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Effects of Methylprednisolone and Its Liver-Targeted Dextran Prodrug on Ischemia–Reperfusion Injury in a Rat Liver Transplantation Model

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Abstract

Purpose

To evaluate the effectiveness of a liver-targeted dextran prodrug (DMP) of methylprednisolone (MP) in cold preservation–warm reperfusion injury associated with liver transplantation.

Methods

The effects of donor pretreatment with single 5 mg/kg doses of MP or DMP on ischemia–reperfusion damage to the liver were studied after 8 or 24 h of cold preservation in both isolated perfused rat liver (IPRL) and syngeneic orthotopic rat liver transplantation (OLT) models.

Results

In IPRL studies, donor pretreatment with DMP, and to a lesser degree MP, significantly improved the uptake of hyaluronic acid (HA), a marker of endothelial cell function, following 8 h of cold preservation. However, neither pretreatment was protective after 24 h of preservation. In the OLT model using 24-h-preserved livers, the seven-day survival of untreated grafts was 50%. DMP pretreatment of donors significantly improved graft survival to 100%, whereas MP pretreatment was ineffective. Additionally, only DMP significantly increased the blood glucose concentrations and decreased the plasma concentrations of tumor necrosis factor-α after OLT. Other measured markers of liver injury were not affected by either pretreatment.

Conclusions

Selective delivery of methylprednisolone to the liver as a donor pretreatment strategy improves 24-h preserved graft survival in the OLT model.

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Acknowledgement

This work was partially supported by a grant from the National Institute of General Medical Sciences of NIH (R01 GM069869). The authors would like to acknowledge Imam H. Shaik for his technical assistance.

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Author notes

  1. Anjaneya P. Chimalakonda

    Present address: Bristol-Myers Squibb Co., Pennington, New Jersey, USA

Authors and Affiliations

  1. School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter, Amarillo, Texas, 79106, USA

    Anjaneya P. Chimalakonda & Reza Mehvar

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  1. Anjaneya P. Chimalakonda
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  2. Reza Mehvar
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Correspondence to Reza Mehvar.

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Chimalakonda, A.P., Mehvar, R. Effects of Methylprednisolone and Its Liver-Targeted Dextran Prodrug on Ischemia–Reperfusion Injury in a Rat Liver Transplantation Model. Pharm Res 24, 2231–2238 (2007). https://doi.org/10.1007/s11095-007-9414-1

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  • DOI: https://doi.org/10.1007/s11095-007-9414-1

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