Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Alkali or alkaline earth chloride
Reexamination Certificate
1999-12-15
2001-06-26
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Alkali or alkaline earth chloride
C424S682000, C424S686000, C424S687000
Reexamination Certificate
active
06251439
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to reducing the risk, and optimally preventing, carcinogenesis through modification of diet. In particular, ingestion of calcium results in reduced risk of recurrence of colorectal adenomas.
BACKGROUND OF THE INVENTION
Dietary patterns have repeatedly been associated with the risk of colorectal neoplasia: a diet rich in vegetables and fruits is associated with a lower risk, while intake of animal fat and red meat seems to increase risk (Sandler, Gastroenterology Clinics NA, 25:717-735, 1996). The underlying mechanisms are not clear, but may in part be due to alterations in bile acids, which are carcinogenic in animal models (Nagengast et al., Eur. J. Cancer, 1995, 31A:1067-70).
Newmark and colleagues (Newmark et al., J. Natl. Cancer Inst., 1984, 72:1323-1325) proposed that calcium binds bile acids in the bowel lumen, inhibiting their proliferative and carcinogenic effects. In support of this hypothesis, animal studies have indicated a protective effect of dietary calcium on bile-induced mucosal damage and experimental bowel carcinogenesis (Pence, Mut. Res., 1993, 290:87-95; Pence, Carcinogenesis, 1988, 9:187-190). However, human epidemiological research has been inconsistent; in some studies a decreased risk of colorectal cancer has been associated with calcium intake, while in others, no association was found (Blergsma-Kadijk et al., Epidemiology, 1996, 7:590-597; Martinez and Willett, Cancer Epidemiol. Biomarkers Prev., 1998, 7:163-168). Similarly mixed results have been reported regarding large bowel adenomas, likely precursors for most colorectal cancers (Morson et al.,, Cancer Surv., 1983, 2:451-477).
SUMMARY OF THE INVENTION
The present invention advantageously provides a method for reducing a risk of carcinogenesis in a subject comprising administering a dose of calcium to the subject that is effective to reduce carcinogenesis. Particularly provided is a method for reducing the risk of recurrence of colorectal adenomas, comprising administering a dose of calcium carbonate effective to reduce the risk of colorectal adenomas.
DETAILED DESCRIPTION OF THE INVENTION
In its broadest aspect, the present invention provides a method for reducing a risk of carcinogenesis in a subject comprising administering a dose of calcium to the subject that is effective to reduce carcinogenesis. Preferably, the carcinogenesis is development of a colorectal adenoma, e.g., a recurrence of an adenoma. Thus, in a specific embodiment, the method provides for reducing the risk of recurrence of colorectal adenomas, comprising administering a dose of calcium carbonate effective to reduce the risk of colorectal adenomas.
More particularly, the present invention is able to reduce the risk ratio of adenoma recurrence, resulting in a risk ratio of 0.74 to 0.98, e.g., about 0.85, with a 95% confidence interval. Indeed, as demonstrated in the Example, infra, the risk ratio of at least one adenoma was by 0.67 to 0.99, e.g., about 0.81, with a 95% confidence interval.
The effective dose of elemental calcium can be readily established. In particular, a dose ranging from about I mg/kg/day to about 100 mg/kg/day, preferably from about 1 mg/kg/day to about 50 mg/kg/day, and more preferably about 20 mg/kg twice a day, can be used. In a specific embodiment, the dose of elemental calcium is about 1200 mg twice a day.
Elemental calcium can be derived from many sources. Usually, it is found in a salt. Examples of calcium sources include, but are by no means limited to, calcium carbonate, calcium citrate, calcium hydroxide, calcium phosphate (including tricalcium phosphate and dicalcium phosphate), calcium chlorophosphate, or combinations thereof. In a specific embodiment, the calcium is provided as calcium carbonate.
When calcium carbonate is administered to the subject, a preferred dose is from about 20 to about 80 mg/kg twice a day, and more preferably about 40 mg/kg twice a day. In a specific embodiment, the dose is about 3000 mg twice a day.
The present invention is based, in part, on the discovery that 1200 mg of elemental calcium (supplied in 3000 mg of calcium carbonate) administered twice daily resulted in decreased risk of recurrent colorectal adenomas in patients with a history of colorectal adenomas. In particular, 930 patients with a recent history of colorectal adenomas were randomized to calcium carbonate (3 gm daily; 1,200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas and 95% confidence intervals were calculated as measures of effect.
As a result of this treatment protocol, there was a lower risk of recurrent adenomas in subjects randomized to calcium. Among the 913 subjects who had at least one study examination, the adjusted risk ratio of any adenoma recurrence was 0.85 (95% confidence interval 0.74 to 0.98; P=0.03). 832 patients completed both follow-up examinations and so were included in the main analysis; the adjusted risk ratio of at least one adenoma was 0.81 (95% confidence interval 0.67 to 0.99; P=0.04); the adjusted ratio of the average numbers of adenomas was 0.76 (95% confidence interval 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation can prevent a proportion of colorectal adenomas, precursors of most colorectal cancers.
As used herein, the term “carcinogenesis” refers to the development of a carcinoma, particularly an adenocarcinoma of the colon or rectum. In a specific embodiment, carcinogenesis refers to development of an adenoma. In more specific embodiment, carcinogenesis refers to recurrent adenomas.
In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
The various elements of the invention are further elaborated in the following sections concerning carcinomas, calcium sources, formulations, and administration. These sections are provided for the sake of convenience, and are not intended to limit the scope of the invention.
Carcinomas
A carcinoma is malignant new growth that arises from epithelium, found in skin or, more commonly, the lining of body organs, for example: breast, prostate, lung, stomach or bowel. Carcinomas tend to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example: to bone, liver, lung or the brain. An adenocarcinoma is a form of cancer that involves cells from the lining of the walls of many different organs of the body. Colorectal cancer is a type of adenocarcinoma. While the present invention focuses on carcinogenesis of the lower intestinal tract, it is believed to impact carcinogenesis broadly. Thus, though the application focuses on carcinogenesis in colorectal cancer (or carcinoma or adenocarcinoma), it should be generally considered as relating to carcinogenesis in general.
Colorectal cancer is a malignancy that arises from the lining of either the colon or the rectum. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. The risk can be reduced when following a diet which is low in fat and high in fiber.
As used herein, a polyp is a growth, usually benign, protruding from a mucous membrane. Colorectal polyps can be precursors to carcinomas.
Surgery is the primary method of treatment for polyp removal and the treatment of colorectal cancer. The extent of surgery and the need for follow-up treat
Darby & Darby
Reamer James H.
Trustee of the Dartmouth College
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