Excess toxicity

Whooping-cough (Pertussis) (aceiiuiar)t Cultures of Bord. pertussis 1 Harvest 2 Extraction and blending of cell components As for whole-cell whooping-cough vaccine Weight gain test in mice to exclude excess toxicity... 

The use of insecticides on the edible parts of plants presents the problem of removal or avoidance of excessive toxic residues on the harvested crops. This paper shows the magnitude of residues that may result from the application of sprays containing parathion and DDT insecticides. 

D-Phenothrin (I) Not likely to be carcinogenic to humans. Rat liver tumors occurred only at excessively toxic doses (limit dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical significance (p < 0.01). Additionally, acceptable mutagenicity studies were negative for mutagenic potential [97] No tumorigenicity was observed [11]. 

Regulatory guidelines require that there be maternal toxicity at the highest dosage level in embryo-fetal developmental toxicity studies. It is important to avoid excessive toxicity in these studies since it is known that marked maternal toxicity can cause secondary developmental toxicity (see discussion in Section 8.4.3, Association between Developmental and Maternal Toxicity ). This secondary developmental toxicity is irrelevant to the assessment of the developmental hazard of the test agent and thus simply confounds the interpretation of the data. 

When reduced survival is related to factors other than excessive toxicity, the number of animals at risk for tumor development may be inadequate, and the validity of the study may be compromised even in the absence of a drug effect on survival. Obviously, the adjustments described above for excessive, drug-related toxicity are not relevant to this situation. 

Many toxicologists are concerned about possible misinterpretation of bioassay results when the MTD (the highest bioassay dose) has turned out to produce serious toxicity as well as a tumor response. They contend that the excessive toxicity that somehow decreased... 

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. 

This coupling between halides and aldehydes is a chromium-induced redox reaction. A key advantage is the high chemoselectivity toward aldehydes. A disadvantage is the use of excess toxic chromium salts. 

Despite its wide application in glycoside synthesis, the Koenigs-Knorr reaction suffers from several disadvantages (i) the glycosyl halides are unstable, (ii) excess toxic heavy metals are needed to activate the donor, and (iii) a desiccant (to absorb any liberated water) and an acid acceptor (to absorb the liberated hydrogen halide and can be a promoter itself) are often needed to increase the yield and suppress side reactions. 

Reproductive or developmental toxicity endpoints must be interpreted in the context of general toxicity that could also occur in the same animals. Toxic effects reported from other studies can be particularly valuable because excessive toxicity could significantly confound the interpretation of a reproductive or developmental toxicity study. Observations from studies of other toxicity endpoints might either strengthen or weaken the conclusions to be drawn from a reproductive or developmental study and provide information about target organs that should be evaluated further in developing animals. 

Methotrexate inhibits folic acid, so leucovorin (folinic acid) is prescribed in adequate dosage to prevent excessive toxicity to the bone marrow, mucosae and liver. 

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