HEGPOL: Randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312]

Abstract

BackgroundKupffer cell-dependent ischemia / reperfusion (I/R) injury after liver transplantation is still of high clinical relevance, as it is strongly associated with primary dysfunction and primary nonfunction of the graft. Glycine, a non-toxic, non-essential amino acid has been conclusively shown in various experiments to prevent both activation of Kupffer cells and reperfusion injury. Based on both experimental and preliminary clinical data this study protocol was designed to further evaluate the early effect of glycine after liver transplantation.Methods / designA prospective double-blinded randomized placebo-controlled multicenter study with two parallel groups in a total of 130 liver transplant recipients was designed to assess the effect of multiple intravenous doses of glycine after transplantation. Primary endpoints in hierarchical order are: peak levels of both aspartat-amino-transaminase (AST) and alanine-amino-transaminase (ALT) as surrogates for the progression of liver related injury, as well as both graft and patient survival up to 2 years after transplantation. Furthermore, the effect of glycine on cyclosporine A-induced nephrotoxicity is evaluated.DiscussionThe ongoing clinical trial represents an advanced element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a randomized, prospective, controlled double-blinded clinical trial. If the data of this ongoing research project confirm prior findings, glycine would improve the general outcome after liver transplantation.

Glycine inhibits angiogenesis in colorectal cancer: role of endothelial cells

“…Thus, pharmacokinetics and pharmacodynamics of this substance and possible side effects, like wound healing deficiencies, are well known and well documented (Evins et al 2000;Luntz et al 2005).…”

“…Glycine is a simple amino acid that can be applied orally or intravenously without relevant toxicity (Luntz et al 2005;Kaufman et al 2009;Evins et al 2000;Gannon et al 2002). Besides being a major inhibitory neurotransmitter via the activation of the glycine receptor (GlyR) in central nervous system, glycine has been shown to protect against acute liver injury that occurs after warm or cold ischemia, or after toxic liver injury possibly resulting from the chemotherapy regimens commonly used for CRC Hoffmann et al 2011;Mikalauskas et al 2011;Schindler et al 2009;Zhong et al 2003;Schemmer et al 2002;Wheeler et al 1999;Amin et al 2003).…”

Glycine Protects the Liver from Reperfusion Injury following Pneumoperitoneum

“…There is no toxicity detected after oral or intravenous glycine application [7][8][9]. Furthermore, several studies have demonstrated that glycine prevents acute liver injury occurring after warm or cold ischemia by the inhibition of KC activation [10][11][12][13][14][15].…”

“…Furthermore, several studies have demonstrated that glycine prevents acute liver injury occurring after warm or cold ischemia by the inhibition of KC activation [10][11][12][13][14][15]. This inhibition most likely occurs through a glycine-gated voltage-sensitive Cl channel in the surface membrane of the KCs [7,10]. After glycine binds to this channel, Cl ions enter the cell and hyperpolarize the KC membranes, which makes it more difficult to open Ca ion channels.…”

Control of Ischemia-Reperfusion Injury in Liver Transplantation: Potentials for Increasing the Donor Pool

“…A prospective randomized clinical trial on recipient preconditioning with glycine is currently ongoing [32]. Glycine and taurine preconditioning in steatotic rat livers were shown to be equally effective in the prevention of IRI, most likely via Kupffer cell-dependent mechanisms by decreasing interactions between leukocytes and platelets with endothelial cells and phagocytosis [33].…”