An underlying role for hepatobiliary dysfunction in cyclosporine A nephrotoxicity

Aleo, Michael D.; Doshna, Colleen M.; Fritz, Carol A.

doi:10.1016/j.taap.2008.02.011

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…Thus, both liver and kidney toxicity are major limitations when using CsA clinically. [ 42,52 ] It is well‐known that three interconnected mechanisms namely increased oxidative stress, inflammation, and apoptosis play an important role in mediating CsA induced organ damage. An imbalance between the harmful prooxidants and protective antioxidants has been shown to disrupt normal cellular functioning and membrane integrity.…”

Section: Discussionmentioning

confidence: 99%

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

Vangaveti

Das

Kumar

2020

J Biochem & Molecular Tox

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The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor‐alpha, prostaglandin E2), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)‐2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose‐dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX‐2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long‐term CsA treatment to maintain their liver and kidney functions.

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Section: Discussionmentioning

confidence: 99%

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

Vangaveti

Das

Kumar

2020

J Biochem & Molecular Tox

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“…Conversely, chronic CsA nephrotoxicity represents a more serious concern in patients receiving long-term (lifetime) CsA treatment, and it is associated with progressive and irreversible renal interstitial fibrosis, and clinically significant renal dysfunction eventually leading to end-stage renal failure (Cattaneo et al, 2004;Danovitch, 2005;Fellstrom, 2004;Paul and de Fijter, 2004). Renal exposure to and accumulation of systemically derived cysteinyl leukotrienes, such as leukotriene C4 and D4 products, may be underlying factors in CsA nephrotoxicity (Aleo et al, 2008). Our study protocol consisted of brief administration (24 h) of a therapeutic dose of CsA within the recognized dosing range of 5-6 mg=kg, and was associated with none of these effects.…”

Section: Effect Of Csa On Renal Functionmentioning

confidence: 99%

“…This did not seem to be CsA-related, as this was also seen in the placebo group. In the literature, hyperbilirubinemia has been related to disturbed bile secretion, rather than hepatocellular damage, and no hepatic histological lesions have been described in humans after the use of CsA (Aleo et al, 2008;Danovitch, 2005;Min and Monaco, 1991;Rezzani, 2004).…”

Section: Effects Of Csa On Hepatic Functionmentioning

confidence: 99%

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

Mazzeo

Brophy

Gilman

et al. 2009

Journal of Neurotrauma

100

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Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg=kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg=kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

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“…Leukotrienes are also contributory to drug and chemical induced toxicity (Gonzalez et al, 1994; Scuito and Hurt, 2004; Aleo et al, 2008) with renal vasoconstrictor leukotrienes playing a key role in cyclosporine A nephrotoxicity (Butterly et al, 2000; Atakan et al, 2008). The results of this study provide additional evidence that leukotrienes contribute to NDPS nephrotoxicity, at least at minimal nephrotoxic doses.…”

Section: Discussionmentioning

confidence: 99%

Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats

Rankin¹,

Hong²,

Anestis³

et al. 2012

Toxicology

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The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4 mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500 mg/kg, ip), an inhibitor of LTA4 synthesis, 1h before NDPS (0.4 mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4 mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1 mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD4 receptor antagonist LY171883 (100 mg/kg, po) was administered 0.5 h before and again 6 h after NDHS (0.1 mmol/kg, ip) or 2-NDHSA (0.1 mmol/kg, ip) or vehicle. Renal function was monitored for 48 h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.

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An underlying role for hepatobiliary dysfunction in cyclosporine A nephrotoxicity

Cited by 6 publications

References 45 publications

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats

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