Transplantation, liver

Liver diseases Alcoholic hepatitis (A), hepatitis B and C (A), non-alcoholic steatohepatitis (A), liver transplantation (A), Wilson s disease (A)... 

IDN-6556 Idun Pharm. (Pfizer) Caspase-1, -3, -6, -7, -8, -9 (irreversibly) IC50 25 nM Hepatitis C Liver transplantation Phase II... 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Haddad EM, McAlister VC, Renouf E et al (2006) Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev (4) CD005161... 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

Ealagas ME, Paya C, Ruthazer R, Badley A, Patel R, Wiesner R et al. (1998) Significance of cytomegalovirus for long-term survival after orthotopic liver transplantation a prospective derivation and validation cohort analysis. Transplantation 66 1020-1028 Field AK (1999) Human cytomegalovirus challenges, opportunities and new drug development. Antivir Chem Chemother 10 219-232... 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

At present, severe ai-antitrypsin deficiency liver disease can be successfully treated by liver transplantation. In the future, introduction of the gene for normal ttj-antitrypsin into hepatocytes may become possible, but this would not stop production of the PiZ protein. Figure 50-7 is a scheme of the causation of this disease. 

Atalla, S.L., Toledo-Pereyra, L.H., MacKenzie, G.H. and Cederna, J.P. (1985). Influence of oxygen derived free radical scavengers on ischaemic livers. Transplantation 40, 584-590. 

Parks, D.A., Tan, S., Poplawski, S.C., Baldwin, S. and Sweeney, S.D. (1992). Uric acid oxidation products indicator of oxidant stress in human liver transplantation. Gastroenterology 102, A232. 

Liver transplantation is increasingly used for treatment of end-stage liver disease and thousands of transplants are... 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

As stated at the beginning of this article, the liver is the most intensively studied animal tissue in biochemistry. In the context of the role of free radicals in human diseases, the liver is not obviously at centre stage, since heart disease and cancer are more important in the industrialized world than, for example, cirrhosis. Free-radical biochemistry of the liver will remain a fertile area of work, however, not least because so many original ideas and techniques are developed there and then applied to the study of other tissues. The increasing use of liver transplantation, following the acceptance of kidney and heart transplants as almost routine, will surely increase the interest in the study of ischaemia-reperfusion injury in... 

Connor, H.D., Gao, W., Nukina, S., Lemasters, J.J., Mason, R.P. and Thurman, KG. (1992). Evidence that free radicals are involved in graft failure following orthotopic liver transplantation in the rat an electron paramagnetic resonance spin trapping study. Transplantation 54, 199-204. 

Managing viral hepatitis involves both prevention and treatment. Prevention of hepatitis A and B (and indirectly for hepatitis D) can be achieved with immune globulin or vaccines. There is no specific pharmacologic treatment for acute viral hepatitis A, B, C, D, or E only supportive care is available. Individuals with mild to moderate symptoms rarely require hospitalization. Occasionally, hospitalization is required in individuals experiencing significant nausea, vomiting, diarrhea, and encephalopathy. Liver transplantation may be required in rare instances if fulminant hepatitis develops. 

While there are no FDA-approved treatments for hepatitis D, interferon has been shown to be effective.46 48 Various doses have been evaluated, with the most effective treatment being 9 million units three times weekly.47 Seventy-one percent of patients who were treated with this regimen for 48 weeks had normalized ALT levels.47 Adverse effects and monitoring parameters for interferon therapy are similar to treatment for hepatitis C. In some situations, patients infected with hepatitis D who develop hepatic decompensation and ESLD may need to undergo liver transplantation. 

First successful living-donor liver transplant 1989... 

An intestine transplant may involve the use of an entire intestine or just a shortened segment. Most intestine transplants completed in the United States have involved the transplant of the full organ and often are performed in conjunction with a liver transplant. Although most intestine transplants involve organs harvested from a deceased donor, recent advances in the field now have made it possible for living-donor intestinal segment transplants. There were 178 intestinal transplant recipients (171 deceased donors, 7 living donors) in 2005.3... 

Muronomab-CD3 (OKT-3) is a murine monoclonal antibody that targets the CD3 receptor. The CD3 receptor is only found on activated T cells and medullary thymocytes.10,11,14 After binding with the CD3 receptor, complement-mediated T cell lysis occurs rapidly. This agent is dosed at 5 mg/day. This dose is given daily for 10 to 14 days. Lower doses have been used successfully in liver transplant recipients.14... 

The most common adverse events reported with sirolimus are leukopenia (20%), thrombocytopenia (13% to 30%), and hyperlipidemia (38% to 57%).11,31 Other adverse effects include delayed wound healing, anemia, diarrhea, arthralgias, rash, and mouth ulcers. Sirolimus has an FDA black-box warning in newly transplanted liver and lung recipients.11 In liver transplant recipients, use of sirolimus immediately after transplant is associated with an increased risk of hepatic artery thrombosis, graft loss, and death. In lung transplant... 

Hyperlipidemia is seen in up to 60% of heart, lung, and renal transplant patients and greater than 30% of liver transplant patients.64 66 As a result of elevated cholesterol levels, transplant recipients are not only at an increased risk of atherosclerotic events, but emerging evidence also shows an association between hyperlipidemia and allograft vasculopathy.66 Hyperlipidemia, along with other types of cardiovascular disease, is now one of the primary causes of morbidity and mortality in long-term transplant survivors.67... 

Reding R, Davies HF. Revisiting liver transplant immunology from the concept of immune engagement to the dualistic pathway paradigm. Liver Transpl 2004 10 1081-1086. 

Thummel, K. E. etal. (1994). Use of midazolam as a human cytochrome P450 3A probe II. Characterization of inter- and in train dividual hepatic CYP3A variability after liver transplantation. /. Pharmacol. Exp. Ther., 271, 557-66. 

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