Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-11
2003-04-22
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S400000, C514S460000, C514S474000, C514S557000, C514S561000, C514S564000, C514S574000, C424S630000, C424S638000, C424S639000, C424S641000, C424S643000, C424S646000
Reexamination Certificate
active
06552072
ABSTRACT:
The present invention relates to novel therapies to treat gastrointestinal symptoms and gastrointestinal microbes. In particular, therapies are provided for common gastrointestinal symptoms such as dyspepsia and non-infectious diarrhoea and for common gatrointestinal infections such as
Helicobacter pylori
and Salmonella. The use of complexes of dietary metals in preparing therapeutic agents for use in such methods is also provided.
Gastrointestinal infections cause widespread diarrhoea and debility and account for a large proportion of antibiotic use worldwide. The non-specificity of antibiotics has meant that resistant pathogens are an increasing problem leading to more complex treatments. Furthermore, many antibiotics have side effects that reduce compliance, while cost may preclude their use in developing countries where infections are more common. Even in the western world complex treatment is often required, for example,
H. pylori
infection of the gastric mucosa requires “triple therapy” for successful eradication. There are however few gut-specific antimicrobials and antibiotics designed for absorption and systemic action are mainly used.
Toxic metal compounds have been in use for some considerable time in the treatment of gastrointestinal symptoms and of gastrointestinal and even systemic infections, but significant side effects occur, such as the encephalopathy seen with bismuth complexes (Gorbach S. L.,
Gastrenterology,
99:863-875 (1990)). Newer “colloidal” bismuth compounds such as De-Noltab™ (bismuth sub-citrate) and Pepto-Bismol™ (bismuth sub-salicylate) are not well absorbed in man and have some activity against gastrointestinal bacteria. However, it has been shown that significant and prolonged plasma levels of bismuth are found following ingestion of such preparations (Nwokolo er al,
Alimentary, Pharmacology and Therapeutics,
4:163-169 (1990)) (up to 135 &mgr;g/l for De-Noltab™ and 5 &mgr;g/l for Pepto-Bismol™).
These earlier metal-based therapies in the gastrointestinal tract have, unknowingly, been mainly effective against gastrointestinal pathogens due to their physiological effects on the gut, rather than due to any antimicrobial properties, as unlike in vitro, sufficient concentrations of bismuth appear not to reach the bacteria in vivo. This has been confirmed by work we have carried out on the therapeutic role of bismuth compounds in the eradication of
H. pylori.
In view of the effectiveness, but potential toxic effects, of bismuth we have looked at “dietary metals” as possible treatments for gastrointestinal symptoms and infections. These metals, unlike bismuth, form part of normal dietary requirements and therefore, firstly it is not necessary to ensure that minimal absorption of the metal-ion takes place, while secondly normal homeostatic mechanisms in higher animals will regulate the metal absorption. In order to improve their antimicrobial efficacy the dietary metals can be complexed with ligands.
One example of a microbial infection treatable by the methods described herein is that cused by
H. pylori. H. pylori
is a Gram negative bacteria that has been strongly implicated in chronic active gastritis and peptic ulcer disease (Marshall et al,
Medical Journal of Australia,
142:439-444 (1985); Buck, G. E.,
Journal of clinical Microbiology,
3:1-12 (1990)). More recently, it has also been implicated in the development of gastric cancer and lymphoma. As mentioned above,
H. pylori
infection is one example where complex triple therapies are required for eradication. One example is based on omeprazole™ (20 mg b.d.) with amoxycillin (500 or 750 mg t.d.s.) and metronidazole (400 mg t.d.s.). It would be particularly useful therefore to have available a simpler, less expensive therapy with good eradication rates.
We have now found that the use of complexes of dietary metal ions optionally together with one or more antibiotics and/or other therapeutic agents represent an effective therapeutic method for the eradication of gastrointestinal microbes and improvement of gastrointestinal symptoms in vivo. For example, for infections caused by
H. pylori
the dietary metal complexes can be used in conjunction with antibiotic(s) and/or agents such as proton pump inhibitors (e.g. omeprazole™).
Thus, in a first aspect, the present invention provides a method of treating gastrointestinal symptoms or gastrointestinal microbes in a mammal which comprises the step of administering orally or rectally to a subject an effective amount of a complex of at least one dietary metal ion.
In the context of the present invention “dietary metal” means a metal that forms part of normal dietary requirements for mammals, e.g. humans. In the case of humans examples of such dietary metals include zinc, copper, cobalt, manganese and iron. Preferred dietary metal ions include zinc, copper, manganese and iron.
The “complex” will comprise the dietary metal ion and at least one form of counter ion. Particularly suitable counter ions include ligands of relatively low molecular weight being either common dietary ligands or natural or synthesised ligands. It will be apparent to the skilled man that the “complex” could be formed in situ by separately administering a salt of a dietary metal and one or more suitable ligands. Thus, methods based on separate administration of dietary metal salts and ligands fall within the scope of the invention.
Therefore the methods of the invention make use of common dietary metals and thus avoid the problems associated with therapies based on foreign metals such as bismuth.
Examples of suitable dietary ligands that form complexes with the dietary metals include ascorbate, aspartate, citrate, histidine, malate, maltol (3-hydroxy-2-methyl-4-pyrone), gluconate, glutamate, glutamine, succinate and tartrate. Preferred dietary ligands include ascorbate, citrate, histidine, malate, maltol (3-hydroxy-2-methyl-4-pyrone), gluconate and tartrate. Examples of other ligands include lawsone (2-hydroxy-1,4-napthoquinone) and tropolone (2-hydroxy-2,4,6-cycloheptatrienone). The ligand used could also be an antibiotic itself or any other suitable compound. For example, in the case of
H. pylori
infection, metal-ion pump inhibitors or urease inhibitors can be used as the ligand. Suitable ratios of metal:ligand fall in the range 1:1 to 1:10.
In one embodiment the complex is administered orally.
There is available on the market in the UK a proprietary product, which is marketed as a dietary supplement which provides zinc. The product is listed as a zinc sulphate preparation. However, the product is first dissolved in water before being taken orally. When it is dissolved a zinc citrate complex (citrate also being present in the formulation) is formed with three citrate ions for each zinc ion. Thus, such a product can be used in the methods of the present invention as a source of zinc citrate.
H. pylori
infection represents one form of gastrointestinal infection which can be treated using the methods of the invention and thus, methods of treating
H. pylori
infection form an embodiment of the invention. In a preferred embodiment of the invention the dietary metal/counter ion complex is administered in combination with one or more antibiotics, e.g. amoxycillin or metronidazole. In a particularly preferred embodiment for the treatment of
H. pylori
infections the dietary metal complex is administered with at least one antibiotic and/or another compound which is used in conventional ulcer treatments and/or which is used to treat gastrointestinal symptoms/infections. Such compounds include ranitidine™, which is an H
2
receptor antagonist, and proton pump inhibitors such as omeprazole™.
Although, in preferred embodiments, the methods of the present invention will be used to treat humans, it will be appreciated that they will be equally applicable as veterinary treatments of gastrointestinal symptoms and/or infections in animals, e.g. swine dysentry.
In a second aspect the present invention provides a pharmaceutical formulation for use in the treatment of gastrointestinal s
Aline Chevalier Sylvaine Francoise
Hepworth Thompson Richard Paul
Phillips Rosemary Helen
Powell Jonathan Joseph
Cook Rebecca
Kilpatrick & Stockton LLP
Pfylori Limited
LandOfFree
Use of metal complexes to treat gastrointestinal infections does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of metal complexes to treat gastrointestinal infections, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of metal complexes to treat gastrointestinal infections will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3060940