Hepatitis liver transplantation

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... 

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. 

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. 

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. 

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... 

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. 

Chazouilleres, O., et al. (1994). Quantitation of hepatitis C virus RNA in liver transplant recipients. Gastroenterology 106,994-999. 

Pessoa, M. G., et al. (1997). Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation. Hepatology 25,1266-1270. 

Svoboda-Newman SM, Greenson JK, Singleton TP, et al. Detection of hepatitis C by RT-PCR in formalin-fixed paraffin-embedded tissue from liver transplant patients. Diagn. Mol. Pathol. 1997 6 123-129. 

In cases in which drug treatment management is not successful, liver transplantation can be used. This is a highly effective treatment to correct the hepatic and metabolic problems, but neurologic symptoms and signs are often irreversible. 

Thummel, K.E., Shen, D.D., Podoll,T.D., Kunze, K.L., Trager, W.F., Bacchi, C.E., Marsh, C.L., McVicar, J.P., Barr, D.M., Perkins, J.D., Carithers, R.L. (1994) Use of midazolam as a human cytochrome P450 3A probe. II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. Journal of Pharmacology and Experimental Therapeutics, 271 (1), 557-566. 

The main indications for liver transplantation include chronic hepatitis C, alcoholic liver disease, nonalcoholic fatty liver disease, and cryptogenic cirrhosis. 

Rare cases of hepatic failure, some leading to death or liver transplant, have occurred with the use of terbinafine for the treatment of onychomycosis in individuals with and without pre-existing liver disease. In the majority of liver cases reported in association with terbinafine use, the patients had serious underlying systemic conditions and an uncertain causal relationship with terbinafine. Terbinafine is not recommended for patients with chronic or active liver disease. Before prescribing terbinafine, assess pre-existing liver disease. Hepatotoxicity may occur in patients with and without preexisting liver disease. Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking terbinafine. 

Hepatic failure Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine for the treatment of onychomycosis in individuals with and without pre-existing liver disease. 

Renal/Hepatic function impairment The use of tacrolimus in liver transplant recipients experiencing posttransplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

Hepatic artery thrombosis In de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in P.1153... 

Hepatotoxicity Hepatotoxicity has been noted in 4%, 7%, and 4% of renal, cardiac, and liver transplantation cases, respectively. This usually occurred during the first month of therapy when high doses were used, and consisted of elevated hepatic enzymes and bilirubin. 

Hepatic function impairment Severe liver dysfunction, leading to hepatic failure requiring liver transplantation, has been reported very rarely in patients taking interferon beta. 

Wall WJ, Liver transplantation for hepatic and biliary malignancy. Semin Liver Dis 2000 20(4) 425-136. 

Gene expression inhibition. Chloroform/ methanol extract (1 1) of the dried leaf, in cell culture, was active on hepatoma-Cos-7, IC50 600.0 pg/mL vs TAT-dependent activation of HIV promoter hioassay - . Hepatotoxic activity. The leaf, taken orally by a female adult, was active - . A patient consumed 15 tablets of the leaf per day for 4 months. Approximately 1 year after stopping consumption, liver enzymes returned to normal and fatigue was no longer a complaint - ". Infusion of the dried leaf, taken orally by a female adult at variable doses, was active. The 60-year-old woman who took Lama tridentata for 10 months developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient s condition deteriorated and required orthotropic liver transplantation - " . Dried leaves, administered orally to adults at variable doses, were active. A public warning has been issued by the US Centers for Disease Control based on reports of liver toxicity after use of Lama tridentata tea - " k Dried leaves, administered orally to adults of both sexes at variable doses, were active - ". The plant, administered orally to adults at variable doses, was active - ". Dried leaves, administered orally to adults at variable doses, were active. One case of hepatotoxicity induced by Larrea tridentata taken as a nutritional supplement was reported - ". Thirteen patients were identified for whom Larrea tridentata tincture for internal use was prescribed. Additionally, 20 female and three male patients were identified from whom an extract of Larrea tridentata in castor oil for... 

Unlabeled Uses Prophylaxis of liver transplant rejection, treatment of alcoholic cirrhosis, biliary atresia, chronic hepatitis, gallstone formation, sclerosing cholangitis... 

Hepatitis C virus (HCV) is an RNA virus that is a common cause of parenterally acquired viral hepatitis chronic infection follows acute infection in 80% to 85% of cases. Although liver disease resulting from chronic HCV infection is only slowly progressive, HCV is the most common cause of chronic liver disease in the United States, the most common etiology for hepatocellular carcinoma, and the leading indication for liver transplantation [34-36]. 

Liver disease is the most common medical complication of alcohol abuse an estimated 15-30% of chronic heavy drinkers eventually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection with hepatitis or C virus increases the risk of severe liver disease. 

Postoperative hepatic dysfunction is typically associated with factors such as blood transfusions, hypovolemic shock, and other surgical stresses rather than volatile anesthetic toxicity. However, a small subset of individuals who have been previously exposed to halothane may develop potentially life-threatening hepatitis. The incidence of severe hepatotoxicity following exposure to halothane is in the range of one in 20,000-35,000. Obese patients who have had more than one exposure to halothane during a short time interval may be the most susceptible. There is no specific treatment for halothane hepatitis, and therefore liver transplantation may ultimately be required in the most severe cases. 

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