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(12) United States Patent (10) Patent No.: US 8,173,626 B2 Hausknecht (45) Date of Patent: May 8, 2012

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(12) United States Patent (10) Patent No.: US 8,173,626 B2 Hausknecht (45) Date of Patent: May 8, 2012 US008173626B2 (12) United States Patent (10) Patent No.: US 8,173,626 B2 Hausknecht (45) Date of Patent: May 8, 2012 (54) METHODS, DOSING REGIMENS AND OTHER PUBLICATIONS MEDICATIONS USING ANT-PROGESTATIONAL AGENTS FOR THE Lumsden and Wallace, Bailliere's Clinical Obstetrics and Gynaecol TREATMENT OF DISORDERS ogy, 1998; 12(2): 177-195.* Eldar-Geva, Bailliere's Clinical Obstetrics and Gynaecology, (75) Inventor: Richard Hausknecht, Bronx, NY (US) 1998; 12(2):269-288.* Chwalisz et al., Presentation at Advances in Leiomyoma Research (73) Assignee: Danco Laboratories LLC, New York, 2nd NIH International Congress, Feb. 2005, Bethesda, MD.* NY (US) Chu et al. Successful Long-Term Treatment of Refractory Cushings Disease with High-Dose Mifepristone (RU486). J. Clin. Endocrinol. (*) Notice: Subject to any disclaimer, the term of this Metab. Aug. 2001, vol. 86, No. 8, pp. 3568-3573. patent is extended or adjusted under 35 Eisinger et al., Low-Dose Mifepristone for Uterine Lelomyomata. J. U.S.C. 154(b) by 1328 days. Obstet. Gynecol., Feb. 2003, vol. 101, No. 2, pp. 243-250. Xu et al. The Journal of Clinical Endocrinology & Metabolism (21) Appl. No.: 11/715,509 90(2):953-961 (2005). NIH Record, 57(24): 1-12, Dec. 2, 2005. (22) Filed: Mar. 8, 2007 * cited by examiner (65) Prior Publication Data US 2007/021330.6 A1 Sep. 13, 2007 Primary Examiner — San-Ming Hui (74) Attorney, Agent, or Firm — Don J. Pelto, Esquire; Related U.S. Application Data Sheppard, Mullin, Richter & Hampton LLP (60) Provisional application No. 60/780,047, filed on Mar. 8, 2006. (57) ABSTRACT (51) Int. Cl. A6 IK3I/56 (2006.01) The present invention relates to the treatment of disorders (52) U.S. Cl. ....................................................... 514/179 using anti-progestational agents. More specifically, the (58) Field of Classification Search ................... 514/179 present invention relates to the treatment of disorders using See application file for complete search history. low doses of anti-progestational agents. Compared to dosages and lengths of treatment taught by the prior art, the described (56) References Cited methods, dosing regimens and medications use effective dos ages and lengths of treatment that are lower and/or shorter U.S. PATENT DOCUMENTS than previously thought possible. 5,468,741 A 11, 1995 Yen 6,043,234. A 3/2000 Stockemann et al. 6,451,780 B1 9, 2002 ChwalSZ et al. 47 Claims, 5 Drawing Sheets Treatment (nx22) Placebo (r.20) Mean Mean SD) Mediary Range SD) Median Range Age ty) 41,862 43. 295 43.2 (4.7) 30 lody mass index (kg/m. 31.7 (8.7) S. 2-5 27. 5.6) 26 0-39 Education ty) 4.6 (2.3 - 2. 15. 2.5) s 1-22 Gravidity 2.6 (2. 3. e 2.ii 2, .) Parity .8 (.6) t .65 b. Uterine volume (m. 79 (663) 1732,88 449 (236) 3. 20-1,03 African American n (8) 1 (50 -- (55) - SE), standard deviation. U.S. Patent May 8, 2012 Sheet 1 of 5 US 8,173,626 B2 Figure 1 Treatment (ne22) Placebo (n=20) Mean Mean (SO) Media Range (SD) Mediar Range Age ty 4.1.86.2 43. S5 43.2 (1.7) f 30 Body mass index (kg/m. 3,7 (8.7) S. 2-5 2. 5.6) O-3) Education (y) 4.6 (2.3 2.9 15. 2.5) s Gravidity 2.6 (2.1) 3 2.8 2, .) O7 Parity 1.8 (1.6) - .6 .5 2 b literiric voluntern 79 (663) i 3.288 449 (236) 3. 2003 African American n (i)) 50 r 1 (55) - S), standard deviation. U.S. Patent May 8, 2012 Sheet 2 of 5 US 8,173,626 B2 Figure 2 Placebo Treatment U.S. Patent May 8, 2012 Sheet 3 of 5 US 8,173,626 B2 Figure 3 U.S. Patent May 8, 2012 Sheet 4 of 5 US 8,173,626 B2 Figure 4 U.S. Patent May 8, 2012 Sheet 5 of 5 US 8,173,626 B2 Figure 5 US 8,173,626 B2 1. 2 METHODS, DOSING REGIMENS AND Overview of Diagnosis and Treatment, www.womenshealth MEDICATIONS USING services.com (last visited Dec. 12, 2005). Other studies have ANT-PROGESTATIONAL AGENTS FOR THE found that uterine leiomyomata are clinically apparent in TREATMENT OF DISORDERS about 25% to about 50% of women (Buttram & Reiter, 36 Fertil. Steril. 433-45 (1981)), although careful pathologic CROSS REFERENCE TO RELATED examination of the uterus Suggests that the prevalence may be APPLICATION as high as about 80%. Cramer & Patel, 94 Am. J. Clin. Pathol. 435-38 (1990). This application claims the benefit, under 35 U.S.C. S 119, The severity of symptoms associated with uterineleiomyo of provisional U.S. Application Ser. No. 60/780,047, filed 10 mata, as well as their prevalence, requires a treatment for this Mar. 8, 2006, the entire contents and substance of which is condition. Previously, the only effective treatment for uterine hereby incorporated by reference. leiomyomata was hysterectomy, an unacceptable treatment option for many women. FIELD OF THE INVENTION Because hysterectomy is an unacceptable treatment option 15 for many women, other procedures have been developed. For The present invention relates to the treatment of disorders example, myomectomy, the Surgical removal of leiomyomata using anti-progestational agents. More specifically, the from the uterus was developed as an alternative in some cases. present invention relates to the treatment of disorders using Uterine artery embolization has also been developed. In this low doses of anti-progestational agents. The disorders treated radiologic procedure, uterine arteries are partially blocked, can be, but are not limited to, benign gynecological disorders. thus decreasing blood flow to the uterine leiomyomata inhib iting their growth and/or Survival. BACKGROUND OF THE INVENTION Myomectomy can be an effective treatment in some patients, however, there are risks associated with it. Some of Progesterone plays a major role in reproductive health and these risks include Scarring and infection. In some cases, functioning. Its effects on, for example, the uterus, breast, 25 scarring after myomectomy can lead to infertility. Studies of cervix and hypothalamic-pituitary unit are well established. It the effectiveness of uterine artery embolization have indi also has extra-reproductive activities that are less well stud cated that most Subjects have a significant decrease in bleed ied. Such as effects on the brain, the immune system, the ing symptoms, as well as a reduction in uterine size. However, vascular endothelial system and on lipid metabolism. Given uterine artery embolization may also have serious conse this wide array of effects, it is apparent that compounds which 30 quences including infection, massive uterine bleeding, and mimic Some of the effects of progesterone (agonists), antago uterine necrosis, requiring emergency Surgery. Barbieri, 42 nize these effects (antagonists) or exhibit mixed effects (par Clin. Obstet. Gynecol. 196-205 (1999). Subjects can also tial agonists or mixed agonist/antagonist) can be useful in experience significant uterine pain, ischemia, and hypoxic treating a variety of medical conditions. changes following embolization. American College of Obste Information indicating that anti-progestational agents 35 tricians and Gynecologists (ACOG) Practice Bulletin, No. 16 could be effective in a number of medical conditions is avail (May 2000). Based on these negative effects, a need for an able. For example, this information has been Summarized in a acceptable treatment option for uterine leiomyomata report from the Institute of Medicine compiled by Donaldson remains. et al., Editors, Clinical Applications of Mifepristone (RU Although the mechanisms leading to uterine leiomyomata 486) and Other Anti-progestational agents, Committee on 40 tumorogenesis are not completely understood, evidence Sug Anti-progestational agents: Assessing the Science, Institute gests that the development of uterine leiomyomata is ovarian of Medicine, National Academy Press, (1993). The following steroid dependent. Murphy et al., 76(2) J. Clin. Endocrinol. discussion regarding uterine leiomyomata highlights one 513-517 (2005) and Buttram et al., 36 Fertil. Steril. 433 non-limiting example of Such uses. (1981) which are both incorporated herein by reference. Part Uterine leiomyomata (also called leiomyomas or fibroids) 45 of this evidence comes from the findings that uterineleiomyo are monoclonal, generally benign, Smooth muscle tumors of mata contain both estrogen and progesterone receptors (Wil the myometrium, the muscular portion of the uterus com son et al., 55 Obstet. Gynecol. 20-4 (1980); Soules & posed of smooth muscle and connective tissue. While these McCarty 143 Am. J. Obstet. Gynecol. 6-11 (1980)) and that tumors are generally benign, they nonetheless can cause a both of these hormones are thought to be involved in tumor variety of troubling symptoms. For example, uterine lei 50 formation. See www.womenshealth services.com, Supra. Fur omyomata can cause pain in the lower back and abdomen, ther, estrogen and growth hormone are thought to act syner excessive menstrual bleeding (both in terms of volume and gistically to stimulate leiomyomata growth as the two are length of menstrual periods or bleeding between menses elevated during pregnancy when the growth of leiomyomata resulting in anemia and fatigue), pressure on the urinary blad is rapid. That progesterone may play a role in uterine lei der resulting in frequent urination and/or pressure on the 55 omyomata growth is Suggested by the finding of increased rectum causing constipation. Large leiomyomata can press on mitotic count in leiomyomata obtained during the secretory the ureters (tubes going from the kidneys to the bladder) phase than in the proliferative phase of the menstrual cycle. causing obstruction or blockage of urine which can lead to Kawaguchi et al. 160 Am. J. Obstet. Gynecol. 637 (1988). kidney damage. Uterine leiomyomata also can cause infertil Additionally, when the GnRH-agonist and a progesterone ity.
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