6-Endotoxin toxicity

For enzymes intended for parenteral use, the manufacturer must assure that the enzyme preparation is essentially pure and free of endotoxins. Electrophoretic and immunologic tests provide the requisite evidence of purity and homogeneity. Most importandy, the manufacturer must remove toxic impurities, eg, bacterial hpopolysacchati.de (endotoxins) which might cause severe toxic reactions such as anaphylactic shock, fever, and vascular coUapse. 

Lipopolysaccharide (LPS) endotoxins are characteristic Gram-negative outer-cell components which are produced by many cyanobacteria. Although LPS have been characterized and found to be toxic to laboratory animals after isolation from cyanobacteria, their toxicity to rodents is less potent than the endotoxins of enteric pathogens such as Salmonella Typical symptoms of animals suffering from LPS intoxication include vomiting, diarrhoea, weakness and death after hours rather than minutes. 

Preparations of the bacterium Bacillus thuringiensis (BT) are applied as sprays to control insect pests on agricultural crops. The bacterium produces endotoxins that are highly toxic to insects. 

Other toxins that show low lethal toxicity to laboratory test animals include lipopolysaccharide endotoxin produced as part of the cell wall by all cyanobacteria 11) and certain toxins of some cyanobacteria suspected of causing contact irritation in recreational water supplies 4,12 Carmichael and Codd, unpublished results). 

The second B. thuringiensis toxin, the /3-exotoxin has a much broader spectrum encompassing the Lepidoptera, Coleoptera and Diptera. It is an adenine nucleotide, probably an ATP analogue which acts by competitively inhibiting enzymes which catalyse the hydrolysis of ATP and pyrophosphate. This compound, however, is toxic when administered to mammals so that commercial preparations of the B. thuringiensis 5-endotoxin are obtained from strains which do not produce the j8-exotoxin. 

D3. Danenberg, H. D., Alpert, G., Lustig, S., and Ben-Nathan, D., Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production. Antimicrob. Agents Chemother. 36,2275-2279 (1992). 

Gl. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., and Ghezzi, P., Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J. Exp. Med. 173, 1305-1310 (1991). 

After the product has been filled (and sealed) in its final product container. QC personnel then remove representative samples of the product and carry out tests to ensure conformance to final product specification. The most important specifications will relate to product potency, sterility and final volume fill, as well as the absence of endotoxin or other potentially toxic substances. Detection and quantification of excipients added will also be undertaken. Product analysis is considered in Chapter 7. 

Endotoxin activates complement, which then augments the inflammatory response through stimulation of leukocyte chemotaxis, phagocytosis and lysosomal enzyme release, increased platelet adhesion and aggregation, and production of toxic superoxide radicals. 

Clark, G. and Taylor, M., Tumor necrosis factor involvement in the toxicity of TCDD The role of endotoxin in the response, Exp. Clin, Immunogenet., 11, 136, 1994. 

The biomedical importance of infections by gram-negative pathogens and the consequences of septic shock have drawn much attention to lipid A, the toxic subcomponent of the lipopolysaccharide endotoxin of these organisms. A comprehensive account of the chemical structures and biological behavior of the lipid A structures is presented here by Zahrihnger, Lindner, and Rietschel. The chapter incorporates much of their own work from the... 

There are other ways in which endotoxins may act to produce cotton dust induced airway disease. These include 1) an instrinsic toxicity due to lipid A, responsible for both pyro-genicity and tissue damage 2) a hypersensitivity reaction involving anti-lipid A antibodies. Further, changes in mechanical properties of the lung could be explained by the release of histamine or serotonin caused by endotoxins. 

Provocative Inhalation challenge has been used in an attempt to identify byssinogenic agents (52-54, 83-86). Results of these studies have been Inconclusive, but most positive reactions appear to be due to endotoxin contamination of the dust, or to a toxic or irritant factor (52,53). 

Prokaryotic expression E. coli Rapid growth with high yields (up to 50% total cell protein) Extensive range of vectors Simple, well-defined growth media Lack of post-translational processing Product may prove toxic to host Product incorrectly folded and inactive High endotoxin content... 

Quil-A saponin toxicity. Mice fed Quil-A-supplemented diet (a saponin that emulsifies fats and potentiates the immune responses) showed higher level of docosa-pentaenoic acid in the liver. These changes were associated with a significant reduction in the plasma PGEl and PGE2 and thrombohane-B2 levels in response to an intraperitoneal injection of a lethal dose of lipopolysaccharide endotoxin, LDjf, 20 mg/ kg. The data suggest that sesame seed oil and Quil A, when present in the diet, exerted cumulative effects that resulted in a decrease in the levels of dienoic eicosanoids with a reduction in lL-1 P and a con-commitant elevation in the levels of lL-10 that were associated with a marked increase survival in mice . ... 

These are produced by addition of formalin to the toxin of microorganisms and incubating them at 37°G for three to four weeks. Gertain microorganisms produce endotoxins e.g. tetanus and diphtheria. The toxins produced by these organism are detoxicated and used for the preparation of vaccine. The toxoids have lost their toxicity but antigenicity is retained. 

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