Hepatic toxicity

Although it is estimated that 1 in 118,000 patients dies from non-dose-related hepatic failure, no cases have occurred in patients older than 10 years who were receiving valproate monotherapy. Nonetheless, baseline liver function tests are indicated. If baseline test results are normal, monitoring for clinical signs of hepatotoxic-ity is more important than routine monitoring of liver enzyme levels, which has little predictive value and may be less effective than clinical monitoring (Pellock and WiUmore 1991). 

Transient, mild increases in liver enzyme levels, up to three times the upper limit of normal, do not necessitate discontinuation of valproate. Although y-glutamyltransferase levels are often checked by clinicians, these levels are often increased, without clinical significance, in patients receiving valproate and carbamazepine (Dean and Penry 1992). Likewise, plasma ammonia levels are often increased transiently during valproate treatment, but this finding does not necessitate interruption of treatment (Jaeken et al. 1980). Increases in transaminase levels are often dose dependent. If no 

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This drug is usually well tolerated, but nausea, vomiting, headache, dizziness, abdominal pain, and pruritus may be seen. Most adverse reactions are mild and transient. On rare occasions, hepatic toxicity may be seen, and use of the drug must be discontinued immediately. Periodic hepatic function tests are recommended to monitor for hepatic toxicity. 

Bone marrow depression, hepatic toxicity, nausea, vomiting, stomatitis, hyperuricemia... 

The mechanism of action for liver toxicity and carcinogenicity may involve the formation of reactive products (Bonse and Henschler 1976 Bonse et al. 1975 Fisher et al. 1991 Larson and Bull 1992b). Methods for reducing the destructive damage caused by these intermediates, or for blocking their formation through inhibition of metabolic pathways may prove effective in reducing hepatic toxicity but are not currently available for clinical use. 

Tolot F, Viallier J, Roullett A, et al. 1964. [Hepatic toxicity of trichloroethylene.] Arch Mai Prof 25 9-15. (French)... 

Although generally well tolerated, probenecid can cause gastrointestinal side effects such as nausea and other adverse reactions, including fever, rash, and rarely, hepatic toxicity. Patients should be instructed to maintain an adequate fluid intake and urine output to decrease the risk of uric acid stone formation. Some experts advocate alkalinizing the urine to decrease this risk. 

Systemic adverse effects associated with vaginal azoles are less frequent than with oral products. Local discomfort such as burning may occur with the first application. Fifteen percent of patients experience gastrointestinal side effects with orally administered antifungal agents.13 Oral ketoconazole is associated with hepatic toxicity at a rate of 1 in 15,000.14... 

The answer is d. (Hardman, p 7502) The most consistent of the toxicides of ACT inhibitors is impairment of renal function, as evidenced by proteinuria. Elevations of blood urea nitrogen (BUN) and creatinine occur frequently, especially when stenosis of the renal artery or severe heart failure exists Hyperkalemia also may occur These drugs are to be used very cautiously where prior renal failure is present and in the elderly Other toxicides include persistent dry cough, neutropenia, and angioedema. Hepatic toxicity has not been reported... 

The precise mechanism of monomethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute toxicity of dimethylhydrazine exposure probably involves the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Additionally, renal and hepatic toxicity and hemolytic effects imply alternate mechanisms of toxicity. 

Niacin ER [17,18] 10-22 11 0 10-30 Skin flushing, gastrointestinal, hepatic toxicity... 

It would be comforting to be able to state that the causes of postmarketing withdrawals from drugs were substantially different from those of failure of drugs in clinical trials. While the last few years (refer back to Table 1.1) are seemingly somewhat different from those in the past, the historic causes for the modem era (the last 40 years) are lead off by hepatic toxicity, also the primary cause for safety failure in early clinical trials. 

Approximately 10% of new chemical entities (NCEs) show serious adverse drug reactions (ADRs) after market launch. Such events usually result in new black box warnings by the US Food and Drug Administration (FDA), label change or market withdrawal. The most common causes for these actions are hepatic toxicity, hematologic toxicity and cardiovascular toxicity [2], Reasons for such ADRs, which are identified only after NCEs are launched on the market, include the narrow spectrum of clinical disorders and participating patient profiles in clinical studies as well as the fact that serious ADRs are often rare and that the number of patient exposures required to identify such occurrences sometimes may range over a few millions [3],... 

Tolcapone (Tasmar) Parkinson s disease Hepatic toxicity 1998 [59]... 

No studies were located regarding hepatic toxicity in animals following inhalation exposure to mirex or chlordecone. 

In addition to the adaptive effects described above, marked hepatic toxicity has been observed after acute-duration oral exposure of animals to mirex. The primary form of hepatotoxicity observed in... 

An MRL of 0.4 mg/kg/day has been derived for intermediate-duration oral exposure to di-/ -octylphthalate. This MRL is based on a NOAEL of 40.8 mg/kg/day for liver effects that were observed in rats fed di-w-octylphthalate in the diet at a dose of 350.1 mg/kg/day (males) or 402.9 mg/kg/day (females) (Poon et al. 1995). These hepatic effects consisted of a statistically significant (p<0.05) increase in hepatic ethoxyresorufin-0-deethylase activity and histological changes in hepatic architecture, including accentuation of zonation and perivenous cytoplasmic vacuolation. Thyroid toxicity (decreased colloid density and reduced follicle size) was also noted at this concentration. The NOAEL was divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Support for the use of hepatic toxicity as the basis of the intermediate MRL is provided by other studies that show necrosis and other fatty changes after acute- and intermediate-duration exposure of rats (DeAngelo et al. 1986 Lake et al. 1984, 1986 ... 

When taken in therapeutic doses (approximately 4 g 60mg/kg body weight) paracetamol (N-acetyl-para-ami nophenol, acetaminophen) is a safe and effective analgesic, but overdosage, possibly with the intent of self-harm, is a major cause of drug-induced hepatic toxicity. The cellular damage which may not be evident for up to... 

T. Ogiso, M. Iwaki, T. Tanino, T. Nagai, Y. Ueda, O. Muraoka, G. Tanabe, Pharmacokinetics of Indomethacin Ester Prodrugs Gastrointestinal and Hepatic Toxicity and the Hydrolytic Capacity of Various Tissues in Rats , Biol. Pharm. Bull. 1996, 19, 1178 — 1183. 

Hepatic toxicity 26 Cardiovascular toxicity incl. Arrhythmias 19 (12)... 

Toxicologists classify hepatic toxicants according to the type of injuries they produce. Some cause accumulation of excessive and potentially dangerous amounts of lipids (fats). Others can kill liver cells they cause cell necrosis. Cholestasis, which is decreased secretion of bile leading to jaundice (accumulation of gruesome looking pigments that impart a yellowish color to the skin and eyes) can be... 

Brown BR Jr., Sipes IG, Sagalyn AM. 1974b. Mechanisms of acute hepatic toxicity Chloroform, halothane, and glutathione. Anesthesiology 41 554-561. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

Nutritional factors may influence the toxicity of pesticides. Research in this area has primarily focused on the role of dietary proteins, particularly sulfur-containing amino acids, trace minerals, and vitamins A, C, D, and E. Studies in rats show that inadequate dietary protein enhances the toxicity of most pesticides but decreases, or fails to affect, the toxicity of a few. The results of these studies have shown that at one-seventh or less normal dietary protein, the hepatic toxicity of heptachlor is diminished as evidenced by fewer enzyme changes (Boyd 1969 Shakman 1974). The lower-protein diets may decrease metabolism of heptachlor to heptachlor epoxide. 

Methotrexate is an antimetabolite, which is metabolised by the renal and hepatic systems and may lead to renal and hepatic toxicities. Liver and renal function tests are therefore carried out for patients who are administered the drug. Methotrexate can lead to myelosuppression and therefore full blood counts must be monitored for patients taking it. 

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