Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-04-03
1998-10-06
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514867, 536 2763, A61K 3170, C07H 1916, C07H 19167
Patent
active
058176411
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods of preventing and treating diarrhea by administering compounds which interfere with the adenine nucleotide-dependent guanylyl cyclase C pathways to an individual at risk of or suffering from diarrhea.
BACKGROUND OF THE INVENTION
Bacteria such as E. coli produce a toxin which is resistant to degradation at high temperatures, called the heat-stable enterotoxin (ST). This toxin induces secretion of fluid in the intestine, resulting in diarrhea in individuals infected with these organisms. Indeed, this toxin is a major cause of diarrheal disease in developing countries and a leading cause of morbidity and mortality in the pediatric population worldwide. The toxin induces diarrhea by binding to specific protein receptors in the membranes of intestinal cells which triggers a cascade of biochemical processes eventually leading to fluid secretion into the intestinal lumen. Infectious diarrhea is the fourth leading cause of morbidity and mortality worldwide and the leading cause of morbidity and mortality in the pediatric population. ST-producing bacteria account for the majority of these cases.
Some of the details concerning the cascade of biochemical events in intestinal membranes leading from binding of toxin to the initiation of secretion have been elucidated. Toxin-receptor interaction results in the activation of an enzyme, guanylyl cyclase, which produces a small molecule cyclic GMP. Cyclic GMP directly mediates increased secretion of fluid and electrolytes into the intestine and, consequently, diarrhea.
Receptor guanylyl cyclases are a unique family of proteins whose members contain an extracellular ligand-binding domain directly coupled to a cytoplasmic cyclase catalytic domain (Chinkers et al., (1989) Nature, 338, 78-83; Lowe et al., (1989) EMBO J., 8, 1377-1384; Schulz et al., (1989) Cell, 58, 1155-1162). Guanylyl cyclase C (GC-C), a recently-described member of this family localized in the brush border of intestinal mucosa cells, is a receptor for the Escherichia coli heat-stable enterotoxin (ST; Schulz et al., (1990) Cell, 63, 941-948; deSauvage et al., (1991) J. Biol. Chem., 266, 17912-17918). Guanylin, a peptide derived from a precursor protein synthesized in the intestinal epithelium, was recently identified as an endogenous ligand for GC-C (Schulz et al., (1992) J. Biol. Chem., 267, 16019-16021; Currie et al., (1992) Proc. Natl. Acad. Sci. USA, 89, 947-951). ST-GC-C interaction is coupled to activation of the intrinsic guanylyl cyclase, increases in intracellular cGMP, and alterations in fluid and electrolyte secretion resulting in secretory diarrhea (Field et al., (1978) Proc. Natl. Acad. Sci. USA, 75, 2800-2804; Giannella, R. A., (1981) Annu. Rev. Med., 32, 341-357).
Adenine nucleotides appear to be important in coupling ligand-receptor interaction to enzyme activation in the receptor guanylyl cyclase family. ATP and its analogues potentiate the activation of particulate guanylyl cyclase by ligands such as natriuretic peptides and ST (Gazzano et al., (1991) Biochim. Biophys. Acta, 1077, 99-106; Gazzano et al., (1991) Infect. Immun., 59, 1552-1557; Chinkers et al., (1991) J. Biol. Chem., 266, 4088-4093; Duda et al., (1993) FEBS Lett., 315:143-148). Indeed, it has been suggested that activation of particulate guanylyl cyclase by atrial natriuretic peptides (ANP) absolutely requires adenine nucleotides. In addition, ATP activates basal particulate guanylyl cyclase in some studies. It has been suggested that ATP regulates enzyme activity by directly stabilizing the active conformation and inhibiting the desensitization of ligand-induced guanylyl cyclase (Vaandrager et al., (1993) J. Biol. Chem., 268, 2174-2179; Vaandrager et al., (1993) J. Biol. Chem., 268, 19598-19603).
The specific role of ATP in signal transduction mediated by receptor guanylyl cyclases is confounded by the observation that adenine nucleotides inhibit particulate guanylyl cyclase when manganese is used as the substrate cofactor (Marala et al., (1991) FEBS Lett., 2
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Parkinson Scott J.
Waldman Scott A.
Kunz Gary L.
Thomas Jefferson University
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