Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1982-06-03
1983-10-25
Hazel, Blondel
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
424 88, A61K 39108, A61K 39106
Patent
active
044118880
DESCRIPTION:
BRIEF SUMMARY
Acute diarrheal disease due to transient colonization of the small intestine by enterotoxigenic strains of Escherichia coli (ETEC) is a major health problem of global scope. These organisms and rotavirus are the two principal causes of acute diarrhea in young children, which, according to World Health Organization estimates, accounts for approximately ten million deaths per annum among infants, mostly in those living in underdeveloped tropical countries (See Black, R. E., et al. 1981. Incidence and severity of rotavirus and Escherichia coli diarrhea in rural Bangladesh. Lancet 1:141-143). Enterotoxigenic E. coli are also the principal cause of acute diarrhea among persons from temperature zones who travel to the tropics (turista), a common cause of sporadic episodes of diarrhea among adults living in temperate and tropical areas, and a major problem in animal husbandry by virtue of their causing frequently fatal acute diarrhea among weanling animals, especially in lambs and piglets.
The mechanisms by which ETEC strains cause diarrhea have been elucidated. Following peroral ingestion, the bacteria adhere to the surface of the intestinal mucosa of the proximal small bowel; this process is enhanced by the presence on the surface of the bacteria of plasmid-induced specific fimbrial antigens which are host specific and are referred to as colonization factors in human strains (See, Evans, D. G., et al. 1978. New surface-associated heat-labile colonization factor antigen (CFA/II) produced by enterotoxigenic Escherichia coli of serogroups 06 and 08. Infect. Immun. 21:638-647). There appear to be multiple, antigenically dissimilar fimbrial antigens in human ETEC strains, and no specific fimbrial antigen has been detected in the case of some pathogenic ETEC strains (See Deuke, R. et al. 1981. Serotypes of attachment pili of enterotoxigenic Escherichia coli isolated from humans. Infect. Immunm. 32:1254-1260 and Levine, M. M., et al. 1980. Hemagglutination and colonization factors in enterotoxigenic and enteropathogenic Escherichia coil that cause diarrhea. J. Infec. Dis. 141:733-737). The bacteria proliferate in this location and elaborate two plasmid-induced enterotoxins, either singly or together: a heat-labile (LT) toxin and a heat-stable (ST) toxin.
The holotoxin (complete toxin) of the LT toxin has recently been isolated in purified form and characterized (See, Clements, J. D., et al. 1979. Isolation and characterization of homogeneous heat-labile enterotoxins with high specific activity from Escherichia coli cultures. Infect. Immun. 24:760-769). It consists of five B subunits (MW 12,000 daltons each) and one A subunit (MW 31,500 daltons) as reported by Gill, D. M. et al. 1981. Subunit number and arrangement of Escherichia coli heat-labile enterotoxin. Infec. Immun. 33:677-682. The B subunits are responsible for attaching the toxin to specific GM.sub.1 ganglioside receptors on the surface of the intestinal mucosa, thereby permitting penetration of the cell by the A subunit which stimulates intracellular adenylate cyclase which is responsible for secretion of fluid and electrolytes ito the intestinal lumen. It is noteworthy that the E. coli LT toxin functionally, structurally and immunologically resembles the toxin produced by Vibrio cholerae (cholera toxin). Both LT and cholera toxin (CT) consist of the same type and number of subunits which have approximately the same molecular weight; the subunits serve the same functions, and the LT and CT have shared and distinct antigenic determinants in both of their A and B subunits (See Holmgren, J., 1981. Actions of cholera toxin and the prevention and treatment of cholera. Nature 292:413-417 and Clements, J. D. et al. 1978. Shared and unique immunological determinants of enterotoxins from Vibrio cholerae and Escherichia coli. Infec. Immun. 22:709-713). Further, immunization of rats with LT or cholera toxin provides protection against challenge with the LT toxin (See, Pierce, N. F. 1977. Protection against challenge with Escherichia coli heat-labile enterotoxin by immun
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Clements John D.
Engert Richard E.
Klipstein Frederick A.
Hazel Blondel
Lukacher Martin
The University of Rochester
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