Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-09
2003-02-18
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S332000, C514S337000, C514S456000, C514S841000, C514S454000, C514S437000, C514S432000, C514S411000, C514S412000, C514S438000, C514S468000
Reexamination Certificate
active
06521641
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns methods and compositions for inhibiting or blocking fertility in a male mammal by the administration of a retinoid or retinoid derivative that is able to act as an antagonist or inverse agonist of a retinoic acid receptor (RAR). The effect is reversible upon cessation of treatment with the RAR antagonist or inverse agonist.
BACKGROUND OF THE INVENTION
The prevention of unplanned pregnancy in humans and other mammals is of continuing concern for both the developing and the developed world. A variety of methods and products have been proposed or developed for the prevention of pregnancy; these products include: surgical sterilization, condoms, birth control pills containing progestin or a combination of progestin and estrogen, subdermal implants containing delayed release forms of progesterone, intrauterine devices, spermicidal creams or gels, and intravaginal barriers such as sponges or diaphragms.
These various methods each have certain advantages and certain drawbacks. The most common non-surgical birth control method in the United States is the birth control pill (“the Pill”), which contains synthetic progestin and estrogen; synthetic hormones similar to those produced naturally in a woman's body. The Pill works primarily by suppressing the release of eggs from a woman's ovaries.
Within two years after its introduction in 1960, approximately 1.2 million women were using oral birth control, and by 1973, about 10 million women were using the Pill. However, in recent years questions have arisen about the health risks involved in continued long term use of contraceptive hormones. There have been reports of increased risk of certain forms of cancer, such as breast and cervical cancer, though the use of the Pill.
Surgical sterilization, whether through tubal ligation or vasectomy, is nearly 100% effective, but is only sometimes reversible. Reversal of surgical sterilization usually requires further surgery.
Condoms, made of either synthetic polymer materials or animal skin, are less effective n birth control pills and their effectiveness is further subject to subversion through the possibility that small breaks may be present, permitting leakage of semen. Additionally, the use of a condom requires the affirmative action of the male, usually immediately prior to the initiation of sexual intercourse and some men report a loss of sensation through the use of condoms. Hence, subject noncompliance is also an issue in the use of condoms.
Subdermal implants, such as the NORPLANT® implant device, are quite effective contraceptive means. The implant comprises a set of silicone rods that are inserted under the skin of the upper arm. The implant contains hormones, such as progestin, levonorgestrel and progesterone, that are slowly released over a period of time of up to five years. Side effects may be similar to those involved in the use of birth control pills, and include a risk of developing ovarian cysts. Additionally, while the implant can be removed, the procedure is difficult even for skilled surgeons due to the formation of scar tissue around the implant.
Intrauterine devices (IUDs) are small devices that are typically either made of copper or impregnated with progesterone. These must be inserted (and removed) by a doctor. Depending on the design, the devices appear to interfere with sperm motility or the implantation of the fertilized egg in the uterine wall. Side effects can include cramps, backache, spotting, or heavy periods, and women may have an increased risk of ectopic pregnancy or infertility. IUDs are usually not recommended for women who have not had children or who think they will have children in the future due to these latter risks. Normally, the contraceptive effects are reversible upon removal of the device.
Barriers such as diaphragms and sponges are usually used in conjunction with a spermicidal cream, foam, or gel. The effectiveness of such devices is between about 90% and about 95%. The user can insert them as long as a number of hours before sexual intercourse, and the effects are temporary; if pregnancy is subsequently desired, the woman can discontinue their use with a concomitant return of fertility.
With the exception of surgical sterilization and the use of condoms, all of the methods in common use affect female fertility with no effect on male fertility. As mentioned above, the former of these methods is irreversible and the latter is neither inherently as effective as other methods, nor is compliance as high. A male contraceptive that is not required to be applied immediately prior to intercourse would provide a contraceptive alternative to the traditional methods of contraception.
A number of compositions have been proposed for use as a male contraceptive. Thus, U.S. Pat. No. 5,501,855, to Talwar et al., describes application of neem (
Azadirachta indica
) oil by injection to the vas deferens in an amount effective to block the fertility of the male by spermatogenic arrest. A single injection was reported to be effective to block fertility over the 9 month period of observation reported in the '855 patent.
U.S. Pat. No. 4,677,193 and International Patent Publication No. WO 94/19370, both to Rivier et al., describe a hypothalamic peptide hormone (termed GnRH) that functions to trigger the release of gonadotropic hormones such a luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the female. These references also mention that antagonists of GnRH are effective to arrest spermatogenesis in male mammals. This treatment apparently requires supplemental testosterone to be provided with the treatment in order to maintain libido.
U.S. Pat. No. 5,744,448, to Kelton et al., describes the cloning, expression, and purification of human FSH receptor, or mutants or fragments thereof that retain the ability to bind FSH. One possible use of the FSH receptor is described as a method for preventing spermatogenesis in a male patient.
U.S. Pat. No. 4,182,891, to Metcalf et al., and U.S. Pat. No. 4,134,918, to Bey et al. describe compounds said to be useful in inhibiting spermatogenesis. The '891 patent describes acetylenic derivatives of amino acids, and the '918 patent describes halomethyl derivatives of amines.
International Patent Publication No. WO 97/24901, to Bandman et al., describes the amino acid sequence of a polypeptide termed Lung Growth Factor Variant (LGFV), which is said to play a role in various physiological processes, including spermatogenesis.
U.S. Pat. No. 5,753,231, to Herr, et al., describes a female contraceptive vaccine prepared from antibodies raised to a recombinant primate acrosomal sperm antigen. The vaccine elicits an anti-sperm immune response, resulting in inhibition of fertilization. Also described are contraceptive compositions containing such an antibody in a carrier for vaginal application.
None of the references cited herein are admitted in any manner to be prior art against the present application.
SUMMARY OF THE INVENTION
The present invention concerns the discovery that certain agents that are able to block the binding of retinoic acid (RA) or other RAR ligands to RAR receptors, and thereby prevent activation of RARs, are also able to inhibit spermatogenesis in a male mammal.
It has been known for some time that among the various results of a severe vitamin A (retinol) deficiency in mammals is sterility and blindness. See Eskild, W. & Hansson V.,
Vitamin A Functions in the Reproductive Organs in Vitamin A in Health and Disease
531 (Blomhoff, R. ed., 1994) (hereinafter Eskild). A complete deficiency in retinoids is fatal. Administration of retinoic acid in the absence of retinol can alleviate many of the symptoms of vitamin A deficiency, giving rise to blind and sterile animals that remain otherwise healthy.
Researchers have also noted that treatment of vitamin A-deficient rats (in which there was a complete spermatogenic arrest) with vitamin A replacement results in restoration of normal spermatogenesis; reinitiation of spermatogenesis occurs
Chandraratna Roshantha A.
Klein Elliott S.
Yuan Yang-Dar
Allergan Inc.
Baran Robert J.
Fisher Carlos A.
Voet Martin A.
Webman Edward J.
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