Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-14
2003-02-18
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...
C514S008100, C514S367000, C514S262100
Reexamination Certificate
active
06521645
ABSTRACT:
BACKGROUND OF THE INVENTION
Urinary stone disease, urolithiasis, affects about 2 to 3% of the general population in the United States and other industrialized countries (1). In some population groups the occurrence can be significantly higher. For example, the prevalence of urolithiasis among adults in Taiwan reaches 8 to 9%, and urinary stones were reported to be the third most common disease in northern Italy (2,3). The incidence of urinary stones further increases with age, in part, due to age-related conditions such as arterial hypertension (4). The likelihood that a Caucasian male will develop stone disease by age 70 is about 1 in 8 (1). While extracorporeal shock wave lithotripsy has-simplified urinary stone removal, the recurrence rates remain high, reaching 50% to 70% in 10 years (5,6).
Since a majority of urinary stones (75-80%) are made of calcium oxalate, the control of concentrations of calcium and/or oxalate in urine is an important part of a medical treatment program to prevent stone formation or recurrence. Hypercalciuria is more common in patients with recurrent calcium oxalate renal stones; it is found in 50% of the cases, compared to about 35% for mild hyperoxaluria (1). However, the lowering of urinary oxalate level has a number of advantages. The contribution of oxalate to calcium oxalate saturation is considerably greater than that of calcium. As a result, a relatively small decrease in oxalate concentration could lower the calcium oxalate level below saturation, and thus prevent stone formation. In addition, changing the calcium concentration in urine is difficult, and risks increased oxalate absorption; it may also affect important physiological processes, such as bone calcification.
Control of urinary oxalate through the diet can produce only a partial effect, because dietary oxalate contribution to urinary oxalate is only 8 to 40% (1,7), with the rest of it synthesized endogenously, mainly in liver. The key reactions of oxalate synthesis are the conversion of glycolaldehyde to glycolate by aldehyde dehydrogenase, the conversion of glycolate to glyoxylate by glycolate oxidase and the oxidation of glyoxylate to oxalate by lactate dehydrogenase. Several minor reactions such as catabolism of hydroxyproline and degradation of aromatic amino acids may also contribute to glyoxylate and oxalate synthesis. However, in vivo, the combined contribution from these reactions is probably less than 5% (8). Glyoxylate can be converted back to glycolate by the action of D-glycerate dehydrogenase (8).
The most extreme example of a disease in which an increase in metabolically derived oxalate leads to urinary stone formation is the clinical syndrome of primary hyperoxaluria. Type I primary hyperoxaluria is characterized by a genetic defect in the peroxisomal vitamin B
6
-dependent enzyme alanine:glyoxylate aminotransferase (AGT). This defect results in decreased conversion of glyoxylate to glycine; consequently, conversion of glyoxylate to oxalate increases. Type II primary hyperoxaluria is caused by the deficiency of D-glycerate dehydrogenase (8). Patients with these disorders have severe renal stone disease leading to renal failure, and will eventually require renal and hepatic transplantation. Lowering urinary oxalate in these patients can alleviate the severity of stone disease and avoid costly transplantation procedures.
Acquired hyperoxaluria may be caused by a number of factors, such as the gluttony for oxalate-rich foods, abuse of ascorbic acid (vitamin C), and by small bowel disease or bypass of the small intestine that causes increased colonic oxalate absorption. In these cases, lowering urinary oxalate concentration can significantly diminish the probability of stone formation.
About 25% of all stone formers have no quantifiable abnormalities of urinary composition. This condition, called idiopathic stone disease, is likely caused by low activity of normal urinary inhibitors of crystal nucleation and crystal growth. Even though urinary oxalate in these individuals is within a normal concentration range, lowering it will decrease the contribution of oxalate to calcium oxalate supersaturation, and thus lower the probability of stone formation.
Development of an effective drug therapy that decreases urinary oxalate concentration can be a valuable tool in the prophylaxis and treatment of urinary stone disease. Several pharmacological approaches have been tested in an attempt to develop such therapy. One approach is to inhibit the enzymes involved in oxalate biosynthesis. Several inhibitors of either aldehyde dehydrogenase or glycolate oxidase were tested in both animals and humans with mixed results (9,10). Newer inhibitors of aldehyde dehydrogenase may also be used (11,12). However, one drawback of this approach may be the accumulation of glycolaldehyde, a potentially toxic agent.
Another approach to reduction of urinary oxalate concentration is based on the use of the vitamin B
6
precursor pyridoxine. This treatment benefits only a small number of patients with vitamin B
6
-dependent type I primary hyperoxaluria (13). The mechanism of this effect is not clear, but may be related to the ability of pyridoxal-5′-phosphate to modulate protein expression, in particular, the expression of AGT (14). The reports on the effects of pyridoxine in individuals without Type I primary hyperoxaluria are controversial. The intake of pyridoxine in doses of 40 mg/day is associated with reduced risk of kidney stone formation in women (15) but not in men (16). On the other hand, prescription of 200 mg of pyridoxine daily did not reduce urinary oxalate levels in stone formers (17). If the primary mode of pyridoxine action is the regulation of AGT expression and/or activity, these controversial results may reflect individual differences in enzyme status and, thus, may render many stone formers non-responsive to pyridoxine treatment.
The most recent development in the field has been with an approach to trap glyoxylate in liver and reduce the amount available for conversion to oxalate. It is suggested that this approach has a significant potential because of the proximity of glyoxylate to the terminal step in oxalate synthesis. One of the proposed treatments relies on the reactivity of the glyoxylate carbonyl group with the free sulphydryl group of cysteine. The cysteine precursor, (L)-2-oxothiazolidine-4-carboxylate (OTZ) is used as the therapeutic agent because of its low toxicity. OTZ has been shown to decrease urinary oxalate concentration in a rat model of hyperoxaluria (18). Treatment with OTZ also resulted in decreased urinary oxalate levels in normal individuals (19). However, at elevated levels, free cysteine can interfere with a variety of reduction-oxidation reactions in the cell, and is potentially cytotoxic. In a human study, OTZ administered to patients for only 48 hours, produced a number of the mild to moderate adverse effects (19).
Based on all of the above, there is a need in the art for effective methods to treat and prevent urinary stone disease.
SUMMARY OF THE INVENTION
The present invention provides methods and pharmaceutical compositions for treating or inhibiting urinary stone disease that comprise administering to an individual with urinary stone disease or at risk of developing urinary stone disease an amount effective of pyridoxamine to reduce urinary oxalate concentrations. In one set of embodiments, the methods comprise treating an individual suffering from urinary oxalate stones. In another set of embodiments, the methods comprise treating an individual at risk for urinary stone disease in order to reduce or prevent formation of urinary stones in the individual.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides methods for treating an individual with urinary stone disease with an amount effective of pyridoxamine to reduce urinary oxalate concentrations. As used herein, the term “urinary stone disease” (urolithiasis) means a condition characterized by stone formation in the urine. Conditions leading to urinary stone d
Hudson Billy
Scheimman Jon
Voziyan Paul
Cook Rebecca
The University of Kansas Medical Center
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