mail: sabata.pierno@uniba.it [Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari (Italy)

2016-09-01

Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4–5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly. - Highlights: • This work characterizes the causes of atorvastatin related myotoxicity in aged rats. • Skeletal muscle chloride channel ClC-1 is a target of statin-induced side effects. • ClC-1 dysfunction is worsened by aging process. • Age

[Studies on transdermal delivery of ferulic acid through rat skin treated by microneedle arrays].

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Yang, Bing; Du, Shou-ying; Bai, Jie; Shang, Ke-xin; Lu, Yang; Li, Peng-yue

2014-12-01

In order to investigate the characteristics of transdermal delivery of ferulic acid under the treated of microneedle arrays and the influence on permeability of rat skin capillaries, improved Franz-cells were used in the transdermal delivery experiment with the rat skin of abdominal wall and the length of microneedle arrays, different insertion forces, retention time were studied in the influence of characteristics of transdermal delivery of FA. The amount of FA was determined by HPLC system. Intravenous injection Evans blue and FA was added after microneedle arrays treated. Established inflammation model was built by daubing dimethylbenzene. The amount of Evans blue in the rat skin was read at 590 nm wavelength with a Multiskan Go microplate reader. Compared with passive diffusion group the skin pretreated with microneedle arrays had a remarkable enhancement of FA transport (P Microneedle arrays with different length had a remarkable enhancement of FA transport, but was not related to the increase of the length. The research of FA on the reduce of permeability of rat skin capillaries indicated that the skin pretreated with microneedle arrays could reduce the content of Evans blue in the skins of rat significantly compared with the untreated group. The permeation rate of ferulic acid transdermal delivery had remarkable increase under the treated of microneedle arrays and the length of microneedle arrays ,the retention time so as to the insertion force were important to the transdermal delivery of ferulic acid.

The Histological, Histomorphometrical and Histochemical Changes of Testicular Tissue in the Metformin Treated and Untreated Streptozotocin-Induced Adult Diabetic Rats

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Davoud Kianifard

2011-03-01

Full Text Available In this investigation, diabetes was induced in adult male Sprague-Dawley rats by single intraperitoneal injection of streptozotocin (STZ at 45 mg kg-1 of body weight. A group comprised of 8 diabetic rats was treated with metformin at 100 mg kg-1 of body weight for reducing the elevated blood glucose level. The results revealed that, in the untreated diabetic rats, the body and testicular weight reduced in comparison with the control rats (P < 0.05 , the metformin treated diabetic rats showed body weight loss in comparison with the control group (P < 0.05. In the untreated diabetic rats, the blood glucose level significantly increased in comparison with control and metformin treated diabetic rats. Histomorphological examinations revealed a reduction in testicular capsule diameter, seminiferous tubules (STs and germinal epithelium height, increase of amorphous material of interstitial tissue, germ cell depletion, decrease in cellular population and activity and disruption of spermatogenesis in the untreated diabetic rats in comparison with control group. In metformin treated diabetic rats, the histomorphological alterations were seen in lesser part in comparison with untreated diabetic group. The results from this study proved that, there was a direct relationship between increased levels of blood glucose as a result of STZ-induced diabetes and the histomorphological changes of testicular tissue.

EFFICACY OF DIFFERENT IMMUNOSUPPRESSIVE PROTOCOLS WITH CYCLOSPORINE AND METHOTREXATE FOR PATIENTS WITH SYSTEMIC VARIANT OF JUVENILE RHEUMATOID ARTHRITIS

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E.I. Alexeeva

2007-01-01

Full Text Available The article provides information on efficiency of different protocols of therapy with cyclosporine and methotrexate for patients suffering from severe systemic juvenile rheumatoid arthritis (JRA. it shows that a therapy combining cyclosporine with dosage of 4,4 ± 0,58 mg/kg of body per day and methotrexate with dosage of 8,1 ± 1,07 mg/m2 a week is more efficient than monotherapy with each of the same medications of same dosage. Combined use of immunosuppressants induces remission of articular syndrome and constitutional manifestations, as well as provides normalization of laboratory disease activity indications in more than 50% of cases of long clasting systemic variant of JRA on the average a year after the initiation of treatment. Combining cyclosporine with methotrexat improves the curative action of each of the medications without aggravation of their toxic influence. High efficiency of combining cyclosporine with methotrexate makes enables lowering the dosage of glucocorticoids to be taken orally, as well as not prescribing prednisolone to the severe cases of systemic variant of JRA.Key words: juvenile rheumatoid arthritis, treatment, cyclosporine, methotrexate, combined therapy, children.

Protective Effect of Brazilian Propolis against Liver Damage with Cholestasis in Rats Treated with α-Naphthylisothiocyanate

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Tadashi Nakamura

2013-01-01

Full Text Available We examined the protective effect of Brazilian propolis against liver damage with cholestasis in rats treated with α-naphthylisothiocyanate (ANIT in comparison with that of vitamin E (VE. Rats orally received Brazilian propolis ethanol extract (BPEE (25, 50, or 100 mg/kg, VE (250 mg/kg or vehicle at 12 h after intraperitoneal injection of ANIT (75 mg/kg and were killed 24 h after the injection. Vehicle-treated rats showed liver cell damage and cholestasis, judging from the levels of serum marker enzymes and components. The vehicle group had increased serum total cholesterol, triglyceride, phospholipid, and lipid peroxide levels, increased hepatic lipid peroxide, reduced glutathione, and ascorbic acid levels and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. BPEE (50 mg/kg administered to ANIT-treated rats prevented liver cell damage and cholestasis and attenuated these serum and hepatic biochemical changes except hepatic ascorbic acid, although administered BPEE (25 or 100 mg/kg was less effective. VE administered to ANIT-treated rats prevented liver cell damage, but not cholestasis, and attenuated increased serum lipid peroxide level, increased hepatic lipid peroxide level and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. These results indicate that BPEE protects against ANIT-induced liver damage with cholestasis in rats more effectively than VE.

Hippocampal synapsin I, growth-associated protein-43, and microtubule-associated protein-2 immunoreactivity in learned helplessness rats and antidepressant-treated rats.

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Iwata, M; Shirayama, Y; Ishida, H; Kawahara, R

2006-09-01

Learned helplessness rats are thought to be an animal model of depression. To study the role of synapse plasticity in depression, we examined the effects of learned helplessness and antidepressant treatments on synapsin I (a marker of presynaptic terminals), growth-associated protein-43 (GAP-43; a marker of growth cones), and microtubule-associated protein-2 (MAP-2; a marker of dendrites) in the hippocampus by immunolabeling. (1) Learned helplessness rats showed significant increases in the expression of synapsin I two days after the attainment of learned helplessness, and significant decreases in the protein expression eight days after the achievement of learned helplessness. Subchronic treatment of naïve rats with imipramine or fluvoxamine significantly decreased the expression of synapsin I. (2) Learned helplessness increased the expression of GAP-43 two days and eight days after learned helplessness training. Subchronic treatment of naïve rats with fluvoxamine but not imipramine showed a tendency to decrease the expression of synapsin I. (3) Learned helplessness rats showed increased expression of MAP-2 eight days after the attainment of learned helplessness. Naïve rats subchronically treated with imipramine showed a tendency toward increased expression of MAP-2, but those treated with fluvoxamine did not. These results indicate that the neuroplasticity-related proteins synapsin I, GAP-43, and MAP-2 may play a role in the pathophysiology of depression and the mechanisms of antidepressants.

Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

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Ni, Cheng; Li, Zhengqian; Qian, Min; Zhou, Yang; Wang, Jun; Guo, Xiangyang, E-mail: puthmzk@163.com

2015-05-15

Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD. - Highlights: • Isoflurane induces hippocampal calcineurin activation. • Isoflurane induces hippocampal NFAT, especially NFATc4, nuclear import. • Cyclosporine A attenuates isoflurane induced aberrant calcineurin/NFAT signaling. • Cyclosporine A rescues isoflurane induced cognitive impairment. • Calcineurin/NFAT signaling is the upstream mechanism of isoflurane induced synaptic dysfunction and cognitive impairment.

Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

International Nuclear Information System (INIS)

Ni, Cheng; Li, Zhengqian; Qian, Min; Zhou, Yang; Wang, Jun; Guo, Xiangyang

2015-01-01

Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD. - Highlights: • Isoflurane induces hippocampal calcineurin activation. • Isoflurane induces hippocampal NFAT, especially NFATc4, nuclear import. • Cyclosporine A attenuates isoflurane induced aberrant calcineurin/NFAT signaling. • Cyclosporine A rescues isoflurane induced cognitive impairment. • Calcineurin/NFAT signaling is the upstream mechanism of isoflurane induced synaptic dysfunction and cognitive impairment

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

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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

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

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Sanders, J. Michael; Coulter, Sherry J.; Knudsen, Gabriel A.; Dunnick, June K.; Kissling, Grace E.; Birnbaum, Linda S.

2016-01-01

Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 h following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats. - Highlights: • Perturbation of estrogen homeostasis in TBBPA-treated female rats was investigated. • Gene expression changes were observed in the liver and uterus of these rats. • Genes associated with estrogen biosynthesis and metabolism were affected. • Genes associated with thyroid homeostasis and cell division/growth were affected. • A mechanism of uterine toxicity via endocrine disruption was indicated.

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

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Sanders, J. Michael, E-mail: sander10@mail.nih.gov [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Coulter, Sherry J.; Knudsen, Gabriel A. [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Dunnick, June K.; Kissling, Grace E. [National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Birnbaum, Linda S. [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)

2016-05-01

Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 h following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats. - Highlights: • Perturbation of estrogen homeostasis in TBBPA-treated female rats was investigated. • Gene expression changes were observed in the liver and uterus of these rats. • Genes associated with estrogen biosynthesis and metabolism were affected. • Genes associated with thyroid homeostasis and cell division/growth were affected. • A mechanism of uterine toxicity via endocrine disruption was indicated.

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.

Oxidative stress is reduced in Wistar rats exposed to smoke from tobacco and treated with specific broad-band pulse electromagnetic fields

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Bajić V.

2009-01-01

Full Text Available There have been a number of attempts to reduce the oxidative radical burden of tobacco. A recently patented technology, pulse electromagnetic technology, has been shown to induce differential action of treated tobacco products versus untreated products on the production of reactive oxygen species (ROS in vivo. In a 90-day respiratory toxicity study, Wistar rats were exposed to cigarette smoke from processed and unprocessed tobacco and biomarkers of oxidative stress were compared with pathohistological analysis of rat lungs. Superoxide dismutase (SOD activity was decreased in a dose-dependent manner to 81% in rats exposed to smoke from normal cigarettes compared to rats exposed to treated smoke or the control group. These results correspond to pathohistological analysis of rat lungs, in which those rats exposed to untreated smoke developed initial signs of emphysema, while rats exposed to treated smoke showed no pathology, as in the control group. The promise of inducing an improved health status in humans exposed to smoke from treated cigarettes merits further investigation.

Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies.

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Di Tommaso, Claudia; Bourges, Jean-Louis; Valamanesh, Fatemeh; Trubitsyn, Gregory; Torriglia, Alicia; Jeanny, Jean-Claude; Behar-Cohen, Francine; Gurny, Robert; Möller, Michael

2012-06-01

Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated

Locomotion and physical development in rats treated with ionizing radiation in utero

International Nuclear Information System (INIS)

Zaman, M.S.; Hupp, E.W.; Lancaster, F.E.

1993-01-01

Effects of ionizing radiation on the emergence of locomotor skill, and physical development were studied in laboratory rats (Fisher F-344 inbred strain). Rats were treated with 3 different doses of radiation (150 rad, 15 rad, and 6.8 rad) delivered on the 20th day of prenatal life. Results indicated that relatively moderate (15 rad) to high (150 rad) doses of radiation had effects on certain locomotion and physical development parameters. Exposure to 150 rad delayed pivoting, cliff-avoidance, upper jaw tooth eruption, and decreased body weights. Other parameters, such as negative geotaxis, eye opening, and lower jaw tooth eruption were marginally delayed in the 150 rad treated animals. Exposure to 15 rad delayed pivoting and cliff-avoidance

Self-assembling colloidal system for the ocular administration of cyclosporine A.

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Luschmann, Christoph; Tessmar, Joerg; Schoeberl, Simon; Strauß, Olaf; Luschmann, Karl; Goepferich, Achim

2014-01-01

In this study, we developed a self-assembling micellar system to deliver cyclosporine A (CsA) in an aqueous solution to the cornea. Two nonionic surfactants of the poly(ethylene glycol)-fatty alcohol ether type (Sympatens AS and Sympatens ACS) were characterized in terms of micelle size, shape, and charge, and their encapsulation efficiency for CsA. In an in situ single dose bioavailability study, the corneal CsA levels were determined in an enucleated porcine eye model. A commercial formulation and a 2% CsA olive oil solution served as references. Both surfactants formed spherical micelles with a size of 9 to 12 nm in water. A concentration as low as 0.3% (wt/vol) Sympatens AS was sufficient to entrap therapeutic levels of at least 0.1% (wt/vol) CsA. In the porcine in situ model, exceptionally high drug levels in the cornea were obtained for the micellar CsA solution (1557 ± 407 ngCsA/gcornea). They were significantly higher than those of Restasis (545 ± 137 ngCsA/gcornea) or the olive oil solution (452 ± 142 ngCsA/gcornea). In conclusion, we have shown a promising simple and efficient approach for the application of CsA in an aqueous solution to the cornea to treat inflammatory corneal diseases.

Impaired redox state and respiratory chain enzyme activities in the cerebellum of vitamin A-treated rats

International Nuclear Information System (INIS)

Oliveira, Marcos Roberto de; Fonseca Moreira, Jose Claudio

2008-01-01

Vitamin A is a micronutrient that participates in the maintenance of the mammalian cells homeostasis. However, excess of vitamin A, which may be achieved through increased intake of the vitamin either therapeutically or inadvertently, induces several deleterious effects in a wide range of mammalian cells, including neuronal cells. Vitamin A is a redox-active molecule, and it was previously demonstrated that it induces oxidative stress in several cell types. Therefore, in the present work, we investigated the effects of vitamin A supplementation at clinical doses (1000-9000 IU/(kg day)) on redox environment and respiratory chain activity in the adult rat cerebellum. Glutathione-S-transferase (GST) enzyme activity was also measured here. The animals were treated for 3, 7, or 28 days with vitamin A as retinol palmitate. We found increased levels of molecular markers of oxidative damage in the rat cerebellum in any period analyzed. Additionally, vitamin A supplementation impaired cerebellar mitochondrial electron transfer chain (METC) activity. GST enzyme activity was increased in the cerebellum of rats chronically treated with vitamin A. Based on our results and data previously published, we recommend more caution in prescribing vitamin A at high doses even clinically, since there is a growing concern regarding toxic effects associated to vitamin A intake

Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

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Chiasson, Valorie L; Bounds, Kelsey R; Chatterjee, Piyali; Manandhar, Lochana; Pakanati, Abhinandan R; Hernandez, Marcos; Aziz, Bilal; Mitchell, Brett M

2018-01-01

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. © 2017 American Heart Association, Inc.

Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder.

Science.gov (United States)

Modi, Hiren R; Ma, Kaizong; Chang, Lisa; Chen, Mei; Rapoport, Stanley I

2017-08-01

Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro. Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro. VCD like VPA will reduce brain AA turnover in unanaesthetized rats. A therapeutically relevant (50mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1- 14 C]AA in unanaesthetized rats for 10min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. VCD's ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD. Published by Elsevier B.V.

Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats.

Science.gov (United States)

Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly; Bailey, Adam; Lernmark, Ake; Osborne, William

2011-04-01

Obesity and type 2 diabetes (T2D) are two prevalent chronic diseases that have become a major public health concern in industrialized countries. T2D is characterized by hyperglycemia and islet beta cell dysfunction. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. Leptin receptor deficient male rats are obese and diabetic and provide a model of T2D. We hypothesized that their treatment by sustained expression of GLP-1 using encapsulated cells may prevent or delay diabetes onset. Vascular smooth muscle cells (VSMC) retrovirally transduced to secrete GLP-1 were seeded into TheraCyte(TM) encapsulation devices, implanted subcutaneously and rats were monitored for diabetes. Rats that received cell implants showed mean plasma GLP-1 level of 119.3 ± 10.2pM that was significantly elevated over control values of 32.4 ± 2.9pM (P<0.001). GLP-1 treated rats had mean insulin levels of 45.9 ± 2.3ng/ml that were significantly increased over control levels of 7.3±1.5ng/ml (P<0.001). In rats treated before diabetes onset elevations in blood glucose were delayed and rats treated after onset became normoglycemic and showed improved glucose tolerance tests. Untreated diabetic rats possess abnormal islet structures characterized by enlarged islets with α-cell infiltration and multifocal vacuolization. GLP-1 treatment induced normalization of islet structures including a mantle of α-cells and increased islet mass. These data suggest that encapsulated transduced cells may offer a potential long term treatment of patients. Copyright © 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Histological changes in kidneys of adult rats treated with Monosodium glutamate: A light microscopic study

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Singh BR, Ujwal Gajbe, Anil Kumar Reddy, Vandana Kumbhare

2015-01-01

Full Text Available Introduction: Monosodium Glutamate (MSG, which is chemically known as AJI-NO-MOTO also familiar as MSG in routine life. MSG is always considered to be a controversial food additive used in the world. It is a natural excitatory neurotransmitter, helps in transmitting the fast synaptic signals in one third of CNS. Liver and kidney play a crucial role in metabolism as well as elimination of MSG from the body. Present study is to detect structural changes in adult rat kidney tissue treated with MSG; observations are done with a light microscope. Materials & Methods: The study was conducted in the department of Anatomy, J.N.M.C, Sawangi (M Wardha. Thirty (30 adult Wistar rats (2-3 months old weighing about (200 ± 20g were used in the current study, animals were divided into three groups (Group – A, B, C. Group A: Control, Group B: 3 mg /gm body weight, Group C: 6 mg /gm body weight, MSG were administered orally daily for 45 days along with the regular diet. Observations & Results: The Mean values of animals weight at the end of experiment (46th day respectively were 251.2 ± 13, 244.4 ± 19.9 and 320 ± 31.1. Early degenerative changes like, Glomerular shrinkage (GSr, loss of brush border in proximal convoluted tubules and Cloudy degeneration was observed in sections of kidney treated with 3 mg/gm body weight of MSG. Animals treated with 6 mg/gm body weight of MSG showed rare changes like interstitial chronic inflammatory infiltrate with vacuolation in some of the glomeruli, and much glomerular shrinkage invaginated by fatty lobules. Conclusion: The effects of MSG on kidney tissues of adult rats revealed that the revelatory changes are directly proportional to the doses of MSG.

Treatment of psoriasis with cyclosporin | Nevin | South African ...

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South African Medical Journal. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 85, No 11 (1995) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Treatment of psoriasis with cyclosporin. R.J. Nevin, E.J. Schulz. Abstract.

The Lipid Lowering and Cardioprotective Effects of Vernonia calvoana Ethanol Extract in Acetaminophen-Treated Rats

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Godwin Eneji Egbung

2017-12-01

Full Text Available Background: Paracetamol overdose/abuse as a result of self-medication is a common occurrence amongst people living in low/middle income countries. The present study was designed to investigate the hypolipidemic and cardioprotective potentials of Vernonia calvoana (VC ethanol extract in acetaminophen (paracetamol-treated rats. Methods: Thirty-five Wistar rats weighing 100–150 g were randomly assigned into five groups of seven rats each. Groups 2–5 received high doses of paracetamol to induce liver damage, while group 1 was used as normal control. Afterwards, they were allowed to receive varying doses of VC (group 3 and 4 or vitamin E (group 5, whilst groups 1 and 2 were left untreated. The treatment period lasted for twenty one days after which sera were harvested and assayed for serum lipid indices using standard methods. Results: Groups 3 to 5 treated animals indicated significant decrease (p < 0.001 in low density lipoprotein cholesterol (LDL-c, total cholesterol (TC and triacylglycerol (TG levels relative to the normal and acetaminophen-treated controls, the atherogenic index showed a significant decrease (p < 0.001 in all treated groups compared with normal and acetaminophen-treated controls. However, the VC- and vitamin E-treated groups showed significant (p < 0.001 increase in high density lipoprotein cholesterol (HDL-C relative to the controls. Conclusions: Data from our study suggest that ethanol leaf extract of VC possesses probable hypolipidemic and cardioprotective effects.

Effect of ascorbic acid on thyroid functions and some biochemical activities in rats treated with cadmium chloride

International Nuclear Information System (INIS)

El-Sherbiny, E.M.; Osman, H.F.

2006-01-01

This study was carried out to investigate the role of oral administration of ascorbic acid (vitamin C) in rats at a dose level of 100 mg/kg body weight in reducing disturbances caused by cadmium at a dose level of 1.2 mg CdCl 2 /Kg body weight (1/4 LD 50 ). Cadmium treatment induced thyroid dysfunction and disturbance in blood count and some elements in sera of male rats. The rats were divided into four groups. The first group (I) of rats served as normal control, the second group (II) was treated with CdCl 2 , the third group (III) was treated with CdCl 2 followed by 2 weeks rehabilitation and the fourth one (IV) was treated with CdCl 2 followed by ascorbic acid treatment. Serum total T3, total T4, hemoglobin, red blood cell count, and hematocrit value, blood indices as well as white blood cell count, total serum calcium, phosphorus and alkaline phosphatase were evaluated in all rats.The results revealed that treatment with cadmium in groups II and III led to significant decreases in T3 and T4 levels and most of blood count parameters.In rats treated with ascorbic acid, a non-significant improvement in serum T3 level was obtained, whereas, serum T4 level was significantly increased and its level was reached around corresponding control value. Also, ascorbic acid treatment led to significant increases in Hb, RBCs, Hct, MCV, MCH and MCHC values, which were comparable to those obtained in control, whereas WBCs count was slightly improved in group (IV) in comparison with both groups treated with Cd but it was highly significantly decreased in both groups treated with Cd as compared to control. Serum total calcium and alkaline phosphatase activity were non-significantly decreased, whereas inorganic phosphorus concentrations was significantly decreased in groups III and IV as compared to control

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

OpenAIRE

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

1988-01-01

A new procedure for measuring cyclosporine in plasma has been introduced by Abbott Laboratories, involving their TDx instrumentation and fluorescence polarization immunoassay. Radioimmunoassay (RIA) and high-performance liquid chromatography are currently the conventional methods for measuring cyclosporine in plasma and whole blood. In an effort to find a method that will decrease the radioactive hazard, the reagent and supply cost, and the labor requirements associated with RIA procedures, w...

Analytical performance evaluation of the Elecsys® Cyclosporine and Elecsys® Tacrolimus assays on the cobas e411 analyzer

Directory of Open Access Journals (Sweden)

Maki Sasano

2017-08-01

Full Text Available Background: Cyclosporine (CsA and tacrolimus (TAC are immunosuppressant drugs that are often used to treat autoimmune diseases and as transplantation therapy; therefore, their concentrations need to be monitored carefully. We herein evaluated the analytical performance of the Elecsys® Cyclosporine and Elecsys® Tacrolimus assay kits, which have been newly developed to measure CsA and TAC concentrations in the whole blood. Methods: We used residual whole blood samples from autoimmune disease and transplantation patients who were being treated with CsA or TAC. CsA concentrations were measured using an affinity chrome-mediated immunoassay (ACMIA and an electrochemiluminescence immunoassay (ECLIA. TAC concentrations were measured using a chemiluminescence immunoassay (CLIA and ECLIA. We investigated assay precision, linearity, lower limit of quantitation (LOQ, stability of calibration, influence of interference substances and the hematocrit, correlation of ACMIA with ECLIA, and correlation of CLIA with ECLIA. Results: Within-assay coefficients of variation were 1.8−3.6% (CsA: 94−1238 ng/mL and 2.9−3.9% (TAC: 2.1−17.8 ng/mL, whereas day-to-day coefficients of variation ranged between 3.0−4.1% (CsA and 2.8−3.9% (TAC. The limits of quantitation were defined as the concentration at which the CV was approximately 10%. Each lower LOQ obtained was 16 ng/mL (CsA, and 0.95 ng/mL (TAC. CsA and TAC calibrations were stable for at least 21 days. Neither the presence of conjugated bilirubin, unconjugated bilirubin, chyle, and rheumatoid factor nor the hematocrit affected these assays. A method comparison using a standardized major axis regression analysis of ACMIA and ECLIA was r=0.995, y=0.924x −1.175, n=200 (CsA, while that of CLIA and ECLIA was r=0.994, y=1.080x −0.197, n=200 (TAC. Conclusions: The analytical performances of the Elecsys® Cyclosporine and Elecsys®Tacrolimus assays were acceptable

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...

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: Size does not matter

International Nuclear Information System (INIS)

Venkatpurwar, V.P.; Rhodes, S.; Oien, K.A.; Elliott, M.A.; Tekwe, C.D.; Jørgensen, H.G.; Kumar, M.N.V. Ravi

2015-01-01

Highlights: • The particulate delivery allows an increase in dose range without accrual of toxicities. • The altered haematological and biochemical changes are drug, but not particle dependent. • PLGA nano/microparticles are safe on subacute peroral dosing over 28 days. • Nano-toxicology, drug needs to be considered. - Abstract: Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral ® 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is

Using bosentan to treat paraquat poisoning-induced acute lung injury in rats.

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Zhongchen Zhang

Full Text Available BACKGROUND: Paraquat poisoning is well known for causing multiple organ function failure (MODS and high mortality. Acute lung injury and advanced pulmonary fibrosis are the most serious complications. Bosentan is a dual endothelin receptor antagonist. It plays an important role in treating PF. There is no related literature on the use of bosentan therapy for paraquat poisoning. OBJECTIVE: To study the use of bosentan to treat acute lung injury and pulmonary fibrosis as induced by paraquat. METHOD: A total of 120 adult Wister male rats were randomly assigned to three groups: the paraquat poisoning group (rats were intragastrically administered with paraquat at 50 mg/kg body weight once at the beginning; the bosentan therapy group (rats were administered bosentan at 100 mg/kg body weight by intragastric administration half an hour after paraquat was administered, then the same dose was administered once a day; and a control group (rats were administered intragastric physiological saline. On the 3rd, 7th, 14th, and 21st days following paraquat exposure, rats were sacrificed, and samples of lung tissue and venous blood were collected. The levels of transforming growth factor-β1 (TGF-β1, endothelin-1 (ET-1, and hydroxyproline (HYP in the plasma and lung homogenate were determined. Optical and electronic microscopes were used to examine pathological changes. RESULT: The TGF-β1, ET-1, and HYP of the paraquat poisoning group were significantly higher than in the control group, and they were significantly lower in the 21st day therapy group than in the paraquat poisoning group on the same day. Under the optical and electronic microscopes, lung tissue damage was observed to be more severe but was then reduced after bosentan was administered. CONCLUSION: Bosentan can reduce inflammation factor release. It has a therapeutic effect on acute lung injury as induced by paraquat.

treated rats

African Journals Online (AJOL)

aghomotsegin

2014-01-08

Jan 8, 2014 ... nucleus, bizarre segmentation; (I) shows hypersegmentation, bizarre segmentation of neutrophils in the shape of ring nucleus with polychromatophilic RBCs. 1998; Muller and Tobin, 1980). The current study shows that rats administered C. edulis hydro-ethanol extract, orally for 28 days, developed anemia, ...

Insular neural system controls decision-making in healthy and methamphetamine-treated rats.

Science.gov (United States)

Mizoguchi, Hiroyuki; Katahira, Kentaro; Inutsuka, Ayumu; Fukumoto, Kazuya; Nakamura, Akihiro; Wang, Tian; Nagai, Taku; Sato, Jun; Sawada, Makoto; Ohira, Hideki; Yamanaka, Akihiro; Yamada, Kiyofumi

2015-07-21

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

Supplementation of Citrus maxima Peel Powder Prevented Oxidative Stress, Fibrosis, and Hepatic Damage in Carbon Tetrachloride (CCl4) Treated Rats.

Science.gov (United States)

Chowdhury, Mohammed Riaz Hasan; Sagor, Md Abu Taher; Tabassum, Nabila; Potol, Md Abdullah; Hossain, Hemayet; Alam, Md Ashraful

2015-01-01

Citrus maxima peel is rich in natural phenolic compounds and has a long use in the traditional medicine. HPLC-DAD analysis on Citrus maxima peel powder exhibited the presence of various phenolic compounds such as caffeic acid and (-)-epicatechin. To determine the plausible hepatoprotective activity of Citrus maxima peel powder, we used carbon tetrachloride (CCl4) treated rat model. Liver damage in rats was confirmed by measuring the AST, ALT, and ALP enzyme activities. In addition, lipid peroxidation products (MDA), nitric oxide, advanced protein oxidation products level (APOP), and catalase activities were also analyzed along with the histological profiling for the inflammatory cell infiltration, collagen, and iron deposition in liver. Dietary supplementation of Citrus maxima peel powder exhibited significant reduction of serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. Moreover, Citrus maxima peel powder also showed a significant reduction of the oxidative stress markers (MDA, NO, and APOP level) and restored the catalase activity in CCl4 treated rats. Histological examination of the liver section revealed reduced inflammatory cells infiltration, collagen, and iron deposition in CCl4 treated rats. The results from this study demonstrated that Citrus maxima peel powder produced significant hepatoprotective action in CCl4 administered rats.

Supplementation of Citrus maxima Peel Powder Prevented Oxidative Stress, Fibrosis, and Hepatic Damage in Carbon Tetrachloride (CCl4 Treated Rats

Directory of Open Access Journals (Sweden)

Mohammed Riaz Hasan Chowdhury

2015-01-01

Full Text Available Citrus maxima peel is rich in natural phenolic compounds and has a long use in the traditional medicine. HPLC-DAD analysis on Citrus maxima peel powder exhibited the presence of various phenolic compounds such as caffeic acid and (−-epicatechin. To determine the plausible hepatoprotective activity of Citrus maxima peel powder, we used carbon tetrachloride (CCl4 treated rat model. Liver damage in rats was confirmed by measuring the AST, ALT, and ALP enzyme activities. In addition, lipid peroxidation products (MDA, nitric oxide, advanced protein oxidation products level (APOP, and catalase activities were also analyzed along with the histological profiling for the inflammatory cell infiltration, collagen, and iron deposition in liver. Dietary supplementation of Citrus maxima peel powder exhibited significant reduction of serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. Moreover, Citrus maxima peel powder also showed a significant reduction of the oxidative stress markers (MDA, NO, and APOP level and restored the catalase activity in CCl4 treated rats. Histological examination of the liver section revealed reduced inflammatory cells infiltration, collagen, and iron deposition in CCl4 treated rats. The results from this study demonstrated that Citrus maxima peel powder produced significant hepatoprotective action in CCl4 administered rats.

Prolonged skin graft survival by administration of anti-CD80 monoclonal antibody with cyclosporin A

NARCIS (Netherlands)

Ossevoort, MA; Lorre, K; Boon, L; van den Hout, Y; de Boer, M; De Waele, P; Jonker, M; VandeVoorde, A

Costimulation via the B7/CD28 pathway is an important signal for the activation of T cells. Maximal inhibition of T-cell activation and the induction of alloantigen-specific nonresponsiveness in vitro was achieved using anti-CD80 monoclonal antibody (mAb) in combination with cyclosporin A (CsA).

Anthriscus nemorosa essential oil inhalation prevents memory impairment, anxiety and depression in scopolamine-treated rats.

Science.gov (United States)

Bagci, Eyup; Aydin, Emel; Ungureanu, Eugen; Hritcu, Lucian

2016-12-01

Anthriscus nemorosa (Bieb.) Sprengel is used for medicinal purposes in traditional medicine around the world, including Turkey. Ethnobotanical studies suggest that Anthriscus essential oil could improve memory in Alzheimer's disease. The current study was hypothesized to investigate the beneficial effects of inhaled Anthriscus nemorosa essential oil on memory, anxiety and depression in scopolamine-treated rats. Anthriscus nemorosa essential oil was administered by inhalation in the doses of 1% and 3% for 21 continuous days and scopolamine (0.7mg/kg) was injected intraperitoneally 30min before the behavioral testing. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by elevated plus-maze and forced swimming tests. As expected, the scopolamine alone-treated rats exhibited the following: decrease the percentage of the spontaneous alternation in Y-maze test, increase the number of working and reference memory errors in radial arm-maze test, decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. However, dual scopolamine and Anthriscus nemorosa essential oil-treated rats showed significant improvement of memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. These results suggest that Anthriscus nemorosa essential oil inhalation can prevent scopolamine-induced memory impairment, anxiety and depression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effects of cyclosporine A pretreatment of deceased organ donors on kidney graft function (Cis-A-rein): study protocol for a randomized controlled trial.

Science.gov (United States)

Orban, Jean-Christophe; Fontaine, Eric; Cassuto, Elisabeth; Baumstarck, Karine; Leone, Marc; Constantin, Jean-Michel; Ichai, Carole

2018-04-17

Renal transplantation represents the treatment of choice of end-stage kidney disease. Delayed graft function (DGF) remains the most frequent complication after this procedure, reaching more than 30%. Its prevention is essential as it impedes early- and long-term prognosis of transplantation. Numerous pharmacological interventions aiming to prevent ischemia-reperfusion injuries failed to reduce the rate of DGF. We hypothesize that cyclosporine as an early preconditioning procedure in donors would be associated with decreased DGF. The Cis-A-rein study is an investigator-initiated, prospective, multicenter, double-blind, randomized, controlled study performed to assess the effects of a donor preconditioning with cyclosporine A on kidney grafts function in transplanted patients. After randomization, a brain dead donor will receive 2.5 mg kg -1 of cyclosporine A or the same volume of 5% glucose solution. The primary objective is to compare the rate of DGF, defined as the need for at least one dialysis session within the 7 days following transplantation, between both groups. The secondary objectives include rate of slow graft function, mild and severe DGF, urine output and serum creatinine during the first week after transplantation, rate of primary graft dysfunction, renal function and mortality at 1 year. The sample size (n = 648) was determined to obtain 80% power to detect a 10% difference for rate of DGF at day 7 between the two groups (30% of the patients in the placebo group and 20% of the patients in the intervention group). Delayed graft function is a major issue after renal transplantation, impeding long-term prognosis. Cyclosporine A pretreatment in deceased donors could improve the outcome of patients after renal transplantation. ClinicalTrials.gov, ID: NCT02907554 Registered on 20 September 2016.

The efficacy of cyclosporine A in cats with presumed atopic dermatitis: a double blind, randomised prednisolone-controlled study.

Science.gov (United States)

Wisselink, Marinus A; Willemse, Ton

2009-04-01

The objective of this study was to compare the efficacy of cyclosporine A (CsA) and prednisolone in feline atopic dermatitis (AD) in a randomised, controlled double blind study. Twenty-nine cats with feline AD were randomly allocated to two groups. Eleven cats were treated orally with prednisolone (1mg/kg SID) and 18 were treated with CsA (5mg/kg/day) for 4 weeks. At day 0 (D0) and D28, skin lesions were graded by means of the canine atopic dermatitis extent and severity index (CADESI). Skin biopsies and intradermal allergy tests were performed at D0 and blood samples for haematology and serum biochemistry were collected at D0 and D28. During the trial the cat owners were asked to evaluate the intensity of the pruritus once weekly on a linear analog scale and to record side effects. Based on the CADESI there was no significant difference between the two groups in the amount of remission (P=0.0562) or in the number of cats that improved by >25% (P=0.0571). The effect of CsA and prednisolone on pruritus as evaluated by the owners was not significantly different (P=0.41) between the two groups. No serious side effects were observed. The conclusion was that CsA is an effective alternative to prednisolone therapy in cats with presumed atopic dermatitis.

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

Science.gov (United States)

Arman, Aysegul; Demirseren, Duriye Deniz; Takmaz, Tamer

2015-01-01

To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints. 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. 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 (Ptreatment 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 (Ptreatment 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.

Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil.

Science.gov (United States)

Bergman, Ebba; Lundahl, Anna; Fridblom, Patrik; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans

2009-12-01

The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 +/- 3.5 and 35.7 +/- 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC(bile)/AUC(VH) ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC(50) values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 +/- 0.06; TII, 0.46 +/- 0.13) and increased the AUC(VP) and AUC(VH) by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and f(e, bile) were reduced by approximately 50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.

Effects of dihydrotestosterone administration on the expression of reproductive and body weight regulatory factors in ovariectomized and estradiol-treated female rats.

Science.gov (United States)

Iwasa, Takeshi; Matsuzaki, Toshiya; Yano, Kiyohito; Mayila, Yiliyasi; Irahara, Minoru

2018-01-01

To clarify the direct effects of androgens, the changes in the hypothalamic levels of reproductive and appetite regulatory factors induced by chronic dihydrotestosterone (DHT) administration were evaluated in female rats. DHT treatment increased the BW and food intake of the ovariectomized rats, but not the estradiol (E2)-treated rats. DHT administration suppressed the expression of a hypothalamic anorexigenic factor. Although the kisspeptin (Kiss1) mRNA levels of the anterior hypothalamic block (the anteroventral periventricular nucleus, AVPV) were increased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the AVPV in the ovariectomized or E2-treated rats. Conversely, DHT administration reduced the Kiss1 mRNA levels of the posterior hypothalamic block (the arcuate nucleus, ARC) in the ovariectomized rats. Although the Kiss1 mRNA levels of the posterior hypothalamic block (ARC) were decreased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the ARC in these rats. Serum luteinizing hormone levels of these groups exhibited similar patterns to the Kiss1 mRNA levels of the ARC. These results showed that DHT affects the production of hypothalamic reproductive and appetite regulatory factors, and that these effects of DHT differ according to the estrogen milieu.

Protective effect of pumpkin seed extract on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide.

Science.gov (United States)

Aghaei, S; Nikzad, H; Taghizadeh, M; Tameh, A A; Taherian, A; Moravveji, A

2014-10-01

Cancer treatment with cyclophosphamide (CP) may result in reproductive toxicity as one of its side effects. The pumpkin seed is a rich natural source of antioxidant. We have assessed the possible protective efficacy of pumpkin seed extract on sperm characteristics, biochemical parameters and epididymal histology of CP-treated rats. Male adult Wistar rats were categorised into four groups. Group 1 served as control and received intraperitoneal (IP) injection of isotonic saline solution. Group 2 rats were treated with CP by IP injection in a single dose of 100 mg/kg body weight, only once. Group 3 and 4 received CP plus 300 and 600 mg/kg pumpkin seed extract respectively. Six weeks after treatment, sperm characteristics, biochemical parameters and histopathological changes were examined. Results showed that, sperm characteristics in CP-treated rats were significantly decreased. Biochemical analysis results showed that the co-administration of 300 mg pumpkin seed extract could increase the total antioxidant capacity (TAC) level significantly. In CP-treated rats, histopathological changes such as vacuolisation, disorganisation and separation of epididymal epithelium were observed as well. Interestingly, pumpkin seed extract could improve the above-mentioned parameters remarkably in CP-treated rats. Our findings indicated that pumpkin seed extract might be used as protective agent against CP-induced reproductive toxicity. © 2013 Blackwell Verlag GmbH.

Gene expression profiling in rat liver treated with compounds inducing phospholipidosis

International Nuclear Information System (INIS)

Hirode, Mitsuhiro; Ono, Atsushi; Miyagishima, Toshikazu; Nagao, Taku; Ohno, Yasuo; Urushidani, Tetsuro

2008-01-01

We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA using these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity

Mast cell concentration and skin wound contraction in rats treated with Brazilian pepper essential oil (Schinus terebinthifolius Raddi).

Science.gov (United States)

Estevão, Lígia Reis Moura; Medeiros, Juliana Pinto de; Simões, Ricardo Santos; Arantes, Rosa Maria Esteves; Rachid, Milene Alvarenga; Silva, Regildo Márcio Gonçalves da; Mendonça, Fábio de Souza; Evêncio-Neto, Joaquim

2015-04-01

To evaluate wound contraction and the concentration of mast cells in skin wounds treated with 5% BPT essential oil-based ointment in rats. Twenty rats, male, of adult age, were submitted to skin surgery on the right (RA) and left antimeres (LA) of the thoracic region. They were divided into two groups: control (RA - wounds receiving daily topical application of vaseline and lanolin) and treated (LA - wounds treated daily with the topical ointment). The skin region with wounds were collected at days 4, 7, 14 and 21 after surgery. Those were fixed in 10% formaldehyde and later processed for paraffin embedding. Sections were obtained and stained by H.E for histopathology analysis. The degree of epithelial contraction was measured and mast cell concentration were also evaluated. The treated group showed higher mast cell concentrations (poil increases mast cell concentration and promotes skin wound contraction in rats.

Bound residues in corn plants treated with 14C-atrazine and bioavailability to rats

International Nuclear Information System (INIS)

Khan, S.U.

1986-01-01

Corn plants, about 3.5 months old and treated with 14 C-atrazine, were used in an experiment in which the aerial portion of the plants was exhaustively extracted with solvents. The extracted dried material containing bound 14 C-residues was fed to rats. The extracted aerial portion of control corn plants fortified with 14 C-atrazine was also fed to rats. After four days, 88% and 32% of the radioactivity was excreted in the faeces, and 10% and 60% radioactivity was voided in the urine from rats fed plant material containing bound and fortified 14 C-residues, respectively. The data suggest that the bioavailability to rats of bound 14 C-residues in corn material is low. (author)

Effects of cyclosporin A induced T-lymphocyte depletion on the course of avian Metapneumovirus (aMPV) infection in turkeys.

Science.gov (United States)

Rubbenstroth, Dennis; Dalgaard, Tina S; Kothlow, Sonja; Juul-Madsen, Helle R; Rautenschlein, Silke

2010-05-01

The avian Metapneumovirus (aMPV) causes an economically important acute respiratory disease in turkeys (turkey rhinotracheitis, TRT). While antibodies were shown to be insufficient for protection against aMPV-infection, the role of T-lymphocytes in the control of aMPV-infection is not clear. In this study we investigated the role of T-lymphocytes in aMPV-pathogenesis in a T-cell-suppression model in turkeys. T-cell-intact turkeys and turkeys partly depleted of functional CD4(+) and CD8(+) T-lymphocytes by Cyclosporin A (CsA) treatment were inoculated with the virulent aMPV subtype A strain BUT 8544. CsA-treatment resulted in a significant reduction of absolute numbers of circulating CD4(+) and CD8alpha(+) T-lymphocytes by up to 82 and 65%, respectively (P<0.05). Proportions of proliferating T-cells within mitogen-stimulated peripheral blood mononuclear cells were reduced by similar levels in CsA-treated birds compared to untreated controls (P<0.05). CsA-treated turkeys showed delayed recovery from aMPV-induced clinical signs and histopathological lesions and a prolonged detection of aMPV in choanal swabs. The results of this study show that T-lymphocytes play an important role in the control of primary aMPV-infection in turkeys. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

Science.gov (United States)

D'Argenio, Giuseppe; Cariello, Rita; Tuccillo, Concetta; Mazzone, Giovanna; Federico, Alessandro; Funaro, Annalisa; De Magistris, Laura; Grossi, Enzo; Callegari, Maria L; Chirico, Marilena; Caporaso, Nicola; Romano, Marco; Morelli, Lorenzo; Loguercio, Carmela

2013-05-01

Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. © 2013 John Wiley & Sons A/S.

Hormones of thyroid gland in sera of rats treated with different dose of concentrated potassium iodine solutions

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Marković Ljiljana

2010-01-01

Full Text Available Introduction Potassium iodine (KI is used as a drug therapy for treating numerous diseases such as small-vessel vasculitis, erythema nodosum, vasculitis nodularis, Sweet's syndrome, tuberculosis and granulomatosis, and for iodized salt. At the same time, KI can be harmful. Iodine intake may increase the frequency of thyroiditis in humans, and may induce the occurrence of experimental thyroiditis (ET in animals. Investigations on an experimental model for the examination of thyroiditis in Wistar rats have clearly showed morphological changes in the rat thyroid evoked by KI administration. Objective The purpose of this study was to compare the effects of low and high doses of KI on the thyroid gland of Wistar rats and determine the effect on hormone status (T4, T3 and TSH in this rat strain. Methods Two groups of rats from the Wistar strain were treated with a low iodine dose (225 μg/g BW and with a high iodine dose (675 μg/g BW of KI solutions. Untreated nonimmunized animals served as controls. The solution was administrated daily intraperitoneally during the period of 26 consecutive days. Results Monitoring hormone status (TSH, T3 and T4 and morphological changes it was found that therapeutic doses of KI applied in treatment induced the occurrence of experimental thyroiditis (chronic destructive Hashimoto's thyroiditis in humans and cell necrosis in animals not carrying a genetic susceptibility. Significant inflammatory changes were observed in rats treated with a high iodine dose. Conclusion The early iodine induced cell necrosis and inflammation in the nonimmunized animals without genetic susceptibility is a new experimental model of thyroiditis. .

Effect of sodium selenite on chosen anti- and pro-oxidative parameters in rats treated with lithium: A pilot study.

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Musik, Irena; Kocot, Joanna; Kiełczykowska, Małgorzata

2015-06-01

Selenium is an essential element of antioxidant properties. Lithium is widely used in medicine but its administration can cause numerous side effects including oxidative stress. The present study aimed at evaluating if sodium selenite could influence chosen anti- and pro-oxidant parameters in rats treated with lithium. The experiment was performed on four groups of Wistar rats: I (control) - treated with saline; II (Li) - treated with lithium (2.7 mgLi/kg b.w. as Li2CO3), III (Se) - treated with selenium (0.5 mgSe/kg b.w. as Na2SeO3), IV (Li+Se) - treated with Li2CO3 and Na2SeO3 together at the same doses as in group II and III, respectively. All treatments were performed by stomach tube for three weeks in form of water solutions. The following anti- and pro-oxidant parameters: total antioxidant status (TAS) value, catalase (CAT) activity, concentrations of ascorbic acid (AA) and malonyldialdehyde (MDA) in plasma as well as whole blood superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured. Selenium given alone markedly enhanced whole blood GPx and diminished plasma CAT vs. Lithium significantly decreased plasma CAT and slightly increased AA vs. Selenium co-administration restored these parameters to the values observed in control animals. Furthermore, selenium co-administration significantly increased GPx in Li-treated rats. All other parameters (TAS, SOD and MDA) were not affected by lithium and/or selenium. Further research seems to be warranted to decide if application of selenium as an adjuvant in lithium therapy is worth considering. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

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Mai, Yang; Afonso-Pereira, Francisco; Murdan, Sudaxshina; Basit, Abdul W

2017-09-30

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (pbioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (pbioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. Copyright © 2017 Elsevier B.V. All rights reserved.

Value-based medicine, comparative effectiveness, and cost-effectiveness analysis of topical cyclosporine for the treatment of dry eye syndrome.

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Brown, Melissa M; Brown, Gary C; Brown, Heidi C; Peet, Jonathan; Roth, Zachary

2009-02-01

To assess the comparative effectiveness and cost-effectiveness (cost-utility) of a 0.05% emulsion of topical cyclosporine (Restasis; Allergan Inc, Irvine, California) for the treatment of moderate to severe dry eye syndrome that is unresponsive to conventional therapy. Data from 2 multicenter, randomized, clinical trials and Food and Drug Administration files for topical cyclosporine, 0.05%, emulsion were used in Center for Value-Based Medicine analyses. Analyses included value-based medicine as a comparative effectiveness analysis and average cost-utility analysis using societal and third-party insurer cost perspectives. Outcome measures of comparative effectiveness were quality-adjusted life-year (QALY) gain and percentage of improvement in quality of life, and for cost-effectiveness were cost-utility ratio (CUR) using dollars per QALY. Topical cyclosporine, 0.05%, confers a value gain (comparative effectiveness) of 0.0319 QALY per year compared with topical lubricant therapy, a 4.3% improvement in quality of life for the average patient with moderate to severe dry eye syndrome that is unresponsive to conventional lubricant therapy. The societal perspective incremental CUR for cyclosporine over vehicle therapy is $34,953 per QALY and the societal perspective average CUR is $11,199 per QALY. The third-party-insurer incremental CUR is $37,179 per QALY, while the third-party-insurer perspective average CUR is $34,343 per QALY. Topical cyclosporine emulsion, 0.05%, confers considerable patient value and is a cost-effective therapy for moderate to severe dry eye syndrome that is unresponsive to conventional therapy.

Exhaustive physical exercise increases the number of colonic preneoplastic lesions in untrained rats treated with a chemical carcinogen.

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Demarzo, Marcelo Marcos Piva; Garcia, Sérgio Britto

2004-12-08

Aberrant crypt foci (ACF) have been used for early detection of factors that influence colorectal carcinogenesis in rats. It has been observed that exhaustive exercise increases free radical DNA oxidative damage and depresses immune function, events also related to the increased risk for cancer development. Fifteen days after a single exhaustive swimming bout in untrained rats treated with a colon carcinogen, we observed a statistically significant increased number of ACF when compared to the non-exercised group. Thus, we concluded that exhaustive exercise increased the susceptibility for colon cancer in rats. From our finding and literature data, we hypothesize that, similarly to the suggested relationship between exercise and infections, exercise could be protective against cancer or it could increase the risk for this disease depending on its type, dose and duration.

Effect of Topical Cyclosporine in grading of Vernal keratoconjunctivitis.

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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.

Evaluation of lipid profile and oxidative stress in STZ-induced rats treated with antioxidant vitamin

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Danielle Ayr Tavares de Almeida

2012-08-01

Full Text Available The present study investigated the effect of supplementation of vitamin E on streptozotocin (STZ-induced diabetic rats by measuring blood glucose, changes in body weight, food and water intake, lipid profile, serum urea and creatinine level, and antioxidant enzyme activity. Male Wistar rats were divided into four groups: control rats (GI; rats receiving vitamin E (GII; STZ-induced diabetic rats (GIII and STZ-induced diabetic rats treated with vitamin E (GIV. Vitamin E reduced (p<0.05 blood glucose and urea, improved the lipid profile (decreased the serum levels of total cholesterol, LDL cholesterol, VLDL cholesterol and triacylglycerols, and increased HDL cholesterol and increased total protein in STZ-induced diabetic rats (GIV. Vitamin prevented changes in the activity of SOD and GSH-Px and in the concentration of lipid hydroperoxide. These results suggested that vitamin E improved hyperglycaemia and dyslipidaemia while inhibiting the progression of oxidative stress in STZ-induced diabetic rats.

Tissue dyslipidemia in salmonella-infected rats treated with amoxillin and pefloxacin

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Rotimi Solomon O

2012-11-01

Full Text Available Abstract Background This study investigated the effects of salmonella infection and its chemotherapy on lipid metabolism in tissues of rats infected orally with Salmonella typhimurium and treated intraperitoneally with pefloxacin and amoxillin. Methods Animals were infected with Salmonella enterica serovar Typhimurium strain TA 98. After salmonellosis was confirmed, they were divided into 7 groups of 5 animals each. While one group served as infected control group, three groups were treated with amoxillin (7.14 mg/kg body weight, 8 hourly and the remaining three groups with pefloxacin (5.71mg/kg body weight, 12 hourly for 5 and 10 days respectively. Uninfected control animals received 0.1ml of vehicle. Rats were sacrificed 24h after 5 and 10 days of antibiotic treatment and 5 days after discontinuation of antibiotic treatment. Their corresponding controls were also sacrificed at the same time point. Blood and tissue lipids were then evaluated. Results Salmonella infection resulted in dyslipidemia characterised by increased concentrations of free fatty acids (FFA in plasma and erythrocyte, as well as enhanced cholesterogenesis, hypertriglyceridemia and phospholipidosis in plasma, low density lipoprotein-very low density lipoprotein (LDL-VLDL, erythrocytes, erythrocyte ghost and the organs. The antibiotics reversed the dyslipidemia but not totally. A significant correlation was observed between fecal bacterial load and plasma cholesterol (r=0.456, p Conclusion The findings of this study suggest that salmonella infection in rats and its therapy with pefloxacin and amoxillin perturb lipid metabolism and this perturbation is characterised by cholesterogenesis.

Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

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Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal

2011-08-01

Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

The treatment of peripheral nerve injuries using irradiated allografts and temporary host immunosuppression (in a rat model)

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Easterling, K.J.; Trumble, T.E. (Yale Univ. School of Medicine, New Haven, CT (USA))

1990-10-01

Irradiation of allografts prior to transplantation and host immunosuppression with cyclosporin-A were studied separately and in combination as means of lessening the rejection of transplanted peripheral nerve tissue. Lewis and Brown Norway rats were used in the animal model, as they differ at both major and minor histocompatibility loci. Sciatic nerve grafts (2.5 cm) were used and the animals were followed for 16 weeks after nerve grafting. The outcome was studied by functional measurements (sensory testing, gait analysis, joint flexion contracture, and muscle weight), as well as by measurements of biochemical and histologic parameters (hydroxyproline concentration and axon counts, respectively). Sensory testing was not reliable because of crossover innervation by the saphenous nerve. Evaluation by standard gait-testing techniques was found to be unsatisfactory. However, the allografted animals receiving cyclosporin-A had significantly smaller flexion contractures, compared to the allografted animals without immunosuppression (17 degrees +/- 12 degrees vs. 44 degrees +/- 13 degrees and 51 degrees +/- 13 degrees, p less than 0.005). Allografted animals receiving short-term cyclosporin-A had contractures that were not significantly different from those seen in isografted control animals (17 degrees +/- 12 degrees vs. 22 degrees +/- 15 degrees, NS). Muscle hydroxyproline concentration analysis revealed a lower hydroxyproline concentration among the allografted groups that received irradiated allografts, compared to groups receiving nonirradiated allogeneic grafts. The studies of muscle hydroxyproline concentration and muscle weight both showed substantial reinnervation, even in allografted animals without pretreatment of the grafts or immunosuppression of the recipient animal.

The treatment of peripheral nerve injuries using irradiated allografts and temporary host immunosuppression (in a rat model)

International Nuclear Information System (INIS)

Easterling, K.J.; Trumble, T.E.

1990-01-01

Irradiation of allografts prior to transplantation and host immunosuppression with cyclosporin-A were studied separately and in combination as means of lessening the rejection of transplanted peripheral nerve tissue. Lewis and Brown Norway rats were used in the animal model, as they differ at both major and minor histocompatibility loci. Sciatic nerve grafts (2.5 cm) were used and the animals were followed for 16 weeks after nerve grafting. The outcome was studied by functional measurements (sensory testing, gait analysis, joint flexion contracture, and muscle weight), as well as by measurements of biochemical and histologic parameters (hydroxyproline concentration and axon counts, respectively). Sensory testing was not reliable because of crossover innervation by the saphenous nerve. Evaluation by standard gait-testing techniques was found to be unsatisfactory. However, the allografted animals receiving cyclosporin-A had significantly smaller flexion contractures, compared to the allografted animals without immunosuppression (17 degrees +/- 12 degrees vs. 44 degrees +/- 13 degrees and 51 degrees +/- 13 degrees, p less than 0.005). Allografted animals receiving short-term cyclosporin-A had contractures that were not significantly different from those seen in isografted control animals (17 degrees +/- 12 degrees vs. 22 degrees +/- 15 degrees, NS). Muscle hydroxyproline concentration analysis revealed a lower hydroxyproline concentration among the allografted groups that received irradiated allografts, compared to groups receiving nonirradiated allogeneic grafts. The studies of muscle hydroxyproline concentration and muscle weight both showed substantial reinnervation, even in allografted animals without pretreatment of the grafts or immunosuppression of the recipient animal

Comparative element analysis on femur of antler hemo-treated ovariectomized wistar rats by SRXRF

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Yang Jianhong; Fei Yurong; Wang Ruilin; Cao Yi; Huang Yuying; He Wei

2007-01-01

To investigate the relationship between bone element contents and bone m/neral density (BMD), left femur of sham-operated rats (SHAM, n=5), ovariectomized rats (OVX, n=5) and antler hemo-treated ovariectomized rats (OVX + antler hemo, n=5) were analyzed by synchrotron radiation X-ray fluorescence (SRXRF) microprobe. The results showed that there were very good positive correlations among contents of Ca, P, Zn and Sr. In comparison to the SHAM group, decreased relative intensities of Ca, P, Zn and Sr (especially Ca and P, p<0.05) were observed in femur of the OVX group, which showed significant decrease (p<0.05) of the BMD. The results indicate that loss of Ca and P in bone will cause osteoporosis. On the other hand, increased relative intensities of Ca, P and Zn in femur, and the BMD (p<0.05), of the anlter hemo-treated OVX group were found, in comparison to the OVX group. This suggests that anlter hemo may help cure osteoporosis through maintaining bone contents of Zn, Ca and P, and increasing the BMD. (authors)

Lung allograft rejection in the rat. I. Accelerated rejection caused by graft lymphocytes

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Prop, J.; Nieuwenhuis, P.; Wildevuur, C.R.

1985-01-01

To find out to what extent rejection of lungs differs from that of other organs, functional rejection of lung allografts was studied in five combinations of inbred rat strains. Rejection could be monitored accurately by perfusion scintigraphy, and equally well by chest roentgenography. The rejection of lung grafts was found to proceed remarkably fast, when compared with heart grafts, in combinations with strong RT1-incompatibilities. This accelerated rejection pattern could be converted into rejection at a normal pace by pretreatment of the donor with 10 Gy roentgen irradiation one day before transplantation. Donor pretreatment depleted the lung graft's bronchus-associated lymphoid tissue (BALT) of lymphocytes. When grafts were depleted of all other passenger cells as well--by retransplantation from a cyclosporine-treated intermediate host--they showed an even more reduced immunogenicity, probably because of the loss of donor-type dendritic cells. These results indicate that lymphocytes from the BALT of lung grafts are capable of accelerating the rejection response

Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats.

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Saberi, Shadan; Dehghani, Aghdas; Nematbakhsh, Mehdi

2016-01-01

The angiotensin 1-7 (Ang 1-7), is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR) or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV) female rats. OV female Wistar-rats received estradiol (500 μg/kg/week) or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF), and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE) rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (Pdose <0.001) and A779-treated (Pdose <0.01) animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05). When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals.

Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party.

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Marsh, Judith C; Bacigalupo, Andrea; Schrezenmeier, Hubert; Tichelli, Andre; Risitano, Antonio M; Passweg, Jakob R; Killick, Sally B; Warren, Alan J; Foukaneli, Theodora; Aljurf, Mahmoud; Al-Zahrani, H A; Höchsmann, Britta; Schafhausen, Philip; Roth, Alexander; Franzke, Anke; Brummendorf, Tim H; Dufour, Carlo; Oneto, Rosi; Sedgwick, Philip; Barrois, Alain; Kordasti, Shahram; Elebute, Modupe O; Mufti, Ghulam J; Socie, Gerard

2012-06-07

Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age- and disease severity-matched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P = .009). Transplant-free survival was 52% for rATG and 76% for hATG (P = .002). On multivariate analysis, rATG (hazard ratio = 3.9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848.

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats.

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Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

2016-01-01

In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner.

Simultaneous bone marrow and composite tissue transplantation in rats treated with nonmyeloablative conditioning promotes tolerance1

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Xu, Hong; Ramsey, Deborah M.; Wu, Shengli; Bozulic, Larry D.; Ildstad, Suzanne T.

2012-01-01

Background Approaches to safely induce tolerance in vascularized composite allotransplantation (VCA) with chimerism through bone marrow transplantation (BMT) are currently being pursued. However, the VCA were historically performed sequentially after donor chimerism was established. Delayed VCA is not clinically applicable due to the time constraints associated with procurement from deceased donors. A more clinically relevant approach to perform both the BMT and VCA simultaneously was evaluated. Methods WF (RT1Au) rats were treated with a short course of immunosuppressive therapy (anti-αβ-TCR mAb, FK-506, and anti-lymphocyte serum). One day prior to BMT, rats were treated with varying doses of total body irradiation (TBI) followed by transplantation of heterotopic osteomyocutaneous flaps from hind limbs of ACI (RT1Aabl) rats. Results 80% of rats conditioned with 300 cGy TBI and 40% of rats receiving 400 cGy TBI accepted the VCA. Mixed chimerism was detected in peripheral blood at one month post-VCA, but chimerism was lost in all transplant recipients by 4 months. The majority of peripheral donor cells originated from the BMT and not the VCA. Acceptors of VCA were tolerant of a donor skin graft challenge and no anti-donor antibodies were detectable, suggesting a central deletional mechanism for tolerance. Regulatory T cells (Treg) from spleens of acceptors more potently suppressed lymphocyte proliferation than Treg from rejectors in the presence of donor stimulator cells. Conclusions These studies suggest that simultaneous BMT and VCA may establish indefinite allograft survival in rats through Treg-mediated suppression and thymic deletion of alloreactive T cells. PMID:23250336

Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

International Nuclear Information System (INIS)

Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

2010-01-01

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 μM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt max of 105 ± 8 mN/s in control hearts vs. 49 ± 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 ± 0.2 in control hearts vs. 2.2 ± 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 ± 1 μM cytochrome c/min/mg in control hearts vs. 14 ± 3 μM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

Effects of melatonin on diclofenac sodium treated rat kidney: a stereological and histopathological study.

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Khoshvakhti, Habib; Yurt, K Kübra; Altunkaynak, B Zuhal; Türkmen, Aysın P; Elibol, Ebru; Aydın, Işınsu; Kıvrak, Elfide G; Önger, M Emin; Kaplan, Süleyman

2015-01-01

In this study, we aimed to investigate the effect of diclofenac sodium (DS) and melatonin (MEL) on kidney of the prenatally administered rats. Pregnant rats were divided into the control, physiological saline, DS, and DS + MEL groups. All injections were given beginning from the 5th day after mating to the 15th day of the pregnancy. Physical dissector and Cavalieri principle were used to estimate the numerical density and total number of glomeruli and the volumetric parameters of kidney, respectively. Our stereological results indicated that DS application during the pregnancy lead to decrease in the mean volume, numerical density, and total number of the glomeruli (p  0.05). Light microscopic investigation showed congestion in blood vessels and shrinkage of the Bowman's space in the DS group. Moreover, there was degeneration in nephrons including glomerulosclerosis and tubular defects, and an increase in the connective tissue in the kidneys of the DS-treated group. However, usage of the MEL with the DS caused preventing of these pathological alterations in the kidney. We suggested that DS might lead to adverse effects in the kidneys of the rats that are prenatally subjected to this drug. Fortunately, these adverse effects can be prevented by the melatonin supplementation.

Functional assessments and histopathology of hepatorenal tissues of rats treated with raw and processed herbs

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Ojiako, Okey A.; Chikezie, Paul C.; Ukairo, Doris I.; Ibegbulem, Chiedozie O.; Nwaoguikpe, Reginald N.

2017-01-01

The present study ascertained the functional integrity of hepatic and renal tissues, concurrently with blood lipid patterns, of Wistar rats infused with CCl4 and treated with raw and hydrothermal processed herbs, namely, Monodora myristica, Chromolaena odorata, Buccholzia coriacea and Sphenostylis stenocarpa. Measurement of phytochemical contents of the herbs was according to standard methods. The rats were randomly designated on the bases of diets and treatments received for 28 consecutive d...

BIOCHEMICAL EFFECTS IN NORMAL AND STONE FORMING RATS TREATED WITH THE RIPE KERNEL JUICE OF PLANTAIN (MUSA PARADISIACA)

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Devi, V. Kalpana; Baskar, R.; Varalakshmi, P.

1993-01-01

The effect of Musa paradisiaca stem kernel juice was investigated in experimental urolithiatic rats. Stone forming rats exhibited a significant elevation in the activities of two oxalate synthesizing enzymes - Glycollic acid oxidase and Lactate dehydrogenase. Deposition and excretion of stone forming constituents in kidney and urine were also increased in these rats. The enzyme activities and the level of crystalline components were lowered with the extract treatment. The extract also reduced the activities of urinary alkaline phosphatase, lactate dehydrogenase, r-glutamyl transferase, inorganic pyrophosphatase and β-glucuronidase in calculogenic rats. No appreciable changes were noticed with leucine amino peptidase activity in treated rats. PMID:22556626

Histometric study of alveolar bone healing in rats treated with the nonsteroidal anti-inflammatory drug nimesulide.

Science.gov (United States)

Teófilo, Juliana Mazzonetto; Giovanini, Gabriela Salgueiro; Fracon, Ricardo Nogueira; Lamano, Teresa

2011-04-01

There is extensive experimental and clinical evidence in the orthopedic area that prolonged use of nonselective (inhibitor of both cyclooxygenases 1 and 2) nonsteroidal anti-inflammatory drugs can hinder long bone fracture healing, spinal fusion rate, and new bone formation around implants. The purpose of the present study was to investigate whether nimesulide (Nimesulida, Medley S.A., Campinas, SP, Brazil), a preferential cyclooxygenase-2 inhibitor, can hinder alveolar bone healing, in rats. Treated rats received oral doses (5 mg/kg/rat/day) of nimesulide from the day of tooth extraction until euthanasia 2 weeks later and control rats received tap water (n = 5 per group). The volume of neoformed bone inside the alveolar socket was estimated in semiserial longitudinal histological sections by a differential point-counting method, and the significance of the difference between groups was analyzed by Student t test (P alveolar bone healing in rats.

Cyclosporine A-sensitive, cyclophilin B-dependent endoplasmic reticulum-associated degradation.

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Riccardo Bernasconi

2010-09-01

Full Text Available Peptidyl-prolyl cis/trans isomerases (PPIs catalyze cis/trans isomerization of peptide bonds preceding proline residues. The involvement of PPI family members in protein refolding has been established in test tube experiments. Surprisingly, however, no data is available on the involvement of endoplasmic reticulum (ER-resident members of the PPI family in protein folding, quality control or disposal in the living cell. Here we report that the immunosuppressive drug cyclosporine A (CsA selectively inhibits the degradation of a subset of misfolded proteins generated in the ER. We identify cyclophilin B (CyPB as the ER-resident target of CsA that catalytically enhances disposal from the ER of ERAD-L(S substrates containing cis proline residues. Our manuscript presents the first evidence for enzymatic involvement of a PPI in protein quality control in the ER of living cells.

Cyclosporine A-Sensitive, Cyclophilin B-Dependent Endoplasmic Reticulum-Associated Degradation

Science.gov (United States)

Luban, Jeremy; Molinari, Maurizio

2010-01-01

Peptidyl-prolyl cis/trans isomerases (PPIs) catalyze cis/trans isomerization of peptide bonds preceding proline residues. The involvement of PPI family members in protein refolding has been established in test tube experiments. Surprisingly, however, no data is available on the involvement of endoplasmic reticulum (ER)-resident members of the PPI family in protein folding, quality control or disposal in the living cell. Here we report that the immunosuppressive drug cyclosporine A (CsA) selectively inhibits the degradation of a subset of misfolded proteins generated in the ER. We identify cyclophilin B (CyPB) as the ER-resident target of CsA that catalytically enhances disposal from the ER of ERAD-LS substrates containing cis proline residues. Our manuscript presents the first evidence for enzymatic involvement of a PPI in protein quality control in the ER of living cells. PMID:20927389

The Protective Effect of γ-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats.

Science.gov (United States)

Talebi, Nahid; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Vafapour, Marzieh

2016-01-01

Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of γ-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats. Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 μmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 μg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements. The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P GABA significantly decreased the aforementioned parameters (P levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI.

Immunohistochemical profile of some neurotransmitters and neurotrophins in the seminiferous tubules of rats treated by lonidamine.

Science.gov (United States)

Artico, M; Bronzetti, E; Saso, L; Felici, L M; D'Ambrosio, A; Forte, F; Grande, C; Ortolani, F

2007-01-01

Lonidamine (LND) or [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] is an anticancer and antispermatogenic drug that exerts a large number of effects on tumor cells and germ cells. Sexually mature male Sprague-Dawley rats were housed at 22 degrees C on a 12-h light/12-h dark cycle 1 week before the experiments, with free access to food and water. LND was suspended in 0.5% methylcellulose at a concentration of 10 mg/mL and administered orally at the dose of 10 mL/kg (b.w.) as a single dose. Control rats received an equal amount of vehicle. Testes were removed, fixed for 24 h in 2% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium phosphate (pH 7.2 at 22 degrees C), rinsed with the same buffer, and stored at room temperature. From each sample, a block of tissue was removed by sectioning through the organ. After dehydration in ethanol at increasing concentrations (70-100%), each block was embedded in paraffin and serial 5 mm thick sections were cut using a rotatory microtome. The immunoreactivity for NTs has been observed in spermatogonia of untreated rats, while the rats treated with LND showed an immunohistochemical localization in all the stages of germinal cells. The generally well-expressed immunoreactivity for the neurotrophins receptors in treated rats observed in our study is presumably attributable to alterations of the receptors' structure and/or expression leading to changes of the activity, affinity, localization or protein interactions that may depend on sensitization of ion channels (induced by LND). Neurotrophins (NTs) appear to be interesting proteins for the modulation of sperm maturation and motility with a prominent role for the nerve growth factor (NGF), that may exert an autocrine or paracrine role. We therefore investigated the location and distribution of immunoreactivity for some neurotransmitters (SP, VIP, CGRP, nNOS, Chat), neurotrophins (NGF, BDNF, NT-3) and their own receptors (TrKA, TrKB, TrKC, p75) in the seminiferous tubules

Immunohistochemical profile of some neurotransmitters and neurotrophins in the seminiferous tubules of rats treated by lonidamine

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M Artico

2009-06-01

Full Text Available Lonidamine (LND or [1-(2,4-dichlorobenzyl-1H-indazole-3- carboxylic acid] is an anticancer and antispermatogenic drug that exerts a large number of effects on tumor cells and germ cells. Sexually mature male Sprague-Dawley rats were housed at 22°C on a 12-h light/12-h dark cycle 1 week before the experiments, with free access to food and water. LND was suspended in 0.5% methylcellulose at a concentration of 10 mg/mL and administered orally at the dose of 10 mL/kg (b.w. as a single dose. Control rats received an equal amount of vehicle. Testes were removed, fixed for 24 h in 2% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium phosphate (pH 7.2 at 22°C, rinsed with the same buffer, and stored at room temperature. From each sample, a block of tissue was removed by sectioning through the organ. After dehydration in ethanol at increasing concentrations (70-100%, each block was embedded in paraffin and serial 5 mm thick sections were cut using a rotatory microtome. The immunoreactivity for NTs has been observed in spermatogonia of untreated rats, while the rats treated with LND showed an immunohistochemical localization in all the stages of germinal cells. The generally well-expressed immunoreactivity for the neurotrophins receptors in treated rats observed in our study is presumably attributable to alterations of the receptors’ structure and/or expression leading to changes of the activity, affinity, localization or protein interactions that may depend on sensitization of ion channels (induced by LND. Neurotrophins (NTs appear to be interesting proteins for the modulation of sperm maturation and motility with a prominent role for the nerve growth factor (NGF, that may exert an autocrine or paracrine role.We therefore investigated the location and distribution of immunoreactivity for some neurotransmitters (SP, VIP, CGRP, nNOS, Chat, neurotrophins (NGF, BDNF, NT-3 and their own receptors (TrKA, TrKB, TrKC, p75 in the seminiferous tubules of

Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)

DEFF Research Database (Denmark)

Bramow, S; Ott, P; Thomsen Nielsen, F

2001-01-01

then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9...... secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most...... CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA....

Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats.

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Andrés Quesada

Full Text Available This study analyzes the fluorimetric determination of alanyl- (Ala, glutamyl- (Glu, leucyl-cystinyl- (Cys and aspartyl-aminopeptidase (AspAp urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG, albumin, and neutrophil gelatinase-associated lipocalin (NGAL. Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p0.259 with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

Temperature-dependent binding of cyclosporine to an erythrocyte protein

International Nuclear Information System (INIS)

Agarwal, R.P.; Threatte, G.A.; McPherson, R.A.

1987-01-01

In this competitive binding assay to measure endogenous binding capacity for cyclosporine (CsA) in erythrocyte lysates, a fixed amount of [ 3 H]CsA plus various concentrations of unlabeled CsA is incubated with aliquots of a test hemolysate. Free CsA is then adsorbed onto charcoal and removed by centrifugation; CsA complexed with a cyclosporine-binding protein (CsBP) remains in the supernate. We confirmed the validity of this charcoal-separation mode of binding analysis by comparison with equilibrium dialysis. Scatchard plot analysis of the results at 4 degrees C yielded a straight line with slope corresponding to a binding constant of 1.9 X 10(7) L/mol and a saturation capacity of approximately 4 mumol per liter of packed erythrocytes. Similar analysis of binding data at 24 degrees C and 37 degrees C showed that the binding constant decreased with increasing temperature, but the saturation capacity did not change. CsBP was not membrane bound but appeared to be freely distributed within erythrocytes. 125 I-labeled CsA did not complex with the erythrocyte CsBP. Several antibiotics and other drugs did not inhibit binding between CsA and CsBP. These findings may explain the temperature-dependent uptake of CsA by erythrocytes in whole blood and suggest that measurement of CsBP in erythrocytes or lymphocytes may help predict therapeutic response or toxicity after administration of CsA

An investigation on body weights, blood glucose levels and pituitary-gonadal axis hormones in diabetic and metformin-treated diabetic female rats

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Pouya Pournaghi

2012-06-01

Full Text Available Diabetes is a metabolic disorder which affects whole body systems including reproductive system. Diabetes is also a contributing factor to infertility. Metformin is one of the most common drugs to control hyperglycemia. In this study, 36 adult Sprague-Dawley female rats (170-210 g were divided into 3 groups (control, diabetic and diabetic-treated by metformin. In second and third groups, diabetes was induced by streptozotocin injection (45 mg kg-1, IP and the third group was treated by metformin hydrochloride (100 mg kg-1 day-1, PO for 8 weeks. Body weights were compared and blood glucose, gonadotropins and sexual hormones were measured. In diabetic group the blood glucose level significantly (P < 0.05 increased in comparison with that of control and metformin-treated diabetic rats. The results also revealed that, in the untreated diabetic rats, the mean body weights and pituitary-gonadal axis hormones were significantly (P < 0.05 reduced in comparison with the control. Although there were significant (P < 0.05 reduction in mean body weights in metformin-treated diabetic rats, reduction in pituitary-gonadal axis hormones was not as sharp as in untreated diabetic rats and only level of progesterone was significantly (P < 0.05 reduced in comparison with the control. The results of this investigation revealed that there was a clear relationship between experimental diabetes with body weight and pituitary-gonadal axis hormones, and treatment with metformin relatively restored diabetic complications.

Inability of donor total body irradiation to prolong survival of vascularized bone allografts: Experimental study in the rat

International Nuclear Information System (INIS)

Gonzalez del Pino, J.; Benito, M.; Randolph, M.A.; Weiland, A.J.

1990-01-01

At the present time, the toxic side effects of recipient immunosuppression cannot be justified for human non-vital organ transplantation. Total body irradiation has proven effective in ablating various bone-marrow-derived and endothelial immunocompetent cellular populations, which are responsible for immune rejection against donor tissues. Irradiation at a dose of 10 Gy was given to donor rats six days prior to heterotopic transplantation of vascularized bone allografts to host animals. Another group of recipient rats also received a short-term (sixth to fourteenth day after grafting), low dose of cyclosporine. Total body irradiation was able merely to delay rejection of grafts across a strong histocompatibility barrier for one to two weeks, when compared to nonirradiated allografts. The combination of donor irradiation plus cyclosporine did not delay the immune response, and the rejection score was similar to that observed for control allografts. Consequently, allograft viability was quickly impaired, leading to irreversible bone damage. This study suggest that 10 Gy of donor total body irradiation delivered six days prior to grafting cannot circumvent the immune rejection in a vascularized allograft of bone across a strong histocompatibility barrier

Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons: Mechanisms underlying hypoalgesia in Buruli ulcer.

Science.gov (United States)

Anand, U; Sinisi, M; Fox, M; MacQuillan, A; Quick, T; Korchev, Y; Bountra, C; McCarthy, T; Anand, P

2016-01-01

Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone. Morphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401. Mycolactone induces toxic effects in DRG

Pixe analysis of trace elements in tissues of rats treated with anticonvulsants

Science.gov (United States)

Hurd, R. W.; Van Rinsvelt, H. A.; Kinyua, A. M.; O'Neill, M. P.; Wilder, B. J.; Houdayer, A.; Hinrichsen, P. F.

1987-04-01

Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex.

PIXE analysis of trace elements in tissues of rats treated with anticonvulsants

Energy Technology Data Exchange (ETDEWEB)

Hurd, R.W.; Van Rinsvelt, H.A.; Kinyua, A.M.; O' Neill, M.P.; Wilder, B.J.; Houdayer, A.; Hinrichsen, P.F.

1987-04-01

Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex.

PIXE analysis of trace elements in tissues of rats treated with anticonvulsants

International Nuclear Information System (INIS)

Hurd, R.W.; Van Rinsvelt, H.A.; Kinyua, A.M.; O'Neill, M.P.; Wilder, B.J.; Florida Univ., Gainesville; Houdayer, A.; Hinrichsen, P.F.

1987-01-01

Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex. (orig.)

Transplantation of embryonic porcine neocortical tissue into newborn rats

DEFF Research Database (Denmark)

Castro, Anthony J; Meyer, Morten; Møller Dall, Annette

2003-01-01

cavities made in newborn rats. Sacrifice at 3-12.5 weeks posttransplantation revealed healthy looking grafts in several animals. Apparent graft rejection evidenced by areas of necrosis and OX1 reactivity was observed in some of the older transplants. Treatment of nursing mothers or of postweaning newborns...... with cyclosporin A did not appear to promote graft survival. Some transplants grew to extremely large proportions and were characterized by bands of cells and bundles of axons as observed using immunohistochemical staining for pig neurofilament. Neurofilament-positive axons projected from several of the grafts...

The influence of surgical transection and anastomosis on the rate of cell proliferation in the colonic epithelium of normal and DMH-treated rats.

Science.gov (United States)

Barkla, D H; Tutton, P M

1983-10-01

Normal and DMH-treated male rats aged 18-20 weeks underwent surgical transection and anastomosis of the transverse colon. Animals were subsequently killed at intervals of 14, 30 and 72 days. Three hours prior to sacrifice animals were injected with vinblastine sulphate and mitotic indices were subsequently estimated in histological sections. Possible differences between experimental and control groups were tested using a Student's t-test. The results show that the accumulated mitotic indices in normal and DMH-treated colon are statistically similar. The results also show that transection and anastomosis stimulates cell division in both normal and DMH-treated colon and that the increase is of greater amplitude and more prolonged duration in the DMH-treated rats. Carcinomas developed close to the line of anastomosis in DMH-treated but not in control rats. The results support the hypothesis that non-specific injury to hyperplastic colonic epithelium promotes carcinogenesis.

Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloride-treated rats

Science.gov (United States)

Kanter, Mehmet; Coskun, Omer; Budancamanak, Mustafa

2005-01-01

AIM: To investigate the effects of Nigella sativa L (NS) and Urtica dioica L (UD) on lipid peroxidation, antioxidant enzyme systems and liver enzymes in CCl4-treated rats. METHODS: Fifty-six healthy male Wistar albino rats were used in this study. The rats were randomly allotted into one of the four experimental groups: A (CCl4-only treated), B (CCl4+UD treated), C (CCl4+NS treated) and D (CCl4+UD+NS treated), each containing 14 animals. All groups received CCl4 (0.8 mL/kg of body weight, sc, twice a week for 60 d). In addition, B, C and D groups also received daily i.p. injections of 0.2 mL/kg NS or/and 2 mL/kg UD oils for 60 d. Group A, on the other hand, received only 2 mL/kg normal saline solution for 60 d. Blood samples for the biochemical analysis were taken by cardiac puncture from randomly chosen-seven rats in each treatment group at beginning and on the 60th d of the experiment. RESULTS: The CCl4 treatment for 60 d increased the lipid peroxidation and liver enzymes, and also decreased the antioxidant enzyme levels. NS or UD treatment (alone or combination) for 60 d decreased the elevated lipid peroxidation and liver enzyme levels and also increased the reduced antioxidant enzyme levels. The weight of rats decreased in group A, and increased in groups B, C and D. CONCLUSION: NS and UD decrease the lipid per-oxidation and liver enzymes, and increase the anti-oxidant defense system activity in the CCl4-treated rats. PMID:16425366

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

Science.gov (United States)

Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

2016-12-01

Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

Requirements of glycerol and fatty acid for triglyceride synthesis and ketogenesis by hepatocytes from normal and triiodothyronine-treated rats

International Nuclear Information System (INIS)

Olubadewo, J.O.; Heimberg, M.

1985-01-01

Hepatocytes from T3-treated rats synthesized less triglyceride and more ketone bodies from [1- 14 C]oleate at all concentrations from 0-2 mM, than did hepatocytes from euthyroid animals; addition of 1.0 mM glycerol increased triglyceride synthesis and reduced ketogenesis in hepatocytes from T3-treated rats to the rates observed in euthyroid hepatocytes in the absence of added glycerol. Glycerol did not alter triglyceride synthesis, but reduced ketogenesis genesis by euthyroid hepatocytes. It is probable from these and other data that, in the hyperthyroid rat, glycero-3-P, and not fatty acid, is rate limiting for synthesis of triglyceride, and, secondarily for reducing rates of ketogenesis in the hepatocyte

Changes in cell proliferation and morphology in the large intestine of normal and DMH-treated rats following colostomy.

Science.gov (United States)

Barkla, D H; Tutton, P J

1987-04-01

Colostomies were formed in the midcolon of normal and DMH-treated rats. Changes in cell proliferation in the mucosa adjacent to the colostomy and in the defunctioned distal segment were measured at seven, 14, 30, and 72 days using a stathmokinetic technique. Animals were given intraperitoneal injections of vinblastine and sacrificed three hours later; counts of mitotic and nonmitotic cells were made in tissue sections, and three-hour accumulated mitotic indexes were estimated. The results show that, except at seven days in DMH-treated rats, cell proliferation was unchanged in the colon proximal to the colostomy. Morphologic evidence of hyperplasia was seen in some animals at seven and 14 days. The defunctioned segment showed rapid atrophy of both mucosa and muscularis and a gradual but progressive decrease in cell proliferation. The morphology of the mucosa adjacent to the suture line in both functioning and defunctioned segments in normal and DMH-treated rats was abnormal in many animals. Abnormalities that were seen included collections of dysplastic epithelial cells in the submucosa, focal adenomatous changes, and intramural carcinoma formation. Aggregates of lymphoid tissue often were associated with carcinomas.

Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.

Science.gov (United States)

Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe; Dalby, Nils Ole

2014-09-01

A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in macrophage phenotype

Czech Academy of Sciences Publication Activity Database

Hájková, M.; Javorková, Eliška; Zajícová, Alena; Trošan, Peter; Holáň, Vladimír; Krulová, Magdaléna

2017-01-01

Roč. 11, č. 5 (2017), s. 1456-1465 ISSN 1932-6254 R&D Projects: GA ČR(CZ) GAP304/11/0653; GA ČR(CZ) GAP301/11/1568; GA ČR(CZ) GA14-12580S; GA MZd(CZ) NT14102 Institutional support: RVO:68378041 Keywords : mesenchymal stem cells * cyclosporine A * macrophages Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 3.989, year: 2016

Brain catalase in the streptozotocin-rat model of sporadic Alzheimer's disease treated with the iron chelator-monoamine oxidase inhibitor, M30.

Science.gov (United States)

Sofic, E; Salkovic-Petrisic, M; Tahirovic, I; Sapcanin, A; Mandel, S; Youdim, M; Riederer, P

2015-04-01

Low intracerebroventricular (icv) doses of streptozotocin (STZ) produce regionally specific brain neurochemical changes in rats that are similar to those found in the brain of patients with sporadic Alzheimer's disease (sAD). Since oxidative stress is thought to be one of the major pathologic processes in sAD, catalase (CAT) activity was estimated in the regional brain tissue of animals treated intracerebroventricularly with STZ and the multitarget iron chelator, antioxidant and MAO-inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline]. Five-day oral pre-treatment of adult male Wistar rats with 10 mg/kg/day M30 dose was followed by a single injection of STZ (1 mg/kg, icv). CAT activity was measured colorimetrically in the hippocampus (HPC), brain stem (BS) and cerebellum (CB) of the control, STZ-, M30- and STZ + M30-treated rats, respectively, 4 weeks after the STZ treatment. STZ-treated rats demonstrated significantly lower CAT activity in all three brain regions in comparison to the controls (p effects in this non-transgenic sAD model.

Changes in blood sugar levels of rats experimentally infected with Trypanosoma brucei and treated with imidocarb dipropionate and diminazene aceturate

Directory of Open Access Journals (Sweden)

Nwoha Rosemary Ijeoma Ogechi

2016-01-01

Full Text Available Objective: To determine the effect of Trypanosoma brucei (T. brucei on blood sugar level of infected rats. Methods: The experiment was done with 42 albino rats grouped into 3 groups of 14 members each. Group A was uninfected (control group, Group B was infected with T. brucei and treated with diminazene aceturate, and Group C was infected with T. brucei and treated with imidocarb dipropionate. Blood samples were collected from the media canthus of the experimental rats on Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 for the assessment of change in blood sugar levels. The blood sugar levels were determined with a glucometer (Accu-chek active serial No. GN: 10023338. Results: By 4 to 5 days post infection, there was a significant increase (P 0.05 was observed in the groups when compared with the control group till Day 12 of the experiment. Conclusions: T. brucei caused a significant increase in blood sugar of infected rats.

Muscle protein turnover in rats treated with corticosterone (CC) or/and nandrolone decanoate (ND) and fed an adequate or a low-protein diet

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Santidrian, S.; Cuevillas, F.; Goena, M.; Larralde, J.

1986-03-01

In order to investigate the possible antagonistic effect between glucocorticoids and androgens on muscle protein turnover, the authors have measured the fractional rates of gastrocnemius muscle protein synthesis (k/sub s/) and degradation (k/sub d/) by the constant-intravenous-infusion method using L-//sup 14/C/-tyrosine in rats receiving via s.c. per 100 g b.wt. 10 mg of CC, or 2 mg of ND or CC+ND at the indicated doses, and fed either an 18% or 5% protein diets over a period of 5 days. As an additional index of protein synthesis, RNA activity (g of synthesized protein/day/g RNA) was determined as well. Results showed that as compared to vehicle-injected animals fed the adequate diet, CC-treated rats exhibited a reduction of muscle k/sub d/, while ND-treated rats had an outstanding increase of muscle k/sub s/. However, rats receiving CC+ND showed k/sub s/ and k/sub d/ values similar to those displayed by control animals. Nevertheless, when the steroids were injected to rats fed the low-protein diet, CC has a catabolic effect on muscle protein but by reducing k/sub s/, while the anabolic action of ND is still displayed but by a significant reduction of muscle k/sub d/. CC+ND given to these protein-deficient rats caused an increase in muscle k/sub s/ and a reduction in k/sub d/. These results might indicate that, at least in part, ND antagonizes the catabolic action of high doses of CC on muscle protein metabolism.

Muscle protein turnover in rats treated with corticosterone (CC) or/and nandrolone decanoate (ND) and fed an adequate or a low-protein diet

International Nuclear Information System (INIS)

Santidrian, S.; Cuevillas, F.; Goena, M.; Larralde, J.

1986-01-01

In order to investigate the possible antagonistic effect between glucocorticoids and androgens on muscle protein turnover, the authors have measured the fractional rates of gastrocnemius muscle protein synthesis (k/sub s/) and degradation (k/sub d/) by the constant-intravenous-infusion method using L-/ 14 C/-tyrosine in rats receiving via s.c. per 100 g b.wt. 10 mg of CC, or 2 mg of ND or CC+ND at the indicated doses, and fed either an 18% or 5% protein diets over a period of 5 days. As an additional index of protein synthesis, RNA activity (g of synthesized protein/day/g RNA) was determined as well. Results showed that as compared to vehicle-injected animals fed the adequate diet, CC-treated rats exhibited a reduction of muscle k/sub d/, while ND-treated rats had an outstanding increase of muscle k/sub s/. However, rats receiving CC+ND showed k/sub s/ and k/sub d/ values similar to those displayed by control animals. Nevertheless, when the steroids were injected to rats fed the low-protein diet, CC has a catabolic effect on muscle protein but by reducing k/sub s/, while the anabolic action of ND is still displayed but by a significant reduction of muscle k/sub d/. CC+ND given to these protein-deficient rats caused an increase in muscle k/sub s/ and a reduction in k/sub d/. These results might indicate that, at least in part, ND antagonizes the catabolic action of high doses of CC on muscle protein metabolism

Ephedra-Treated Donor-Derived Gut Microbiota Transplantation Ameliorates High Fat Diet-Induced Obesity in Rats.

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Wang, Jing-Hua; Kim, Bong-Soo; Han, Kyungsun; Kim, Hojun

2017-05-23

Changes in gut microbiota (GM) are closely associated with metabolic syndrome, obesity, type 2 diabetes and so on. Several medicinal herbs, including Ephedra sinica (Es), have anti-obesity effects that ameliorate metabolic disorders. Therefore, in this study we evaluated whether Es maintains its anti-obesity effect through Es-altered gut microbiota (EsM) transplantation. GM was isolated from cecal contents of Es treated and untreated rats following repeated transplants into obese rats via oral gavage over three weeks. High-fat-diet (HFD)-induced obese rats transplanted with EsM lost significant body weight, epididymal fat, and perirenal fat weight, but no remarkable changes were observed in abdominal fat, liver, cecum weight and food efficiency ratio. In addition, treatment with EsM also significantly lowered the fasting blood glucose, serum insulin level, and insulin resistance index. Meanwhile, EsM transplantation significantly reduced gene expression of proinflammatory cytokines interleukin-1 and monocyte chemotactic protein-1. Rats treated with EsM also showed changed GM composition, especially blautia, roseburia and clostridium, significantly reduced the level of endotoxin and markedly increased the acetic acid in feces. Overall, our results demonstrated that EsM ameliorates HFD-induced obesity and related metabolic disorders, like hyperglycemia and insulin resistance, and is strongly associated with modulating the distribution of GM, enterogenous endotoxin and enteral acetic acid.

Rats Born to Mothers Treated with Dexamethasone 15 cH Present Changes in Modulation of Inflammatory Process

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Leoni V. Bonamin

2012-01-01

Full Text Available As little information about the effect of ultra high dilutions of glucocorticoid in reproduction is available in the literature, pregnant female Wistar rats (N=12 were blindly subcutaneously treated during all gestational and lactation period with: dexamethasone 4 mg/kg diluted into dexamethasone 15 cH (mixed; or dexamethasone 4 mg/kg diluted in water; or dexamethasone 15 cH, or vehicle. Parental generation had body weight, food and water consumption monitored. The F1 generation was monitored regarding to newborn development. No birth occurred in both groups treated with dexamethasone 4 mg/kg. After 60 days from birth, 12 male F1 rats were randomly selected from each remaining group and inoculated subcutaneously with 1% carrageenan into the footpad, for evaluation of inflammatory performance. Edema and histopathology of the footpad were evaluated, using specific staining methods, immunohistochemistry and digital histomorphometry. Mothers treated with mixed dexamethasone presented reduced water consumption. F1 rats born to dexamethasone 15 cH treated females presented significant increase in mast cell degranulation, decrease in monocyte percentage, increase in CD18+ PMN cells, and early expression of ED2 protein, in relation to control. The results show that the exposure of parental generation to highly diluted dexamethasone interferes in inflammation modulation in the F1 generation.

Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats

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Aghdas Dehghani

2015-01-01

Full Text Available Background. The accompanied role of Mas receptor (MasR, bradykinin (BK, and female sex hormone on renal blood flow (RBF response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779 and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE or vehicle (OV for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP, RBF, and renal vascular resistance (RVR responses to Ang 1-7 (0, 100, and 300 ng kg−1 min−1 were determined. Results. Percentage change of RBF (%RBF in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P<0.05. Infusion of 300 ng kg−1 min−1 Ang 1-7 increased RBF by 6.9±1.9% in OVE group versus 0.9±1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats.

Induction of monooxygenases and incorporation of radioactivity from 2-14C-lysine into hepatic microsomes of phenobarbital-treated rats fed a diet deficient in lysine, methionine, threonine and vitamines A, C, E

International Nuclear Information System (INIS)

Nurmagambetov, T.Zh.; Amirov, B.B.; Kuanysheva, T.G.; Sharmanov, T.Sh.

1992-01-01

The effect of diet on induction of monooxygenases and distribution of radioactivity from 2- 14 C-lysine in fractions of liver homogenate, muscle homogenate and blood of male rats treated with phenobarbital was studied. 2- 14 C-lysin was injected intraperitoneally 24 h before the first injection of phenobarbital. It was demonstrated that monooxygenase induction, increase of relative liver weight and incorporation of radioactivity from 2- 14 C-lysine into fractions of liver homogenate in phenobarbital-treated rats fed diet deficient in lysine, methionine, threonine and vitamins A, C, E were more pronounced as compared with the similarly treated rats which were fed a balanced diet. The possibility of mobilization of deficient essencial components to liver from other organs and tissues for maintenance of monooxygenase induction iis discussed

Hormonal control of fat accumulation in L-glutamate-treated obese rats

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Remke, H.; Wilsdorf, A.; Mueller, F.

1988-01-01

Persistently decreased concentrations of the growth hormone and the tissue-nonepinephrine in connection with growth retardation and obesity were investigated concerning the effects on cells of epididymal adipose tissue in postnatally injured glutamate-treated rats using 14 C-labelled tracers. Diminished secretion of growth hormone causes in adipocytes increased glucose intake, amplification of the insulin effect, and fat accumulation. A supersensitivity towards norepinephrine in adipocytes in vitro is due to diminished concentration of this hormone in the tissue. Insulin resistance is developed at the beginning of the stationary phase of obesity in these animals. (author)

Hepatoprotective activity of Eugenia jambolana Lam. in carbon tetrachloride treated rats

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Sisodia, S.S.; Bhatnagar, M.

2009-01-01

Objective: To estimate the hepatoprotective effects of the methanolic seed extract of Eugenia jambolana Lam. (Myrtaceae), in Wistar albino rats treated with carbon tetrachloride (CCl4). Materials and Methods: Liver damage in rats treated with CCl4 (1ml/kg/Bw, administered subcutaneously, on alternate days for one week) was studied by assessing parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), acid phosphatase (ACP) and bilirubin (total and direct). The effect of co-administration of Eugenia jambolana Lam. (doses 100, 200 and 400 mg/kg p. o.) on the above parameters was investigated. These biochemical observations were supplemented by weight and histological examination of liver sections. Liv.52® was used as positive control. Data were analyzed by one way ANOVA, followed by Scheff's/Dunnett's test. Results: Administration of Eugenia jambolana Lam. (doses 100, 200 and 400 mg/kg p. o.) significantly prevented carbon tetrachloride induced elevation of serum SGOT, SGPT, ALP, ACP and bilirubin (total and direct) level. Histological examination of the liver section revealed hepatic regeneration, after administration of various doses of Eugenia jambolana Lam. The results were comparable to that of Liv.52®. Conclusion: The study suggests preventive action of Eugenia jambolana Lam. in carbon tetrachloride induced liver toxicity. Hepatic cell regeneration process was dose dependent. PMID:20177577

Increased DNA damage in blood cells of rat treated with lead as assessed by comet assay

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Mohammad Arif

2008-06-01

Full Text Available A growing body of evidence suggests that oxidative stress is the key player in the pathogenesis of lead-induced toxicity. The present study investigated lead induced oxidative DNA damage, if any in rat blood cells by alkaline comet assay. Lead was administered intraperitoneally to rats at doses of 25, 50 and 100 mg/kg body weight for 5 days consecutively. Blood collected on day six from sacrificed lead-treated rats was used to assess the extent of DNA damage by comet assay which entailed measurement of comet length, olive tail moment, tail DNA (% and tail length. The results showed that treatment with lead significantly increased DNA damage in a dose-dependent manner. Therefore, our data suggests that lead treatment is associated with oxidative stress-induced DNA damage in rat blood cells which could be used as an early bio-marker of lead-toxicity.

Suppression of feline coronavirus replication in vitro by cyclosporin A

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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.

Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats

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Fiorim, Jonaina; Ribeiro Júnior, Rogério Faustino; Azevedo, Bruna Fernades; Simões, Maylla Ronacher; Padilha, Alessandra Simão; Stefanon, Ivanita; Alonso, Maria Jesus; Salaices, Mercedes; Vassallo, Dalton Valentim

2012-01-01

Seven day exposure to a low concentration of lead acetate increases nitric oxide bioavailability suggesting a putative role of K + channels affecting vascular reactivity. This could be an adaptive mechanism at the initial stages of toxicity from lead exposure due to oxidative stress. We evaluated whether lead alters the participation of K + channels and Na + /K + -ATPase (NKA) on vascular function. Wistar rats were treated with lead (1st dose 4 μg/100 g, subsequent doses 0.05 μg/100 g, im, 7 days) or vehicle. Lead treatment reduced the contractile response of aortic rings to phenylephrine (PHE) without changing the vasodilator response to acetylcholine (ACh) or sodium nitroprusside (SNP). Furthermore, this treatment increased basal O 2 − production, and apocynin (0.3 μM), superoxide dismutase (150 U/mL) and catalase (1000 U/mL) reduced the response to PHE only in the treated group. Lead also increased aortic functional NKA activity evaluated by K + -induced relaxation curves. Ouabain (100 μM) plus L-NAME (100 μM), aminoguanidine (50 μM) or tetraethylammonium (TEA, 2 mM) reduced the K + -induced relaxation only in lead-treated rats. When aortic rings were precontracted with KCl (60 mM/L) or preincubated with TEA (2 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 μM) or charybdotoxin (0.1 μM), the ACh-induced relaxation was more reduced in the lead-treated rats. Additionally, 4-AP and IbTX reduced the relaxation elicited by SNP more in the lead-treated rats. Results suggest that lead treatment promoted NKA and K + channels activation and these effects might contribute to the preservation of aortic endothelial function against oxidative stress. -- Highlights: ► Increased free radicals production ► Increased Na + /K + ATPase activity ► Promotes activation of the K + channels and reduced vascular reactivity ► These effects preserve endothelial function against oxidative stress. ► Low concentrations constitute environmental

Effects of fermented Cordyceps sinensis on oxidative stress in doxorubicin treated rats

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Wu, Rong; Gao, Jian-Ping; Wang, Hui-Lin; Gao, Yan; Wu, Qian; Cui, Xiao-Hua

2015-01-01

Background: Cordyceps sinensis (CS) is one of the rare traditional Chinese herbs, only a very limited amount of natural CS is produced. Fermented CS, as a substitute for natural CS, is widely used in the field of supplementary medical treatment and health products. Its antagonistic effect on oxidative stress (OS) in vivo has not been investigated. Objective: Our aim was to investigate the antagonistic effect of fermented CS on OS in doxorubicin (DOX) treated rats and to compare the anti-OS ef...

The application of lesion sterilization and tissue repair 3Mix-MP for treating rat's dental pulp tissue

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Raditya Nugroho

2015-03-01

Full Text Available Background: Lesion sterilization and tissue repair (LSTR 3Mix-MP are three broad-spectrum antibiotics, including metronidazole, ciprofloxacin and minocycline are mixed with propylene glycol or macrogol. There is the possibility ofthe healing process that marked proliferation ofnew blood vessels and proliferation offibroblasts in the treatment ofirreversible pulpitis by pulp capping LSTR 3MixMP because of  the principle of the method LSTR 3Mix-MP is to kill bacteria. Purpose: The purpose of this study to prove the effect of LSTR 3Mix-MP on chronic inflammation and the healing process in rat dental pulp tissue in vivo. Methods: Rattus norvegicus anaesthetized by using ketamine and xylazine dissolved in sterile isotonic saline solution (0.2 ml/50gr mm on the upper right thigh. Cavity preparation class I to perforation by using a low speed tapered diamond round bur. In the treatment group, rats were treated 3Mix-MP at a dose of10 mg and then covered with glass ionomer cement for 7 days on the pulp that has been opened for 3 days. The control group treated with saline irrigation on the pulp that has been opened for 3 days. Rats were killed after seven days, and then made preparations pulp tissue to count the number oflymphocytes, macrophages, plasma cells, blood vessels, and fibroblasts Results: There is an increase in the average number ofmacrophage cells, plasma, and fibroblasts; and decreased lymphocytes and blood vessels in the treated group exposure LSTR 3Mix-MP. Conclusion:LSTR 3Mix-MP can reduce chronic inflammation process and enhance the healing process in rat dental pulp tissue.

Congenital nephrotic syndrome may respond to cyclosporine A: A case report and review of literature

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Mulić Bilsana

2017-01-01

Full Text Available Introduction. Congenital nephrotic syndrome (CNF is manifested at birth or within the first three months of life. The Finnish-type of CNF is caused by the mutation of the NPHS1 gene, which encodes nephrin in the podocyte slit diaphragm. It is a very severe disease, for which immunosuppressive therapy is not advised. Here we describe a patient with CNF who responded to CsA by partial remission. Case outline. A girl aged 2.5 months presented with severe non-syndromic steroid-resistant nephrotic syndrome. She needed aggressive support including daily albumin infusions and diuretics. Substitution of vitamin D, thyroxin, and anticoagulants were regularly administered. She was also treated with angiotensin converting enzyme inhibitor, without clear benefits regarding proteinuria. In addition, she received intravenous gamma-globulin replacement therapy and antibiotics during frequent infections. While waiting for the results of genetic analyses and faced with many problems related to daily albumin infusions, infections, and thromboembolic complications, cyclosporine A (CsA was introduced as an alternative to early nephrectomy and consequent renal failure. The patient responded by partial remission and CsA treatment continued at home without the albumin infusions. After almost five years since the beginning of the treatment, the patient’s renal function remains unreduced. Conclusion. Our case demonstrates that CsA can induce partial remission in patients with genetic forms of steroid-resistant nephrotic syndrome without influencing the glomerular filtration rate. However, its long-term effect and safety should carefully be monitored. [Project of the Ministry of Education, Science and Technological Development of Republic of Serbia, Grant No. 175079

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

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Deli Giorgio

2008-12-01

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

Effect of aluminum chloride on blood glucose level and lipid profile in normal, diabetic and treated diabetic rats.

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Konda, Venugopala Rao; Eerike, Madhavi; Chary, R Prasanth; Arunachalam, Ruckmani; Yeddula, Venkata Ramana; Meti, Vinayak; Devi, T Sobita

2017-01-01

The objectives of the study were to assess evaluate the effects of aluminum chloride (AlCl 3 ) on blood glucose and lipid levels in normal, diabetic, and glibenclamide-treated diabetic rats. Forty-two male Wistar rats were divided into seven groups of six each. Group I was normal control, Groups II and III were given AlCl 3 50 and 100 mg/kg, and Group IV to VII were administered with streptozotocin (STZ) (60 mg/kg) intraperitoneally. Group IV was diabetic control, Group V in addition was given AlCl 3 50 mg/kg, Group VI glibenclamide (10 mg/kg), and Group VII glibenclamide and AlCl 3 (50 mg/kg) per-oral daily for 28 days. Blood glucose and lipid levels were estimated at base line, after diabetes was set in and on the last day of study. Histopathological changes in pancreas, liver, and kidney were studied. No significant change was observed in blood glucose and lipid levels in Group I. Group II and III showed a dose-dependent significant increase in blood glucose was observed. Group V had a reduction in blood glucose but not to the nondiabetic level. Group VI had significant reduction in blood sugar. In Group VII, treated with glibenclamide and AlCl 3 , there was no significant change in blood glucose reduction compared to Group VI. Lipid levels were reduced in groups treated with AlCl 3 and glibenclamide and not in other groups. Gross tissue damage was seen in pancreas in STZ group and in liver and kidney in AlCl 3 groups. AlCl 3 administration in Wistar rats caused in significant hyperglycemia in normal rats, hypoglycemia in diabetic rats, and did not influenced hypoglycemic effect of glibenclamide and in addition, resulted in reduction in lipid levels.

Partial recovery of erythrocyte glycogen in diabetic rats treated with phenobarbital

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da-Silva C.A.

1997-01-01

Full Text Available Erythrocytes may play a role in glucose homeostasis during the postprandial period. Erythrocytes from diabetic patients are defective in glucose transport and metabolism, functions that may affect glycogen storage. Phenobarbital, a hepatic enzyme inducer, has been used in the treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM, increasing the insulin-mediated glucose disposal. We studied the effects of phenobarbital treatment in vivo on glycemia and erythrocyte glycogen content in control and alloxan-diabetic rats during the postprandial period. In control rats (blood glucose, 73 to 111 mg/dl in femoral and suprahepatic veins the erythrocyte glycogen content was 45.4 ± 1.1 and 39.1 ± 0.8 µg/g Hb (mean ± SEM, N = 4-6 in the femoral artery and vein, respectively, and 37.9 ± 1.1 in the portal vein and 47.5 ± 0.9 in the suprahepatic vein. Diabetic rats (blood glucose, 300-350 mg/dl presented low (P<0.05 erythrocyte glycogen content, i.e., 9.6 ± 0.1 and 7.1 ± 0.7 µg/g Hb in the femoral artery and vein, respectively, and 10.0 ± 0.7 and 10.7 ± 0.5 in the portal and suprahepatic veins, respectively. After 10 days of treatment, phenobarbital (0.5 mg/ml in the drinking water did not change blood glucose or erythrocyte glycogen content in control rats. In diabetic rats, however, it lowered (P<0.05 blood glucose in the femoral artery (from 305 ± 18 to 204 ± 45 mg/dl and femoral vein (from 300 ± 11 to 174 ± 48 mg/dl and suprahepatic vein (from 350 ± 10 to 174 ± 42 mg/dl, but the reduction was not sufficient for complete recovery. Phenobarbital also stimulated the glycogen synthesis, leading to a partial recovery of glycogen stores in erythrocytes. In treated rats, erythrocyte glycogen content increased to 20.7 ± 3.8 µg/g Hb in the femoral artery and 30.9 ± 0.9 µg/g Hb in the suprahepatic vein (P<0.05. These data indicate that phenobarbital activated some of the insulin-stimulated glucose metabolism steps which were

Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine

International Nuclear Information System (INIS)

Irle, C.; Deeg, H.J.; Buckner, C.D.; Swedish Hospital Medical Center, Seattle, WA; Veterans Administration Hospital, Seattle, WA; Washington Univ., Seattle

1985-01-01

Fifty-six patients, 30-47 yr of age, with leukemia in relapse received allogeneic marrow transplants from HLA-identical siblings. All patients were treated with cyclophosphamide (120 mg/kg) and 7 daily fractions of 2.25 Gy of total body irradiation (TBI) for seven consecutive days. Nine patients (16%) are currently alive, free of disease, 324-845 days from transplantation. Actuarial relapse and survival rates at 2 yr were 56% and 9.5% respectively. These data were not remarkably different from those in previous studies using 10 Gy of TBI administered as a single dose. Thirty patients were randomized to receive methotrexate (MTX) and 26 to receive cyclosporine (CSP) as postgrafting prophylaxis for acute graft-versus-host disease (GVHD). Probability of developing significant acute GVHD by day 100 post-transplant was 71% for patients in the MTX group and 45% for patients in the CSP group (p<0.05). Probability of relapse was 37% for patients in the MTX group and 70% for patients in the CSP group (p<0.05). Transplant-related deaths were more frequent in the MTX group and leukemic deaths more frequent in the CSP group although this may have been related to an uneven distribution of high-risk patients. Long term disease-free survival was comparable. (author)

Preoperative preparation of high-risk, specifically hyperimmunized canine renal allograft recipients with total-lymphoid irradiation and cyclosporine

International Nuclear Information System (INIS)

Rapaport, F.T.; Meek, A.G.; Arnold, A.N.; Miura, S.; Hayashi, R.; Strober, S.

1987-01-01

Hyperimmunized subjects are a particularly high-risk and rapidly growing group in the patient population awaiting renal transplantation. In a search for methods designed to ameliorate the prognosis in such cases, dogs of defined DLA genotype were sensitized with DLA incompatible skin allografts and injections of buffy coat. Each recipient was challenged with a renal allograft bearing the same DLA incompatibilities. Five dogs received kidney transplants, without any other treatment, and rejected their transplants at 2.5, 4, 5, 6, and 6.5 days, respectively. Another four dogs were given a 9-11-week course (1760 +/- 35 cGy) of total-lymphoid irradiation (TLI), followed by rabbit antithymocyte globulin (ATG); these animals rejected their renal allografts at 7, 8, 14, and 17 days, respectively. Five other dogs were treated with TLI and received cyclosporine (CsA) and methylprednisolone (MPd) daily until graft rejection. Their renal allografts survived for 7.5, 8.5, 20, 62, and 227 days, respectively. Renal allografts placed in normal recipients under the same conditions of donor-recipient DLA incompatibility had a mean survival time of 12.4 days (range: 10-18 days). At the time of transplantation, the specific anti-DLA antibody titers in the recipients were 81 to 243 in the untreated dogs; 27 to 81 in the TLI-ATG-treated group, and 3 to 243 in the TLI-CsA/MPd-treated group. The titers fell within 24-48 hr after renal transplantation, to 3 to 81 in the untreated sensitized dogs; they were 3 to 9 in the TLI-ATG-treated group, and were 9 to 243 in the TLI-CsA/MPd treated group. The cytotoxic antibody titers reached postoperative peaks of 6500 to 200,000 in the untreated dogs; 729 to 6500 in the TLI-ATG-treated dogs, and 243 to 6500 in the TLI-CsA/MPd-treated recipients

Reproductive performance of rats treated with defatted jojoba meal or simmondsin before or during gestation.

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Cokelaere, M; Daenens, P; Decuypere, E; Flo, G; Kühn, E; Van Boven, M; Vermaut, S

1998-01-01

The effects on food intake, growth and reproductive performance parameters of defatted jojoba meal and pure simmondsin, an extract from jojoba meal, were compared in female Wistar rats. Rats fed 0.15% simmondsin or 3% defatted jojoba meal (equivalent to 0.15% simmondsin) for 8 weeks before conception showed a similar reduction in food intake (about 20%) and a similar growth retardation compared with controls. Both treatments induced a reduction in the number of corpora lutea on gestation day 16: this effect could be ascribed to the lower food intake before conception because it was also observed in rats pair-fed to the treated ones. Rats given feed containing 0.15% simmondsin or 3% defatted jojoba meal during days 1-16 of gestation showed a similar reduction in food intake relative to controls. Foetal and placental weights were reduced, relative to controls, to a similar extent in both groups, and the reductions were slightly greater than in the corresponding pair-fed groups. We conclude that the effects on food intake, growth and reproductive performance that were seen after feeding rats defatted jojoba meal were due to the simmondsin content of the meal. The simmondsin induced reduction in food intake and probably also a relative protein shortage.

Effects of Nigella sativa L. and Urtica dioica L. on selected mineral status and hematological values in CCl4-treated rats.

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Meral, Ismail; Kanter, Mehmet

2003-01-01

This study was designed to investigate the effects of Nigella sativa L. (NS), known as black seed, or/and Urtica dioica L. (UD), known as stinging nettle root, treatments on serum Na, K, Cl, and Ca levels and some hematological values of CCl4-treated rats. Sixty healthy male Sprague-Dawley rats, weighing 250-300 g, were randomly allotted into 1 of 4 experimental groups: A (CCl4-only treated), B (CCl4+UD treated), C (CCl4+NS treated), and D (CCl4+UD+NS treated), each containing 15 animals. All groups received CCl4 (0.8 mL/kg of body weight, subcutaneously, twice a week for 90 d starting d 1). In addition, B, C, and D groups also received the daily ip injection of 0.2 mL/kg NS and/or 2 mL/kg UD oils for 45 d starting d 46. Group A, on the other hand, received only 2 mL/kg normal saline solution for 45 d starting d 46. Blood samples for the biochemical analysis were taken by cardiac puncture from five randomly chosen rats in each treatment group at the beginning, d 45, and d 90 of the experiment. The CCl4 treatment for 45 d significantly (p0.05) the serum Na and Cl levels. NS or UD treatments (alone or combination) for 45 d starting d 46 significantly (p<0.05) decreased the elevated serum K and Ca levels and also increased (p<0.05) the reduced RBC, WBC, PCV, and Hb levels. It is concluded that NS and/or UD treatments might ameliorate the CCl4-induced disturbances of anemia, some minerals, and body's defense mechanism in CCl4-treated rats.

Impaired GABAergic Inhibition in the Prefrontal Cortex of Early Postnatal Phencyclidine (PCP)-Treated Rats

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Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe

2014-01-01

A compromised ¿-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-d-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmissio...... postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life....

Urinary metabonomics study on toxicity biomarker discovery in rats treated with Xanthii Fructus.

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Lu, Fang; Cao, Min; Wu, Bin; Li, Xu-zhao; Liu, Hong-yu; Chen, Da-zhong; Liu, Shu-min

2013-08-26

Xanthii Fructus (XF) is commonly called "Cang-Erzi" in traditional Chinese medicine (TCM) and widely used for the treatment of sinusitis, headache, rheumatism, and skin itching. However, the clinical utilization of XF is relatively restricted owing to its toxicity. To discover the characteristic potential biomarkers in rats treated with XF by urinary metabonomics. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was applied in the study. The total ion chromatograms obtained from control and different dosage groups were distinguishable by a multivariate statistical analysis method. The greatest difference in metabolic profile was observed between high dosage group and control group, and the metabolic characters in rats treated with XF were perturbed in a dose-dependent manner. The metabolic changes in response for XF treatment were observed in urinary samples, which were revealed by orthogonal projection to latent structures discriminate analysis (OPLS-DA), and 10 metabolites could be served as the potential toxicity biomarkers. In addition, the mechanism associated with the damages of lipid per-oxidation and the metabolic disturbances of fatty acid oxidation were investigated. These results indicate that metabonomics analysis in urinary samples may be useful for predicting the toxicity induced by XF. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Histomorphological and morphometric studies of the pancreatic islet cells of diabetic rats treated with aqueous extracts of Momordica charantia (karela fruits

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Mohammad Aftab Hossain

2014-09-01

Full Text Available Objective: To investigate the effect of aqueous extract of Momordica charantia (karela (M. charantia fruits on blood glucose level, pancreatic weight changes and histopathology of pancreatic changes in the streptozotocin (STZ induced diabetic rats. Methods: Thirty-six albino rats were used in the experiment; diabetes mellitus was induced in 30 adult albino rats, using intraperitoneal injection of 55 mg/kg STZ. Six non diabetic rats remained as control (T1 . The diabetic rats were randomly assigned into five equal groups: diabetic control (T2 without any treatment, groups T3, T4, T5 and T6 were treated with aqueous extract of karela fruits daily at a doses of 250, 500 and 750 mg/kg and glibenclamide (5 mg/kg up to 90 d, respectively. At Day 90, all rats were sacrificed, the pancreases of the rats were excised and processed. Results: The results of this study indicate that aqueous extract of M. charantia fruits was able to reduce blood glucose level significantly compared with the diabetic control group (P<0.01. Histopathologically, STZ resulted severe necrotic changes in pancreatic islets. Tissues sections of pancreas in the treated groups showed regeneration of β cells and increased size of pancreatic islets. Conclusions: The present study suggests that oral feeding of M. charantia fruit juice has a significant anti-hyperglycemic effect and may have a role in the regeneration of the β cells in STZ diabetic rats.

Simultaneous Determination of Cyclosporine A, Tacrolimus, Sirolimus, and Everolimus in Whole-Blood Samples by LC-MS/MS

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Mustafa Karapirli

2012-01-01

Full Text Available Objectives. Cyclosporine A (CyA, tacrolimus (TRL, sirolimus (SIR, and everolimus (RAD are immunosuppressive drugs frequently used in organ transplantation. Our aim was to confirm a robust sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS method for determination of CyA, TRL, SIR, and RAD in whole-blood samples. Materials and Methods. We used an integrated online solid-phase extraction-LC-MS/MS system and atmospheric pressure ionization tandem mass spectrometry (API-MS/MS in the multiple reaction monitoring (MRM detection mode. CyA, TRL, SIR, and RAD were simultaneously analyzed in whole blood treated with precipitation reagent taken from transplant patients. Results. System performance parameters were suitable for using this method as a high-throughput technique in clinical practice. The high concentration of one analyte in the sample did not affect the concentration of other analytes. Total analytical time was 2.5 min, and retention times of all analytes were shorter than 2 minutes. Conclusion. This LC-MS/MS method can be preferable for therapeutic drug monitoring of these immunosuppressive drugs (CyA, TRL, SRL, and RAD in whole blood. Sample preparation was too short and simple in this method, and it permits robust, rapid, sensitive, selective, and simultaneous determination of these drugs.

Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status

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Miraglia Sandra M

2010-01-01

Full Text Available Abstract Background Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out. Methods Thirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg, Amifostine (400 mg/kg, Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin and Sham Control (0.9% saline solution. "Standard One Way Anova" parametric and "Anova on Ranks" non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p Results The rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration. Conclusions These results suggest that

Eosinophils, pruritus and psoriasis: effects of treatment with etretinate or cyclosporin-A.

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Schopf, R E; Hultsch, T; Lotz, J; Bräutigam, M

1998-11-01

The antipsoriatic drugs cyclosporin A (CyA) and etretinate have been found to influence proinflammatory eosinophilic leukocytes and pruritus. We compared the number of blood eosinophils, concentration of serum eosinophil cationic protein (ECP), and pruritus in patients with psoriasis treated with either CyA or etretinate. Patients with psoriasis vulgaris were randomly assigned to treatment for 10 weeks with either CyA (n = 21) or etretinate (n = 10). The psoriasis area-and-severity index (PASI-score) and pruritus (according to a 0-3 scale) served as clinical parameters, the blood esosinophil counts (Coulter Counter) and the serum ECP (RIA, Pharmacia) as laboratory parameters. After CyA treatment the PASI-score amounted to 24 +/- 4%, after etretinate to 56 +/- 6% of the initial values (mean +/- SEM). One week after CyA treatment, esosinophils dropped from 190 +/- 21 to 137 +/- 16/microliter (P = 0.038, Wilcoxon test), after 10 weeks to 127 +/- 18/microliter (P = 0.006). By contrast, under etretinate blood eosinophil counts only changed marginally. Before treatment, ECP concentrations of 15.71 +/- 1.30 (CyA) and 15.3 +/- 5.53 micrograms/l (etretinate) were measured (normal range 3-16 micrograms/l), ECP remained constant under both CyA and etretinate or tended to increase after 10 weeks; about 50% of the patients exhibited elevated ECP concentrations. Pruritus diminished more with CyA than etretinate therapy. PASI-scores and pruritus were directly proportional. We conclude that treatment of psoriasis with CyA leads to a rapid drop of blood eosinophils and that the activation state of eosinophils does not decrease after antipsoriatic treatment. Pruritus in psoriasis is coupled to disease severity. The underlying antipsoriatic mechanisms of CyA may be linked to lowering the number of blood eosinophils.

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences.

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Wong, Alexander; Keats, Kirily; Rooney, Kieron; Hicks, Callum; Allsop, David J; Arnold, Jonathon C; McGregor, Iain S

2014-10-01

Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences. Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation. Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THC-COOH) also measured. Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise. These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.

Role of thirst and visual barriers in the differential behavior displayed by streptozotocin-treated rats in the elevated plus-maze and the open field test.

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Rebolledo-Solleiro, Daniela; Crespo-Ramírez, Minerva; Roldán-Roldán, Gabriel; Hiriart, Marcia; Pérez de la Mora, Miguel

2013-08-15

Conflicting results have been obtained by several groups when studying the effects of streptozotocin (STZ)-treated rats in the elevated plus-maze (EPM). Since thirst is a prominent feature in STZ-induced diabetic-like condition, we studied whether the walls of the closed arms of the EPM, by limiting the search for water in the environment, may contribute to the observed differential behavioral outcomes. The aim of this study was to ascertain whether visual barriers within the EPM have an influence on the behavior of STZ-treated rats in this test of anxiety. A striking similarity between STZ-treated (50 mg/kg, i.p., in two consecutive days) and water deprived rats (72 h) was found in exploratory behavior in the EPM, showing an anxiolytic-like profile. However the anxiolytic response of STZ-treated rats exposed to the EPM shifts into an anxiogenic profile when they are subsequently tested in the open-field test, which unlike the EPM is devoid of visual barriers. Likewise, water deprived rats (72 h) also showed an anxiogenic profile when they were exposed to the open-field test. Our results indicate that experimental outcomes based on EPM observations can be misleading when studying physiological or pathological conditions, e.g. diabetes, in which thirst may increase exploratory behavior. © 2013.

Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

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Huang, Han-Chang; Zheng, Bo-Wen; Guo, Yu; Zhao, Jian; Zhao, Jiang-Yan; Ma, Xiao-Wei; Jiang, Zhao-Feng

2016-04-05

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Efficacy of curcumin to reduce hepatic damage induced by alcohol and thermally treated oil in rats

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Nasr A.M.N. El-Deen

2010-03-01

Full Text Available The authors investigated the effect of curcumin on markers of oxidative stress and liver damage in rats that chronically ingested alcohol and heated oil. Nine groups of ten Wistar male rats received combinations of curcumin 100 mg/kg body weight daily, ethanol 5 mg/kg, 15% dietary sunflower oil and 15% heated sunflower oil for 12 weeks. Serum and liver tissue were collected. Groups 4-6, which had received compounds causing oxidative stress, showed increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, triglycerides, low density lipoprotein, very low density lipoprotein and reduced high density lipoprotein, protein and albumin, compared with the controls. Reductions were observed in glutathione peroxidase and reductase gene expression, superoxide dismutase activity, glutathione peroxidase activity, glutathione reductase activity, reduced glutathione concentration and catalase enzyme activity. Groups 7, 8 and 9 which received curcumin with heated oil, ethanol or both, showed lower elevations in serum and oxidative damage markers compared with the corresponding non-curcumin treated groups.It can be concluded that curcumin reduces markers of liver damage in rats treated with heated sunflower oil or ethanol.

Outcome of Cyclosporine Monotherapy in Patients of Aplastic Anemia: Experience of a Tertiary Care Hospital in Eastern India.

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Mandal, Prakas Kumar; Baul, Suvraneel; Dolai, Tuphan Kanti; De, Rajib; Chakrabarti, Prantar

2017-03-01

Immune suppression is a crucial pillar for treatment of aplastic anemia. Cyclosporine monotherapy is an easily available, affordable therapeutic option with good safety profile. This prospective study was conducted over a period of 2 years from June 2012 to July 2014. The diagnosis and response to treatment of aplastic anemia was established as per published criteria. Follow up was done at 3 and 6 months in order to assess the response. 57 patients of acquired aplastic anemia with median age of 37 years (6 to 81 years) were included in the study. 35 (62 %) cases were severe aplastic anemai, 16 (28 %) non severe aplastic anemia and 6 (10 %) were very severe aplastic anemia. At 3 months overall response rate (OR) was 7 (14 %) and at 6 months the OR rate of 11 (19.6 %) was achieved. Transiently raised creatinine, liver function abnormality and gum hypertrophy were the main side effects observed in this cohort. Oral cyclosporine monotherapy at dose of 5 mg/kg/day is a relatively safe treatment option for resource poor patients with aplastic anemia.

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.

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

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Andrews, Jessica L; Newell, Kelly A; Matosin, Natalie; Huang, Xu-Feng; Fernandez-Enright, Francesca

2015-12-03

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that

Analysis of genomic responses in a rat lung model treated with a humidifier sterilizer containing polyhexamethyleneguanidine phosphate.

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Kim, Min-Seok; Jeong, Seok Won; Choi, Seong-Jin; Han, Jin-Young; Kim, Sung-Hwan; Yoon, Seokjoo; Oh, Jung-Hwa; Lee, Kyuhong

2017-02-15

The antimicrobial biocide polyhexamethyleneguanidine (PHMG) phosphate is the main ingredient in the commercially available humidifier disinfectant. PHMG phosphate-based humidifier disinfectants can cause pulmonary fibrosis and induce inflammatory and fibrotic responses both in vivo and in vitro. However, toxicological mechanisms including genomic alterations induced by inhalation exposure to PHMG phosphate have not been elucidated. Therefore, this study evaluated the toxicological effects of the PHMG phosphate-containing humidifier disinfectant. We used DNA microarray to identify global gene expression changes in rats treated with PHMG phosphate-containing humidifier disinfectant for 4 weeks and 10 weeks. Functional significance of differentially expressed genes (DEGs) was estimated by gene ontology (GO) analysis. Four weeks post-exposure, 320 and 392 DEGs were identified in female and male rats, respectively (>2-fold, pPHMG phosphate exposure. In addition, 21 genes were upregulated and 4 genes were downregulated in response to PHMG phosphate in a time-dependent manner. Thus, we predict that changes in genomic responses could be a significant molecular mechanism underlying PHMG phosphate toxicity. Further studies are required to determine the detailed mechanism of PHMG phosphate-induced pulmonary toxicity. Copyright © 2016. Published by Elsevier B.V.

Cholesterol biosynthesis in polychlorinated biphenyl-treated rats