Source: http://www.google.es/patents/US6251439?dq=flatulence
Timestamp: 2017-06-25 05:37:17
Document Index: 260501196

Matched Legal Cases: ['§ 2010', '§ 88', '§ 16', '§ 865', '§ 32', '§ 37', '§ 52', '§ 50']

Patente US6251439 - Composition and method for reducing the risk of carcinogenesis - Google PatentesBúsqueda Imágenes Maps Play YouTube Noticias Gmail Drive Más »Iniciar sesiónPatentesA 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...http://www.google.es/patents/US6251439?utm_source=gb-gplus-sharePatente US6251439 - Composition and method for reducing the risk of carcinogenesis Búsqueda avanzada de patentesTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents. Número de publicaciónUS6251439 B1Tipo de publicaciónConcesión Número de solicitudUS 09/464,047 Fecha de publicación26 Jun 2001 Fecha de presentación15 Dic 1999 Fecha de prioridad16 Dic 1998TarifaPagadasTambién publicado comoUS6488966, US20020025346 Número de publicación09464047, 464047, US 6251439 B1, US 6251439B1, US-B1-6251439, US6251439 B1, US6251439B1 InventoresJohn A. Baron Cesionario originalTrustee Of The Dartmouth CollegeExportar citaBiBTeX, EndNote, RefManCitas de patentes (1), Otras citas (19), Citada por (44), Clasificaciones (16), Eventos legales (9) Enlaces externos: USPTO, Cesión de USPTO, EspacenetComposition and method for reducing the risk of carcinogenesis
US 6251439 B1 Resumen
What is claimed is: 1. A method for reducing a risk of carcinogenesis in a human subject comprising administering a dose of elemental calcium to the subject that is effective to reduce carcinogenesis.
8. The method according to claim I, wherein the dose of elemental calcium ranging from about 1 mg/kg/day to about 100 mg/kg/day.
15. A method for reducing a risk of recurrence of colorectal adenomas in a human subject, comprising administering a dose of calcium carbonate to the subject effective to reduce the risk of colorectal adenomas.
19. The method according to claim 2, wherein the colorectal adenoma is a polyp.
20. The method according to claim 15, wherein the colorectal adenoma is a polyp.
This patent application claims the priority of U.S. Provisional Patent Application Nos. 60/112,426 filed Dec. 16, 1998 and 60/115,668 filed Jan. 13, 1999, which are each incorporated herein by reference.
The research leading to the present invention was supported, in part, by National Institutes of Health Grants No. CA46927 and CA53827.
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).
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.
Stage 0: Carcinoma in situ. Cancer is confined to the inner layer of the colon. There is no corresponding stage for Dukes or Astler-Coller. No treatment after surgery or polypectomy. The survival rate approaches 100 percent.
As with colon cancer, treatment for rectal cancer depends on the stage of the disease.
Stage 0: Cancer has not grown beyond the rectal lining. There is no treatment after surgery, and the survival rate is greater than 90 percent.
Treatment of rectal cancer often combines surgery with chemotherapy and radiation, depending on the stage of the disease (see colon cancer treatment for discussion of these treatments). Sometimes surgery is performed first, and on other occasions, chemoradiation is given prior to surgery. A number different surgical procedures are available to treat rectal cancer, the choice depending on the location and stage of the cancer. These include polypectomy (removal of Stage 0 tumors), local excision, low anterior resection, abdominoperineal resection; and pelvic exenteration; which is only rarely performed.
The phrase “therapeutically effective amount” or “dose . . . that is effective” is used herein to mean a dose or an amount sufficient to reduce the risk of carcinogenesis, such as but not limited to polyp formation, recurrent adenoma, and development of a carcinoma. Preferably, the risk is reduced by a statistically significant amount, e.g., with an acceptable value for p For example, the risk of carcinogenesis may be reduced by at least about 10 percent, preferably by at least 25 percent, more preferably by at least 50 percent, and most preferably completely. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in the host, such as recurrent adenoma.
The solid dosage form may have a film coating to protect the ingredients from moisture, oxygen or light and to mask any undesirable taste or appearance. Suitable coating agents include cellulose, hydroxy-propylmethylcellulose, cellulose phthalate, methacryulic copolymer and shellac. An enteric coating may be employed, as well as coloring agents for identification and, if desired, the solid form may be polished with a waxy composition, such as carnuba wax.
EXAMPLE: CLINICAL EVALUATION OF CALCIUM INTAKE TO PROTECT AGAINST COLORECTAL CARCINOGENESIS
327 (70.2)
296 (70.0)
139 (29.8)
127 (30.0)
61.0 ± 9.1*
61.0 ± 9.1
60.9 ± 9.0
60.7 ± 8.8
72 (15.5)
71 (15.3)
67 (16.4)
62 (15.2)
72 (17.6)
91 (19.6)
Mean Number of Prior Adenomas1 2.6 ± 2.8
2.6 ± 2.9
Mean Daily Caloric Intake (Kcal)§ 2010 ± 756
2040 ± 761
2011 ± 742
2032 ± 756
Mean Total Daily Fat Intake (gms)§ 88.1 + 42.9
87.2 + 41.3
87.9 + 42.2
86.1 + 40.5
Mean Dietary Fiber Intake (mg)§ 16.2 + 7.8
16.6 + 8.0
16.4 + 8.0
16.7 + 8.0
Mean Dietary Calcium Intake (mg)§ 865 + 423
889 + 451
866 + 421
893 + 451
Taking Supplemental Calcium
*Mean ± standard deviation 1Lifetime number of colorectal adenomas found and removed before randomization. §Dietary information was missing for 10 placebo and 13 calcium subjects. NOTE: None of the differences between groups was statistically significant, P<0.05. Of the 930 randomized subjects, 832 (89%) completed two follow-up colonoscopies (Table 2). We could not include 98 subjects (43 placebo and 55 calcium) in the main analyses: 47 had died, 25 no longer wished to participate, 18 could not be examined because they were too ill or had moved, and 8 dropped out for unknown reasons. In addition to the study-mandated colonoscopies, an interval colonoscopy or sigmoidoscopy was performed in the main risk period (second study interval) in 86 (10%) of the patients. The proportions of subjects with an inadequate study colonoscopy or with an interim endoscopy did not differ substantially between treatment groups (Table 2).
Placebo (N %)
Calcium N (%)
466 (100) 464 (100) Died
Dropped out : lost interest
Dropped out : ill or moved
Dropped out : other or unknown reasons
Received first follow-up colonoscopy
459 (98.5)
454 (97.8)
Mean length of 1st surveillance
13.1 ± 0.18*
13.6 ± 0.26
Interim endoscopy during 1st 5 (1.1)
14 (3.1)**
surveillance interval1 Inadequate 1st follow-up colonoscopy1 21 (4.6)
Received 2nd follow-up colonoscopy
423 (90.8)
409 (88.2)
Mean length of 2nd surveillance
36.6 ± 0.16
36.9 ± 0.18
Interim endoscopy during 2nd 51 (12.1)
surveillance interval1 Inadequate 2nd follow-up colonoscopy1 29 (6.9)
*Mean ± standard error. **P for difference in proportions = 0.04 1Proportions of subjects receiving the respective follow-up examinations. Self-reported adherence to the study regimen gradually declined during the trial (Table 3). Nevertheless, even during the fourth year, over 80% of living subjects took study agents 90-100% of the time, and a further 7% took them 50-89% of the time. Use of supplemental calcium was reported at least once by only 19 (2%) patients during the study of (9 placebo, 10 calcium).
% of Tablets Taken
50-89% 42
50-89% 52
50-89% 33
50-89% 31
Note: Numbers of subjects may not sum to 930 because of drop-outs and missing data. Among the 832 subjects who completed the study, at least one colorectal adenoma was diagnosed during the main risk period (the second study interval) in 127 (31.1%) calcium patients and 159 (37.6%) placebo patients (Table 4). The mean size of the largest adenoma was equal in the two groups (0.4 cm; P=0.43), but more adenomas were found in the placebo group (mean 0.73 versus 0.55 for placebo, P=0.03). The unadjusted risk ratio for at least one adenoma was 0.83 ) 95% confidence interval 0.68 to 1.00; P=0.05); after adjustment, this was 0.81 (95% confidence interval 0.67 to 0.99; P=0.04). The unadjusted ratio of the average number of adenomas was 0.75 (95% percent confidence interval 0.58 to 0.97; P=0.03); this was 0.76 (95% confidence interval 0.60 to 0.96; P=0.02) after adjustment. During the main risk period, invasive large bowel cancer was found in four subjects (3 placebo, I calcium), and no adenomas with severe atypia were removed (P for differences in proportions with severe atypia or cancer=0.62). Analysis of adenomas detected on the second follow-up examination (excluding findings on interval endoscopies) yielded identical results (Table 4).
Numbers of subjects with any adenoma recurrence, relative risks of at least one recurrence, and
% with one
adenomas*
of adenomas*
Subjects who have
(423 Placebo,
409 Calcium)
1st Study Interval§ 32.6%
0.78 (0.63 to
0.75 (0.58 to
1st Study Exam
0.75 (0.61 to
0.70 (0.54 to
2nd Study Interval§ 37.6%
0.81 (0.67 to
0.76 (0.60 to
2nd Study Exam
0.83 (0.68 to
0.83 (0.65 to
1st or 2nd Study Interval§ 52.2%
0.85 (0.74 to
0.75 (0.62 to
Subjects who had at least
one endoscopy
(459 Placebo,
454 Calcium)
1st or 2nd Interval§ 50.5%
0.75 (0.63 to
0.84 (0.73 to
0.77 (0.64 to
*Risk ratio of at least one adenoma and ratio of the mean numbers of adenomas. Both estimates adjusted for age, gender, clinical center, number of previous adenomas, and length of follow-up interval. §First study interval, randomization to first follow-up colonoscopy; second study interval, after first follow-up colonoscopy up to and including second follow-up colonoscopy. A similar calcium effect was found during the first study interval. Among the subjects who completed the trial, at least one adenoma was noted in the period up to and including the first follow-up exam in 103 (25%) calcium subjects and 138 (33%) placebo subjects (Table 4). The unadjusted risk ratio for at least one adenoma in this early interval was 0.77 (95% confidence interval 0.62 to 0.96; P=0.02); the unadjusted ratio of the average numbers of adenomas was 0.73 (95% confidence interval 0.54 to 0.97; P=0.03). These estimates were virtually unchanged after multivariate adjustment. Analysis of adenomas detected on the first follow-up examination yielded similar findings. At or before the first follow-up, invasive cancer was found in four patients (2 calcium, 2 placebo), and an adenoma with severe atypia was removed from one participant in each treatment group.
Subjects Hospitalized
Stopped treatment because
Note: There were no statistically significant differences in the proportions between treatment groups. Discussion
Epidemiological data regarding the association between dietary calcium and the risk of colorectal cancer have varied considerably, but in aggregate are consistent with the effect we observed (Blergsma-Kadijk et al, supra; Martinez and Willet, supra). Many studies (Slattery et al., Am. J. Epidemiol., 1988, 125:505-514; Whittemore et al., J. Natl. Cancer. Inst., 1990, 82:915-926; Garland et al., Lancet, 1985, 1:307-9; Bostick et al., Am. J. Epidemiol., 1993, 137:1302-17; Kearney et al., Am. J. Epidemiol., 1996, 43:907-917; and, Martinez et al., J. Natl. Cancer Inst., 1996, 88:1375-1382) found at least suggestions of an inverse association, but others found no relation (Graham et al., Am. J. Epidemiol., 1988, 128:490-503; Boutron et al., Brit. J. Cancer, 1996, 74:145-151), or even the possibility of an increased risk with higher intake (Kampman et al., Cancer Res., 1993, 54:3186-3190; Pritchard et al., Cancer Epidemiol. Biomarkers Prev., 1996, 5:897-900). Investigations of calcium intake and the risk of colorectal adenomas have also been conflicting (Boutron et al., supra; Little et al., Brit. J. Cancer, 1993, 67:177-18; Kampman et al., Am. J. Epidemiol., 1994, 139:16-29; Tseng et al., Am. J. Epidemiol., 1996, 144:1005-1014) as have studies that considered calcium supplementation separately (Bostick et al., supra; Kampman et al., supra; Neugut et al., Cancer, 1996, 78:723-8).
Extensive animal research supports an anti-neoplastic effect of calcium in the large bowel. Calcium inhibits the mucosal injury and hyperproliferation induced by bile acids or carcinogens (Pence, supra), and most studies that used high-fat diets reported lower tumor incidence with supplementations (Pence, supra; Pence and Buddingh, supra). Effects of calcium have been absent or less pronounced among animals fed low-fat diets (McSherry et al., Cancer Res., 1989, 49:6039-43; Sitrin et al., Cancer Res., 1991, 51:5608-5613). One experimental study suggested that dietary calcium particularly inhibited tumors with ras mutations (Llor et al., Cancer Res., 1991, 51:4305-4309), a recent epidemiological study reported similar effects (Bautista et al., Cancer Epidemiol. Biomarkers Prev., 1997, 6:57-61).
Our results are based on adenoma recurrence and do not directly address whether calcium affects the progression of adenomas to invasive cancer or the risk of a first adenoma. The similarity of risk factors for colorectal cancer, recurrent adenomas and incident adenomas (Peipins and Sandler, Epidemiol. Rev., 1994, 16:273-297) provides reassurance regarding the relevance of our finding for colorectal cancer itself. On the other hand, the calcium effect may have been weaker for large adenomas than for small ones, consistent with a limited efficacy for more advanced tumors. The suppressive effect of calcium was seen less than a year after randomization, and the effect did not become stronger with time. Conceivably, increasing efficacy was counterbalanced by decreasing compliance.
Citas de patentes Patente citada Fecha de presentación Fecha de publicación Solicitante TítuloUS4851221 *26 Nov 198625 Jul 1989Mission Pharmacal CompanyLiquid calcium supplementation from readily soluble mixtures of calcium compound and citric acid* Citada por examinadorOtras citasReferencia1Alberts et al, J. Natl. Cancer Inst., vol. 88, No. 2, pp. 81-92 (abstract), Jan. 1996.*2Benito, E., et al., "Diet and Colorectal Adenomas: A Case-Control Study In Majorca" Int. J. Cancer, vol. 55, pp 213-219, 1993.3Bergsma-Kadijk, J.A. "Calcium Does Not Protect against Colorectal Neoplasia", Epidemiology, vol. 7, No. 6, pp 590-597, 1996.4Bostick et al, Cancer Epidemiol. Biomarkers Prev., vol. 6, No. 12, pp. 1021-27 (abstract), Dec. 1997.*5Bostick et al, J. Natl. Cancer Inst., vol. 85, No. 2, pp. 132-41 (abstract), Jan. 1993.*6Bostick et al, J. Natl. Cancer Inst., vol. 87, No. 17, pp. 1307-15 (abstract), Sep. 1995.*7Bostick, Cancer Epideriol. 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OFFree format text: CONFIRMATORY LICENSE;ASSIGNOR:DARTMOUTH COLLEGE;REEL/FRAME:021029/0140Effective date: 2002082018 Sep 2008FPAYFee paymentYear of fee payment: 84 Feb 2013REMIMaintenance fee reminder mailed13 Jun 2013FPAYFee paymentYear of fee payment: 1213 Jun 2013SULPSurcharge for late paymentYear of fee payment: 111 Oct 2013RRRequest for reexamination filedEffective date: 201308019 Sep 2014B1Reexamination certificate first reexaminationFree format text: CLAIM 3 IS CANCELLED.CLAIMS 1, 2, 4, 6 AND 15 ARE DETERMINED TO BE PATENTABLE AS AMENDED.CLAIMS 5, 7-14 AND 16-20, DEPENDENT ON AN AMENDED CLAIM, ARE DETERMINED TO BE PATENTABLE.NEW CLAIMS 21-24 ARE ADDED AND DETERMINED TO BE PATENTABLE.GirarImagen originalPágina principal de Google - Sitemap - Descargas en bloque de USPTO - Política de Privacidad - Condiciones de Servicio - Acerca de Google Patentes - Enviar sugerenciasDatos proporcionados por IFI CLAIMS Patent Services