Dose dependent liver toxicity

In the UK, warning labels on paracetamol (acetaminophen) state that the patient should not exceed 4 g in any one 24-hour period but an acute dose of paracetamol (acetaminophen) greater than 7.5 g or 150 mg/kg body weight will result in acute toxicity. Once the dose reaches 10 g a dose-dependent liver toxicity will be seen. In the UK,... 

Nahnefene (Revex) is another opioid antagonist that appears promising in preliminary clinical tests. It has a number of advantages over naltrexone, including greater oral bioavailability, longer duration of action, and lack of dose-dependent liver toxicity. 

Unfortunately, development of PNU-101033E ended as a result of an unusual dose dependant liver toxicity uncovered during the 90 day path tox studies. However, our Medicinal Chemistry colleagues promptly proposed the replacement candidate PNU-104067. This material should be readily available along the same synthetic pathway via an oxidation of the 6-membered carbocyclic ring. Such an oxidation is handily carried out on laboratory scale using excess DDQ or chloranil. However, these oxidants are invariably used in excess, the reactions rarely go to completion, and a tedious chromatographic... 

Maximum residues (in mg/kg FW) and time post-administration were liver, 0.1, 2 h fat tissue, 0.09, 96 h kidney, 0.07, 4 h skin, 0.03, 8 h brain, 0.01, 4 h muscle, 0.008, 4 h and blood 0.003, 4 h. Half-time persistence was 6.5-13 h for the rapidly decreasing phase, and 4.8—8.9 days for the slowly decreasing phase (Ohno et al. 1986) Dose-dependent alterations of brain potentials without behavioral signs of chronic toxicity (USEPA 1980)... 

Liver toxicity related to 1,2-dibromoethane depends on the metabolic pathway utilized and the amount of damage induced in cellular protein and membrane structures. Humans exposed to low levels of 1,2-dibromoethane are at potential risk of having toxic events occurring within hepatocytes whether these effects will be subcellular or result in cell necrosis may depend on internal dose and a variety of factors. Liver damage that is severe enough to cause clinical disease in humans from low-level exposure is unlikely. 

The metabolism of chloroform is well understood. Approximately 50% of an oral dose of 0.5 grams of chloroform was metabolized to carbon dioxide in humans (Fry et al. 1972). Metabolism was dose-dependent, decreasing with higher exposure. A first-pass effect was observed after oral exposure (Chiou 1975). Approximately 38% of the dose was converted in the liver, and < 17% was exhaled unchanged from the lungs before reaching the systemic circulation. On the basis of pharmacokinetic results obtained in rats and mice exposed to chloroform by inhalation, and of enzymatic studies in human tissues in vitro, in vivo metabolic rate constants (V, 3,C =15.7 mg/hour/kg, = 0.448 mg/L) were defined for humans (Corley et al. 1990). The metabolic activation of chloroform to its toxic intermediate, phosgene, was slower in humans than in rodents. 

In a follow-up study in mice, exposure to DEA, via drinking water or by topical application, caused dose-dependent toxic effects in the liver (hepatocellular cytological alterations and necrosis), kidney (nephropathy and tubular epithelial necrosis in males), heart (cardiac myoqn e degeneration), and skin (site of application ulceration, inflammation, hyperkeratosis, and acanthosis). Doses ranged from 630 to 10,000 ppm in the drinking water and from 80 to 12 50 mg/kg in the topical application study. 

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... 

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24-5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity. 

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