Liver hepatic disease

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... 

Warning associated with the administration of estrogen include an increased risk of endometrial cancer, gallbladder disease, hypertension, hepatic adenoma (a benign tumor of the liver), cardiovascular disease, increased risk of thromboembolic disease and hypercalcemia in those with breast cancer and bone metastases. 

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning.20... 

Chronic hepatitis (disease lasting longer than 6 months) is usually associated with hepatitis B, C, and D. Chronic viral hepatitis may lead to the development of cirrhosis, which may induce end-stage liver disease (ESLD). Complications of ESLD include ascites, edema, jaundice, hepatic encephalopathy, infections, and bleeding esophageal varices. Therefore, prevention and treatment of viral hepatitis may prevent ESLD. 

Human foods that are particularly rich in copper (20 to 400 mg Cu/kg) include oysters, crustaceans, beef and lamb livers, nuts, dried legumes, dried vine and stone fruits, and cocoa (USEPA 1980). In humans, copper is present in every tissue analyzed (Schroeder et al. 1966). A 70-kg human male usually contains 70 to 120 mg of copper (USEPA 1980). The brain cortex usually contains 18% of the total copper, liver 15%, muscle 33%, and the remainder in other tissues — especially the iris and choroid of the eye. Brain gray matter (cortex) has significantly more copper than white matter (cerebellum) copper tends to increase with increasing age in both cortex and cerebellum. In newborns, liver and spleen contain about 50% of the total body burden of copper (USEPA 1980). Liver copper concentrations were usually elevated in people from areas with soft water (Schroeder et al. 1966). Elevated copper concentrations in human livers are also associated with hepatic disease, tuberculosis, hypertension, pneumonia, senile dementia, rheumatic heart disease, and certain types of cancer (Schroeder et al. 1966). 

Active hepatic disease, such as acute hepatitis or active cirrhosis if previous methyidopa therapy has been associated with liver disorders coadministration with MAOIs hypersensitivity to any component of these formulations, including sulfites. 

Hepatic disease Although studies in patients with liver disease have not been done, it is likely that functional hepatic impairment will reduce the clearance of tacrine and its metabolites. 

Liver Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequent, usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have occurred these latter lesions often are not preceded by symptoms or abnormal liver function tests (see Precautions). For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the RA population. 

III.e.3.1. Hepatic disease. The liver, like the gut, has enormous redundancy and up to 80% of the organ can be removed without affecting many of its functions including most of the metabolic processes involved in the metabolism of drugs. 

Pharmacokinetics Poorly absorbed from the G1 tract. Protein binding greater than 98%. Metabolized in the liver. Minimally eliminated in urine. Plasma levels are markedly increased in chronic alcoholic hepatic disease, but are unaffected by renal disease. Half-life 14 hr. 

I Contraindications Active hepatic disease, unexplained elevated liver function test results... 

Geriatric Considerations - Summary Age is not a contraindication to INH prophylaxis or treatment of tuberculosis. Follow adult guidelines for treatment. INH maybe used in patient wit h stable hepatic disease. The risk of clinical hepatitis increases with age and has been reported in 2% of adults aged greater than 50. INH interferes with the metabolism of pyridoxine therefore concomitant pyridoxine therapy at 25mg/day is recommended to prevent neurotoxicity. INH is metabolized via acetylation in the liver. Older adults who are slow acetylators of the drug may require lower doses to achieve effective serum concentrations and prevent adverse effects. Food, especially high-fat meals, delays and reduces absorption therefore administer INH on an empty stomach. 

Pharmacokinetics Well absorbed from theGl tract minimally absorbed after topical application. Protein binding less than 20%. Widely distributed crosses blood-brain barrier. Metabolized in the liver to active metabolite. Primarily excreted in urine partially eliminated in feces. Removed by hemodialysis. Half-life 8 hr (increased in alcoholic hepatic disease). 

Variably absorbed from the GI tract. Readily absorbed after IM or subcutaneous administration. Protein binding 20%-35%. Widely distributed. Metabolized in the liver. Primarily excreted in urine. Removed by hemodialysis. Half-life 2-3 hr (increased in patients with hepatic disease)... 

Periodic assessment of liver transaminases in patients with significant hepatic disease... 

About a third of an administered dose of rocuronium is excreted in the urine, the rest being taken up by the liver and excreted unchanged in the bile. Its elimination half-life is just under 100 minutes (Table 6.4). Unlike other aminosteroid relaxants, only very small amounts of the metabolite 17-desacetyl rocuronium have been found in plasma. The clearance of rocuronium is reduced in patients with significant renal and hepatic disease, with a possible prolongation of effect. The same mechanisms are responsible for prolongation of the block in the elderly. 

The liver is involved in a variety of both synthetic and catabolic functions, including metabolism of amino acids, lipids, carbohydrates, protein synthesis and detoxification [ 1 ]. These metabolic functions are performed mainly by hepatocytes, although the liver is made of three major cell types (hepatocytes, biliary epithelial cells and Kupffer cells). Exerting many different metabolic functions, the liver contains several different and specific enzymes, leakage of which into the bloodstream occurs in hepatic diseases. 

In patients with acute hepatitis and active hepatitis, protein binding of the glucocorticoids will be reduced and peak concentrations of administered glucocorticoids increased. Conversion of prednisone to prednisolone has been reported to be impaired in chronic active liver disease (409). However, although plasma prednisolone concentrations were more predictable after the administration of prednisolone than of prednisone to a group of healthy subjects (410), there was no difference in patients with chronic active hepatitis. There was also impaired elimination of prednisolone in these patients. In a review of the pharmacokinetics of prednisone and prednisolone it was concluded that fear of inadequate conversion of prednisone into prednisolone was not justified (411). Patients with hepatic disease suffer adrenal suppression more readily (111). 

Comparable reports have prompted a questionnaire investigation of 770 patients with type 2 diabetes at the start of acarbose therapy (62). Patients with one or more susceptibility factors for liver damage underwent ultrasonography and autoantibody assays. There was silent liver disease in 13% and 20 patients had a fatty liver without hepatic disease. In 15% of these patients there were slight reversible changes in transaminase activity after acarbose. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

A number of gastrointestinal and hepatic diseases result in disordered calcium and phosphate homeostasis that ultimately leads to bone disease. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur (as it does in renal osteodystrophy). The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D. 

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