guardianactual
MuscleChemistry Registered Member
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol
</br>
</br> AKA 4-hydroxytamoxifen.
</br>
</br> Afimoxifene[1] (4-hydroxytamoxifen) is a selective estrogen receptor modulator which is the active metabolite of tamoxifen.[2] Afimoxifene is a transdermal gel formulation and is being developed by Ascend Therapeutics, Inc. under the trademark TamoGel.[1]
</br>
</br> Afimoxifene has completed a phase II clinical trial for the treatment of cyclical mastalgia.[3]
</br>
</br> A study in France on 55 women showed that rubbing afimoxifene on the skin was as good as tamoxifen tablets at slowing breast cancer growth. A US trial will compare 6 weeks use before breast cancer surgery. Skin application can reduce systemic levels by a factor of nine and this is expected to reduce the unpleasant side-effects of tamoxifen.[4]
</br>
</br> The present invention provides methods for treating and preventing gynecomastia by administering 4-hydroxy tamoxifen to a patient. When percutaneously administered to a patient's breasts, 4-hydroxy tamoxifen concentrates locally, and exerts an anti-estrogenic effect. In patients with gynecomastia, this reduces the effective estrogen-androgen ratio in the breast tissue, thereby reducing ductal proliferation, epithelial and stromal hyperplasia, and pain. In patients at risk for developing gynecomastia, 4-hydroxy tamoxifen's anti-estrogenic effect prevents tissue proliferation and its accompanying pain.
</br>
</br>
</br>
</br> DESCRIPTION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority to U.S. application No. 60/529,415, filed Dec. 15, 2003, and European application No. 03 293 156, filed Dec. 15, 2003, both of which are incorporated herein by reference.
</br>
</br> BACKGROUND OF THE INVENTION The present invention relates to the prevention and treatment of gynecomastia with 4-hydroxy tamoxifen (4-OHT).
</br>
</br> Gynecomastia is a common clinical condition, often presenting secondarily to an underlying disorder, representing the benign and sometimes painful proliferation of breast tissue in young boys and adult males (Mathur and Braunstein, 1997). During the early, or florid phase, of the condition, breast tissue undergoes ductal proliferation accompanied by epithelial and stromal hyperplasia. After prolonged periods of time, the florid phase gives way to a fibrotic phase characterized by increased stromal hyalinization and dilation of the ducts. In many individuals, gynecomastia spontaneously regresses.
</br>
</br> Generally, gynecomastia results from an imbalance, at the breast tissue level, of the hormones estrogen and androgen. Multiple underlying pathophysiological mechanisms may account for this estrogen-androgen imbalance. These pathophysiological mechanisms can be broadly categorized as having physiologic, pathologic or pharmacologic origins. In most affected individuals, gynecomastia results from the combined effects of multiple pathophysiological mechanisms.
</br>
</br> Physiologic gynecomastia may occur in neonatal, pubertal, or senescent individuals. Neonatal onset of the condition is generally transient, and caused by exposure to maternal hormones. Pubertal onset gynecomastia occurs frequently as a result of normal hormonal changes, and usually is self-limiting. In elderly men, gynecomastia occurs based on intrinsic aspects of the aging process, such as progressive primary testicular failure and overall increases in adipose tissue.
</br>
</br> Gynecomastia also may result from various pathologic mechanisms that impart an estrogen-androgen imbalance. The imbalance may result from an increase in serum estrogen through such mechanisms as increased hormone production from the testes, adrenal gland or various neoplasms; increased displacement of estrogen relative to androgen from the blood-borne sex hormone binding globulin (SHBG); decreased estrogen metabolism; or the administration of exogenous estrogen or estrogen-like compounds. The estrogen-androgen imbalance also may result from a decrease in androgens or decrease in the effectiveness of androgens from such mechanisms as congenital or acquired gonadal failure, decreased secretion of androgens from the testes, altered metabolism of androgens, increased binding of androgen relative to estrogen by the SHBG or defects in the androgen receptor. Additionally, gynecomastia may be idiopathic, caused by chronic illness or result from an enhanced sensitivity of the breast tissue to normal concentrations of estrogen.
</br>
</br> The administration of drugs, acting by a wide variety of mechanisms, also may induce gynecomastia. Both prescription and over-the-counter drugs, as well as recreational drugs, may have this effect. For example, drugs like cimetidine, flutamide and spironolactone block the action of androgen receptors and thereby cause an effective estrogen-androgen imbalance at the breast tissue level. The antifungal ketoconazole is known to inhibit testosterone biosynthesis. Cancer chemotherapeutic agents, including alkylating agents, may produce gynecomastia through a direct testicular effect, and cause increasing serum concentrations of gonadotropins. Further, individuals undergoing highly active antiretroviral therapy (HAART) for HIV/AIDS may also develop gynecomastia.
</br>
</br> Environmental and industrial agents, such as pesticides, also can cause gynecomastia.
</br>
</br> Due to the variety of underlying mechanisms, no uniformly acceptable method for preventing or treating gynecomastia exists. The main treatment of transient pubescent and drug-induced gynecomastia is sympathetic reassurance of the affected individual (Lazala and Saenger, 2002). Frequently, drug-induced gynecomastia is treated by discontinued administration of the offending agent (Glass, 1994). However, in cases such as treatment of HIV/AIDS with HAART, limited choice of alternative treatments may prevent the discontinuation of the offending agents. Treatment of underlying disorders, such as hepatic dysfunction, hyperthyroidism, hypogonadism or the like, may also improve or resolve gynecomastia. For individuals with prostate cancer who undergo surgical castration or are medically rendered hypogonadal, low-dose radiation therapy has been prospectively used to prevent gynecomastia (Gagnon et al., 1979). In cases like prostate cancer, where the underlying disorder cannot be successfully treated, medical therapy for the improvement of gynecomastia may also be attempted. Finally, where gynecomastia has been long-term or fails to respond to medical therapy, surgical excision of the excessive tissue may occur (Daniels and Taylor, 2001). Ablation of the breast tissue is well known but has significant drawbacks. Surgical complications include donut deformity of the breasts, nipple necrosis, nipple flattening, inversion, or loss of sensation. Besides the obvious expense and risk involved, surgical scars and asymmetry of the nipple-areolar complex often cause more embarrassment to the affected individual than the original condition. In a majority of cases, cosmetically unsatisfactory results occur that may be correctible with pectoral implants or liposuction.
</br>
</br> Medical therapy is most effective during the florid phase of gynecomastia, because most treatments focus on decreasing the serum estrogen-androgen ratio which causes the ductal proliferation and its accompanying hyperplasia (Lazala and Saenger, 2002). Testosterone therapy yields generally disappointing results because the hormone is aromatized to estrogen, further exacerbating the estrogen-androgen imbalance. Nonaromatizable testosterone derivatives show some benefit. However, these therapies have many undesirable side effects, such as edema, acne and cramps. Estrogen receptor blockade drugs, such as Tamoxifen, have also been used to treat gynecomastia. Although it is not approved for treatment of gynecomastia in the United States, Gruntmanis and Braunstein (2001) suggest the best treatment results can be expected from the estrogen receptor blockage drug Tamoxifen.
</br>
</br> In spite of its benefits, Tamoxifen has significant drawbacks. Its action potentially impacts on every estrogen receptor bearing cell in the body, and as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. Tamoxifen is a known genotoxic agent and has been shown to cause hepatocarcinoma in rats. As such, it has been classified by the International Agency for Research on Cancer as a class I human carcinogen. Adverse effects associated with tamoxifen include nausea and vomiting, bone and tumor pain, hypercalcemia, depression, lightheadedness and headaches, alopecia, rash, liver disturbances, cataracts, deep vein thrombosis, pulmonary embolism, and peripheral blood and platelet disorders such as leucopenia, neutropenia, and thrombocytopenia.
</br>
</br> (****Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the most common type of liver cancer****)
</br>
</br> Therefore, a strong need still exists for gynecomastia treatments and prophylactics that provoke few systemic side effects.
</br>
</br> SUMMARY OF THE INVENTION
</br>
</br> The present invention includes a method of treating gynecomastia by administering 4-hydroxy tamoxifen. This treatment approach, preferably implemented topically, effectively resolves the proliferation of breast tissue.
</br>
</br> The present invention also includes a method of preventing gynecomastia by administering 4-hydroxy tamoxifen. As with the treatment approach, the prophylactic approach is preferably implemented topically.
</br>
</br> For the purposes of prophylaxis and treatment, 4-hydroxy tamoxifen may be administered by any means that delivers it to estrogen receptor-bearing cells in vivo. As noted, it is preferable that the administration be done percutaneously (topically), to avoid the first-pass effect and related liver metabolism of 4-hydroxy tamoxifen. For percutaneous administration, 4-hydroxy tamoxifen may be applied to any skin surface. Application to the breasts during percutaneous administration is advantageous because 4-hydroxy tamoxifen tends to concentrate in local subcutaneous tissues with estrogen receptors.
</br>
</br> A broad range of formulations are suitable for performing the invention, but hydroalcoholic solutions and gels are preferred. The concentration of 4-hydroxy tamoxifen in these formulation may vary, but a dose should result in local 4-hydroxy tamoxifen tissue concentrations that effectively oppose estrogenic driven effects.
</br>
</br> AKA 4-hydroxytamoxifen.
</br>
</br> Afimoxifene[1] (4-hydroxytamoxifen) is a selective estrogen receptor modulator which is the active metabolite of tamoxifen.[2] Afimoxifene is a transdermal gel formulation and is being developed by Ascend Therapeutics, Inc. under the trademark TamoGel.[1]
</br>
</br> Afimoxifene has completed a phase II clinical trial for the treatment of cyclical mastalgia.[3]
</br>
</br> A study in France on 55 women showed that rubbing afimoxifene on the skin was as good as tamoxifen tablets at slowing breast cancer growth. A US trial will compare 6 weeks use before breast cancer surgery. Skin application can reduce systemic levels by a factor of nine and this is expected to reduce the unpleasant side-effects of tamoxifen.[4]
</br>
</br> The present invention provides methods for treating and preventing gynecomastia by administering 4-hydroxy tamoxifen to a patient. When percutaneously administered to a patient's breasts, 4-hydroxy tamoxifen concentrates locally, and exerts an anti-estrogenic effect. In patients with gynecomastia, this reduces the effective estrogen-androgen ratio in the breast tissue, thereby reducing ductal proliferation, epithelial and stromal hyperplasia, and pain. In patients at risk for developing gynecomastia, 4-hydroxy tamoxifen's anti-estrogenic effect prevents tissue proliferation and its accompanying pain.
</br>
</br>
</br>
</br> DESCRIPTION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority to U.S. application No. 60/529,415, filed Dec. 15, 2003, and European application No. 03 293 156, filed Dec. 15, 2003, both of which are incorporated herein by reference.
</br>
</br> BACKGROUND OF THE INVENTION The present invention relates to the prevention and treatment of gynecomastia with 4-hydroxy tamoxifen (4-OHT).
</br>
</br> Gynecomastia is a common clinical condition, often presenting secondarily to an underlying disorder, representing the benign and sometimes painful proliferation of breast tissue in young boys and adult males (Mathur and Braunstein, 1997). During the early, or florid phase, of the condition, breast tissue undergoes ductal proliferation accompanied by epithelial and stromal hyperplasia. After prolonged periods of time, the florid phase gives way to a fibrotic phase characterized by increased stromal hyalinization and dilation of the ducts. In many individuals, gynecomastia spontaneously regresses.
</br>
</br> Generally, gynecomastia results from an imbalance, at the breast tissue level, of the hormones estrogen and androgen. Multiple underlying pathophysiological mechanisms may account for this estrogen-androgen imbalance. These pathophysiological mechanisms can be broadly categorized as having physiologic, pathologic or pharmacologic origins. In most affected individuals, gynecomastia results from the combined effects of multiple pathophysiological mechanisms.
</br>
</br> Physiologic gynecomastia may occur in neonatal, pubertal, or senescent individuals. Neonatal onset of the condition is generally transient, and caused by exposure to maternal hormones. Pubertal onset gynecomastia occurs frequently as a result of normal hormonal changes, and usually is self-limiting. In elderly men, gynecomastia occurs based on intrinsic aspects of the aging process, such as progressive primary testicular failure and overall increases in adipose tissue.
</br>
</br> Gynecomastia also may result from various pathologic mechanisms that impart an estrogen-androgen imbalance. The imbalance may result from an increase in serum estrogen through such mechanisms as increased hormone production from the testes, adrenal gland or various neoplasms; increased displacement of estrogen relative to androgen from the blood-borne sex hormone binding globulin (SHBG); decreased estrogen metabolism; or the administration of exogenous estrogen or estrogen-like compounds. The estrogen-androgen imbalance also may result from a decrease in androgens or decrease in the effectiveness of androgens from such mechanisms as congenital or acquired gonadal failure, decreased secretion of androgens from the testes, altered metabolism of androgens, increased binding of androgen relative to estrogen by the SHBG or defects in the androgen receptor. Additionally, gynecomastia may be idiopathic, caused by chronic illness or result from an enhanced sensitivity of the breast tissue to normal concentrations of estrogen.
</br>
</br> The administration of drugs, acting by a wide variety of mechanisms, also may induce gynecomastia. Both prescription and over-the-counter drugs, as well as recreational drugs, may have this effect. For example, drugs like cimetidine, flutamide and spironolactone block the action of androgen receptors and thereby cause an effective estrogen-androgen imbalance at the breast tissue level. The antifungal ketoconazole is known to inhibit testosterone biosynthesis. Cancer chemotherapeutic agents, including alkylating agents, may produce gynecomastia through a direct testicular effect, and cause increasing serum concentrations of gonadotropins. Further, individuals undergoing highly active antiretroviral therapy (HAART) for HIV/AIDS may also develop gynecomastia.
</br>
</br> Environmental and industrial agents, such as pesticides, also can cause gynecomastia.
</br>
</br> Due to the variety of underlying mechanisms, no uniformly acceptable method for preventing or treating gynecomastia exists. The main treatment of transient pubescent and drug-induced gynecomastia is sympathetic reassurance of the affected individual (Lazala and Saenger, 2002). Frequently, drug-induced gynecomastia is treated by discontinued administration of the offending agent (Glass, 1994). However, in cases such as treatment of HIV/AIDS with HAART, limited choice of alternative treatments may prevent the discontinuation of the offending agents. Treatment of underlying disorders, such as hepatic dysfunction, hyperthyroidism, hypogonadism or the like, may also improve or resolve gynecomastia. For individuals with prostate cancer who undergo surgical castration or are medically rendered hypogonadal, low-dose radiation therapy has been prospectively used to prevent gynecomastia (Gagnon et al., 1979). In cases like prostate cancer, where the underlying disorder cannot be successfully treated, medical therapy for the improvement of gynecomastia may also be attempted. Finally, where gynecomastia has been long-term or fails to respond to medical therapy, surgical excision of the excessive tissue may occur (Daniels and Taylor, 2001). Ablation of the breast tissue is well known but has significant drawbacks. Surgical complications include donut deformity of the breasts, nipple necrosis, nipple flattening, inversion, or loss of sensation. Besides the obvious expense and risk involved, surgical scars and asymmetry of the nipple-areolar complex often cause more embarrassment to the affected individual than the original condition. In a majority of cases, cosmetically unsatisfactory results occur that may be correctible with pectoral implants or liposuction.
</br>
</br> Medical therapy is most effective during the florid phase of gynecomastia, because most treatments focus on decreasing the serum estrogen-androgen ratio which causes the ductal proliferation and its accompanying hyperplasia (Lazala and Saenger, 2002). Testosterone therapy yields generally disappointing results because the hormone is aromatized to estrogen, further exacerbating the estrogen-androgen imbalance. Nonaromatizable testosterone derivatives show some benefit. However, these therapies have many undesirable side effects, such as edema, acne and cramps. Estrogen receptor blockade drugs, such as Tamoxifen, have also been used to treat gynecomastia. Although it is not approved for treatment of gynecomastia in the United States, Gruntmanis and Braunstein (2001) suggest the best treatment results can be expected from the estrogen receptor blockage drug Tamoxifen.
</br>
</br> In spite of its benefits, Tamoxifen has significant drawbacks. Its action potentially impacts on every estrogen receptor bearing cell in the body, and as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. Tamoxifen is a known genotoxic agent and has been shown to cause hepatocarcinoma in rats. As such, it has been classified by the International Agency for Research on Cancer as a class I human carcinogen. Adverse effects associated with tamoxifen include nausea and vomiting, bone and tumor pain, hypercalcemia, depression, lightheadedness and headaches, alopecia, rash, liver disturbances, cataracts, deep vein thrombosis, pulmonary embolism, and peripheral blood and platelet disorders such as leucopenia, neutropenia, and thrombocytopenia.
</br>
</br> (****Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the most common type of liver cancer****)
</br>
</br> Therefore, a strong need still exists for gynecomastia treatments and prophylactics that provoke few systemic side effects.
</br>
</br> SUMMARY OF THE INVENTION
</br>
</br> The present invention includes a method of treating gynecomastia by administering 4-hydroxy tamoxifen. This treatment approach, preferably implemented topically, effectively resolves the proliferation of breast tissue.
</br>
</br> The present invention also includes a method of preventing gynecomastia by administering 4-hydroxy tamoxifen. As with the treatment approach, the prophylactic approach is preferably implemented topically.
</br>
</br> For the purposes of prophylaxis and treatment, 4-hydroxy tamoxifen may be administered by any means that delivers it to estrogen receptor-bearing cells in vivo. As noted, it is preferable that the administration be done percutaneously (topically), to avoid the first-pass effect and related liver metabolism of 4-hydroxy tamoxifen. For percutaneous administration, 4-hydroxy tamoxifen may be applied to any skin surface. Application to the breasts during percutaneous administration is advantageous because 4-hydroxy tamoxifen tends to concentrate in local subcutaneous tissues with estrogen receptors.
</br>
</br> A broad range of formulations are suitable for performing the invention, but hydroalcoholic solutions and gels are preferred. The concentration of 4-hydroxy tamoxifen in these formulation may vary, but a dose should result in local 4-hydroxy tamoxifen tissue concentrations that effectively oppose estrogenic driven effects.
