Use of enzymes, especially bromelain, in the treatment of diarrh

Details Use of enzymes, especially bromelain, in the treatment of diarrh Use of enzymes, especially bromelain, in the treatment of diarrh

1995-02-14

1999-07-27

Witz, Jean C.

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

424 9464, 424 9465, 424 9466, 424 9467, A61K 3848

Patent

active

059286407

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the prophylaxis, management and treatment of diarrhoea.
Diarrhoea, particularly traveller's diarrhoea, can be caused by a change in the microorganisms of the gut. Enterotoxigenic Escherichia coli (ETEC) infections are common and, as many holiday makers and business travellers can testify, can leave the sufferer ambivalent about the virtue of leaving his native country. E. coli is not the only aetiological agent: more seriously, Vibrio cholerea, the causative agent of cholera, can cause diarrhoea as part of its sometimes fatal mode of action.
Enterotoxigenic strains of E. coli (ETEC) are characterised by their ability to produce a heat-labile toxin (LT) and/or heat-stable toxin (ST). Some ETEC strains also produce pilus adhesins called colonisation factor antigens. These adhesins promote attachment of ETEC strains to the small intestinal mucosa, thereby facilitating colonisation and delivery of enterotoxin. Diarrhoeal disease is ultimately dependent on production and efficient delivery of enterotoxin.
The enterotoxins stimulate secretion by cells by activation of signal pathways. Internal signals within cells are carried by "second messengers". At least three signal pathways are known to be important for secretion. One pathway employs the second messenger cyclic adenosine monophosphate (cyclic AMP). Another employs the second messenger cyclic guanosine monophosphate (cyclic GMP). These two messengers are referred to as cyclic nucleotides. The third signal pathway (CA.sup.2+ -dependent pathway) requires Ca.sup.2+ as the second messenger.
The mode of action of LT is virtually identical to that of cholera toxin (CT), which has been well documented. Briefly, the B protomer binds to a ganglioside receptor GM1 ceramide! located on the brush border membrane. Recent studies have shown that LT also binds to a structurally related glycoprotein to which CT does not bind. Binding is followed by translocation of the A subunit through the membrane and release of the A1 fragment into the cytosol after proteolytic activation. Adenylate cyclase activity is stimulated following catalysing the NAD-dependent cyclase complex. As a result, adenylate cyclase is locked into an active form through inhibition of an inherent feed-back regulatory mechanism which normally involves the hydrolysis of GTP to GDP and Pi. Inactivation of the regulatory subunit leads to increased levels of the second messenger, cyclic AMP. cAMP activates an enzyme called protein kinase A which, in turn, phosphorylates proteins. The phosphorylation of proteins (that is, the addition of a phosphate group) results in the opening of chloride channels and therefore secretion. Increased levels of cAMP is also known to inhibit the absorption of NaCl.
The mode of action of ST is less well understood than that of LT. STs produced by ETEC are a heterogeneous group of molecules having a molecular weight of from about 2000 to 5000 Da and which are non-antigenic in their native state. An example of a common ST is ST I which can be either an 18 or a 19 amino acid peptide. In contrast to LT, which activates adenylate cyclase of intestinal cells, ST I stimulates only the particulate form of intestinal guanylate cyclase. The action of ST I is almost instantaneous. The initial step in the biological action of ST is its interaction with membrane-bound guanylate cyclase in the cells, leading to an increase in the intracellular concentration of cyclic GMP followed by activation of cyclic GMP-dependent protein kinase (protein kinase G). This culminates in the inhibition of Na.sup.+ absorption and opening of chloride channels and, hence, stimulation of Cl.sup.- secretion. ST-induced fluid secretion is relatively short-lived and is readily reversed, in contrast to the delayed but sustained and irreversible effects of LT on adenylate cyclase and fluid secretion. The intestinal ST I receptor has been shown to be a guanyl cyclase although other proteins or glycoproteins may also have a role.
Intestinal transcellular absorption and secretion of electrolytes is

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