Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Transferases
Reexamination Certificate
1998-05-22
2001-03-13
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Transferases
C424S093100, C435S193000, C435S196000, C435S232000
Reexamination Certificate
active
06200562
ABSTRACT:
BACKGROUND OF THE INVENTION
Kidney-urinary tract stone disease (urolithiasis) is a major health problem throughout the world. Most of the stones associated with urolithiasis are composed of calcium oxalate alone or calcium oxalate plus calcium phosphate. Other disease states have also been associated with excess oxalate. These include, vulvodynia, oxalosis associated with end-stage renal disease and with Crohn's disease, and other enteric disease states.
Oxalic acid (and/or its salt-oxalate) is found in a wide diversity of foods, and is therefore, a component of many constituents in human diets. Increased oxalate absorption may occur after foods containing elevated amounts of oxalic acid are eaten. Foods such as spinach and rhubarb are well known to contain high amounts of oxalate, but a multitude of other foods and beverages also contain oxalate. Because oxalate is found in such a wide variety of foods, diets that are low in oxalate and which are also palatable are hard to formulate.
Oxalate is also produced metabolically by normal tissue enzymes. Oxalate (dietary oxalate that is absorbed as well as oxalate that is produced metabolically) is not further metabolized by tissue enzymes and must therefore be excreted. This excretion occurs mainly via the kidneys. The concentration of oxalate in kidney fluids is critical, with increased oxalate concentrations causing increased risk for the formation of calcium oxalate crystals and thus the subsequent formation of kidney stones.
The risk for formation of kidney stones revolves around a number of factors that are not yet completely understood. Kidney-urinary tract stone disease occurs in about 2% of the population in Western countries and about 70% of these stones are composed of calcium oxalate or of calcium oxalate plus calcium phosphate. Some individuals (e.g., patients with intestinal disease such as Crohn's disease, inflammatory bowel disease, or steatorrhea and also patients that have undergone jejunoileal bypass surgery) absorb more of the oxalate in their diets than do others. For these individuals, the incidence of oxalate urolithiasis increases markedly. The increased disease incidence is due to increased levels of oxalate in kidneys and urine, and this, the most common hyperoxaluric syndrome in man, is known as enteric hyperoxaluria. Oxalate is also a problem in patients with end-stage renal disease and there is recent evidence (Solomons et al. [1991] “Calcium citrate for vulvar vestibulitis”
Journal of Reproductive Medicine
36:879-882) that elevated urinary oxalate is also involved in vulvar vestibulitis (vulvodynia).
Bacteria that degrade oxalate have been isolated from human feces (Allison et al. [1986] “Oxalate degradation by gastrointestinal bacteria from humans”
J. Nutr.
116:455-460). These bacteria were found to be similar to oxalate-degrading bacteria that had been isolated from the intestinal contents of a number of species of animals (Dawson et al. [1980] “Isolation and some characteristics of anaerobic oxalate-degrading bacteria the rumen”
Appl. Environ. Microbiol.
40:833-839;Allison and Cook [1981] “Oxalate degradation by microbes of the large bowel of herbivores: the effect of dietary oxalate”
Science
212:675-676; Daniel et al. [1987] “Microbial degradation of oxalate in the gastrointestinal tracts of rats”
Appl. Environ. Microbiol.
53:1793-1797). These bacteria are different from any previously described organism and have been given both a new species and a new genus name, formigenes (Allison et al. [1985
] “
Oxalabacter formigenes
gen. nov., sp. nov.: oxalate-degrading anaerobes that inhabit the gastrointestinal tract”
Arch. Microbiol.
141:1-7).
Not all humans carry populations of
O. formigenes
in their intestinal tracts (Allison et al. [1995] “Oxalate-degrading bacteria”In Khan, S. R. (ed.),
Calcium Oxalate in Biological Systems
CRC Press; Doane et al. [1989] “Microbial oxalate degradation: effects on oxalate and calcium balance in humans”
Nutrition Research
9:957-964). There are very low concentrations or a complete lack of oxalate degrading bacteria in the fecal samples of persons who have had jejunoileal bypass surgery (Allison et al. [1986] “Oxalate degradation by gastrointestinal bacteria from humans”
J. Nutr.
116:455-460).
BRIEF SUMMARY OF THE INVENTION
The subject invention pertains to materials and methods which reduce the risk for developing urolithiasis by limiting the amount of dietary oxalate absorbed from the intestinal tract. In one embodiment of the subject invention, a reduction in oxalate absorption is achieved by supplying oxalate-degrading bacteria to the intestinal tract. In a preferred embodiment, these bacteria are
Oxalobacter formigenes.
These bacteria use only oxalate as a growth substrate. This utilization reduces the concentration of soluble oxalate in the intestine and thus the amount of oxalate available for absorption.
In a specific embodiment, the subject invention provides materials and procedures for the delivery of
O. formigenes
to the intestinal tracts of persons who are at increased risk for oxalate related disease. These bacteria and their progeny replicate in the intestine and remove oxalate from the intestinal tract, thereby reducing the amount of oxalate available for absorption and thus reducing the risk for oxalate related disease.
In a further embodiment of the subject invention, a reduction in oxalate absorption is achieved by administering enzymes which act to degrade oxalate. These enzymes may be isolated and purified or they may be administered as a cell lysate of
Oxalobacter formigenes.
In a specific embodiment, the enzymes which are administered are formyl-CoA transferase and oxalyl-CoA decarboxylase. In a preferred embodiment, additional factors which improve enzyme activity can be administered. These additional factors may be, for example, oxalyl CoA, MgCl
2
, and TPP (thiamine diphosphate, an active form of vitamin B
1
).
A further aspect of the subject invention pertains to pharmaceutical compositions for oral administration. These compositions release the oxalate degrading microbes, or oxalate degrading enzymes, in the small intestine of humans. Preferably the microorganisms and/or enzymes are encapsulated in a dose delivery system that decreases the probability of release of the materials in the human stomach but increases the probability of release in the small intestine. The microorganisms and/or enzymes also may be administered as a constituent of foods, such as milk, meats, and yogurt.
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patent: 5286495 (1994-02-01), Batich et al.
patent: 5547870 (1996-08-01), Datta et al.
patent: 5604111 (1997-02-01), Peck
patent: 9531537 (1995-11-01), None
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patent: 9816632 (1998-04-01), None
Lung, Hui-Yu et al. (1991) Cloning and expression of the oxalyl-CoA decarboxylase gene from the bacterium,Oxalobacter formigenes: prospects for gene therapy to control Ca-oxalate kidney stone formation American Journal of Kidney Disease Vo.I. XVII (4): 381-385.
Han, Jian-zhi et al. (1995) “The Relationship ofOxalobacter Formigenesand Calcium Oxalate Calculi” Journal of Tongji Medical University 15(4):249-252.
Daniel, Steven L., Paul A. Hartman, Milton J. Allison (1987) “Microbial Degradation of Oxalate in the Gastrointestinal Tracts of Rats” Applied and Environmental Microbiology 53(8): 1793-1797.
Dawson, Karl A., M.J. Allison, P.A. Hartman (1980) “Isolation and Some Characteristics of Anaerobic Oxalate-Degrading Bacteria from the Rumen”Applied and Environmental Microbiology 40(4):833-839.
Doane, Lori T., Michael Liebman, Daniel R. Caldwell (1989) “Microbial Oxalate Degradation: Effects On Oxalate And Calcium Balance In Humans” Nutrition Research 9:957-964.
Solomons, Clive C., M. Herzl Melmed, Susan M. Heitler (1991) “Calcium Citrate For Vulvar Vestibulitis” The Journal of Reproductive Medicine 36(12):879-882.
Sidhu, H., M.J. Allison, A.B. Peck (1996) “Detection and Characterization ofOxalobacter formigene
Allison Milton J.
Sidhu Harmeet
Ixion Biotechnology, Inc.
Lankford , Jr. Leon B.
Saliwanchik Lloyd & Saliwanchik
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