Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Patent
1995-12-22
1998-10-20
Naff, David M.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
435219, 514885, 514886, A61K 3846, C12N 950
Patent
active
058243054
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to the use of one of the components of the enzyme mixture bromelain in the treatment of various conditions which are dependent on cyclic nucleotide and other intracellular and/or extracellular pathways.
Work has already been carried out on the use of proteolytic enzymes in the treatment of infectious and non-infectious diarrhoea in humans and this is described in our co-pending UK applications Nos. 9213862.7 and 9308164.4 from which WO-A-9400147 claims priority. In those applications, various experiments were described which demonstrate that proteolytic enzymes and, in particular, bromelain, are capable of inhibiting secretion. The applications also disclosed that bromelain can reduce toxin binding activity and can inhibit the secretory effect of toxins such as heat labile toxin (LT) and cholera toxin (CT) and also toxins such as heat stable toxin (ST). This is in spite of the fact that ST has a very different mode of action from LT and CT.
LT and ST are both produced by enterotoxigenic strains of E. coli (ETEC). 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 promoter 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 feedback regulatory mechanism which normally involves the hydrolysis of GTP to GDP and phosphate (Pi). Inactivation of the regulatory subunit leads to increased levels of the second messenger, cyclic AMP (cAMP). 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 are 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 stimulation of Cl.sup.- secretion. ST-induced fluid secretion is relatively s
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Cortecs (UK) Limited
Kerr Janet M.
Naff David M.
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