Toxic dose-high

List the nonhematologic toxicity to high-dose chemotherapy used in myeloablative preparative regimens, specifically busulfan-induced seizures, hemorrhagic cystitis, gastrointestinal toxicities, and sinusoidal obstruction syndrome. 

Figure 2-13 Two toxicants with differing relative toxicities at different doses. Toxicant A is more toxic at high doses, whereas toxicant B is more toxic at low doses.

Use Joseph F. Louvar and B. Diane Louvar, Health and Environmental Risk Analysis Fundamentals with Applications (Upper Saddle River, NJ Prentice Hall, 1998), pp. 287-288, to find the toxicity levels (high, medium, low) for the inhalation of toxic chemicals. 2-29. Use Louvar and Louvar, Health and Environmental Risk Analysis, pp. 287-288, to find the toxicity levels (high, medium, low) for the single dose of a chemical that causes 50% deaths. 

Chagas disease is caused by a kinetoplastid trypanosoma parasite and affects millions of people in Latin America. The disease is currently incurable. Chemotherapy is based mainly on nitrofuran and nitroimidazole compounds and sterol biosynthesis inhibitors such as ketoconazole (337). Toxicity and high doses are the major problems for these organic drugs. Urbina et al. (338, 339) have found that com-plexation of antiparasitic organic agents such as chloroquine (78)... 

Pharmacokinetics and ADME Correlation with Pharmacodynamics Low dose High dose General Toxicity... 

In rats and mice exposed to 1,2-dibromoethane by inhalation, most developmental effects have been observed at doses that produced maternal toxicity. This raises the possibility that the fetuses of pregnant women who were exposed to doses high enough to cause clinical illness would be at risk for development toxicity, depending on the trimester when exposure occurred. 

Some sophisticated guessing goes into dose selection. Knowledge of the minimum acutely toxic dose helps the toxicologist pick the highest dose to be used it will be somewhere below the minimum lethal dose. There is usually little basis for deciding the lowest dose it is often set at some small fraction of the high dose. Whether it turns out to be a NOAEL will not be known until the experiment is completed. Sometimes bioassays have to be repeated to identify the NOAEL. 

HT) into the nerve terminal, the desmethylated metabolites show selectivity as noradrenaline uptake inhibitors. Thus no TCA can be considered to be selective in inhibiting the uptake of either of these biogenic amines. In the case of TCA overdose, the normal oxidative pathways in the liver are probably saturated, which leads to a disproportionately high concentration of the desmethylated metabolite. The practical consequence of this finding is that toxic plasma concentrations of a TCA are very likely to occur if the dose of the drug is increased in those patients who fail to respond to normal therapeutic doses of the drug. Such a transition to toxic doses could occur suddenly. 

Johnson and colleagues made a provocative observation in the course of exploratory preclinical toxicological studies of vincristine, namely, that folinic acid (Leucovorin citrovorum factor 5-formyl-5,6,7,8-tetrahy-drofolic acid) was able to protect mice from the toxicity of high doses of vincristine lb). Vincristine, at a dose of 2.5 mg/kg administered intravenously, resulted in a mortality of 90% over a period of 30 days, but treatment with folinic acid lowered the mortality to 25%. The protection against vincristine toxicity did not occur when folic acid was substituted for folinic acid. A report has appeared (45) indicating that there is no specific protective effect of folinic acid against vincristine toxicity in mice and that the protection can be observed by comparable treatment with isotonic saline solution. As discussed in Section Vll, there is not conclusive evidence that folinic acid is able to ameliorate vincristine toxicity in humans (46). 

Cardiac glycosides are medicinally important steroids. Cardenolides are used in heart therapy, as emetics, diuretics, and purgatives. They affect the Na+/K+-ATPase and are very toxic at high doses. 

High concentrations of acetone were required to produce death in animals the 4-hour inhalation LCso value is 32,OOOppm for rats. Administered in the drinking water for 13 weeks, the minimal toxic doses were 20,000ppm for male rats and mice and... 

Toxicology. 2,4,5-T is of low-order acute toxicity at high doses, it is teratogenic in experimental animals. 

Cardiovascular disease Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by pilocarpine. Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure glaucoma. Administer... 

Toxicity/symptoms high dose - agitation, tremors withdrawal - headache Regulatory facts GRAS (generally recognized as safe)... 

After phase I trials had determined the safety of paclitaxel doses of 45-50 mg/m2/ wk and carboplatin of AUC 2/wk concurrent with standard RT of 66 Gy/7 wk, phase II trials yielded encouraging survival results (69). Acute esophageal grade III or greater toxicity was high (30-50%) however, most patients fully recovered from these acute effects. Choy extended the experience with concurrent radiation and paclitaxel/ carboplatin using hyperfractionated radiation to 69.6 Gy and observed a 1-yr survival of 63% (70). 

The acute toxicity is high by all routes of exposure. The effects are similar to other soluble compounds of barium (see Barium). The oral and subcutaneous lethal doses in dogs are as follows (R. N. Lewis (Sr.). 1996. Sax s Dangerous Properties of Industrial Materials, 9th ed., New York Van Nostrand Reinhold.)... 

Low doses of nicotine stimulate respiration through activation of chemoreceptors in the aortic arch and carotid bodies, while high doses directly stimulate the respiratory centers. In toxic doses, nicotine depresses respiration by inhibiting the respiratory centers in the brainstem and by a complex action at the receptors at the neuromuscular junction of the respiratory muscles. At these neuromuscular receptors, nicotine appears to occupy the receptors, and the end plate is depolarized. After this, the muscle accommodates and relaxes. These central and peripheral effects paralyze the respiratory muscles. 

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