Patent Application
20080261929
The present invention relates to the combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one or a pharmaceutically acceptable derivative or analogue thereof, together with at least one aromatase inhibitor and to the use of said combination for the prophylaxis and treatment of BRCA1- or BRCA2-mediated diseases.
The progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one, also known as ZK230211 or ZK-PRA,
has high antiprogestagenic activity with little or no other endocrinological effects (Fuhrmann, U. et al., J. Med. Chem. 2000, 43, 5010-5016).
BRCA1 and BRCA2 are so-called tumor suppressors, genes that in their normal form protect against cancer. One way they do this is by helping cells repair DNA damage that might otherwise result in cancer-causing mutations. In Poole et al., Science, Vol. 314, December 2006 it is described that the tumor suppressor gene BRCA-1- or BRCA2 participates in the degradation of the progesterone receptor, the gene's protein product apparently controls the progesterone growth-promoting action on breast tissue.
It is shown that mifepristone, an unspecific antiprogestin, blocks the development of mammary tumors in mice that have had the rodent version of BRCA1- or BRCA2 inactivated in their mammary glands. It is further postulated that mifepristone mediated inhibition of mammary tumorgenesis in their Brca1/p53-deficient model provides a molecular framework for future clinical evaluation of antiprogesterones as a potential chemopreventive strategy in women who carry BCRA1- or BRCA2 mutations. However, nothing is described with respect to the activity and reaction of 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one in combination with an aromatase inhibitor.
Aromatase inhibitors, as described herein are those, which are steroidal or none-steroidal.
Rosen et al. describe that normal BRCA1- or BRCA2 inhibits the action of the progesterone receptor, however nothing is mentioned about the mechanism.
Endocrine therapy represents a mainstay of effective, minimally toxic, palliative treatment for metastatic breast cancer. As a standard palliative treatment of non-operable mammary carcinomas as well as for adjuvant therapy after primary treatment of mammary carcinomas, antiestrogens, such as the non-steroidal antiestrogen tamoxifen, are used. However, tamoxifen cannot cure breast cancer. Thus, for secondary therapy progestins or aromatase inhibitors are commonly used. In premenopausal women ovariectomy, tamoxifen and LHRH (luteinizing hormone releasing hormones) analogs achieve comparable results (H. T. Mouridson et al., Eur. J. Cancer Clin. Oncol., 24, pp. 99-105, 1988). Although tamoxifen is widely used for adjuvant therapy of breast cancer, its use as a chemopreventive agent is problematic, because it has been shown that the treatment results in an increase in the incidence of endometrial cancers (I. N. White, Carcinogenesis, 20(7):1153-60, 1999; L. Bergman et al., The Lancet, Vol. 356, Sep. 9, 2000).
Selective Progesterone-receptor antagonists (also termed as antiprogestins) represent a relatively new and promising class of therapeutic agents that could have significant impact on cancer treatment. Certain progesterone-receptor antagonists have recently gained importance in the endocrine therapy of those cancers possessing receptors for progesterone (Nathalie Chabbert-Buffet et al, Human Reproduction Update, Vol. 11, No. 3, 293-307, 2005).
This new strategy in endocrine therapy is based on the antitumor activity of progesterone-receptor antagonists in progesterone receptor-positive human breast cancer cell lines in vitro and in several hormone-dependent mammary tumors of the mouse and rat in vivo. In particular, the antitumor mechanism of the progesterone-receptor antagonists onapristone and mifepristone (RU 486) was investigated using the hormone-dependent MXT mammary tumor model of the mouse as well as the DMBA- and the MNU-induced mammary tumor models of the rat (M. R. Schneider et al., Eur. J. Cancer Clin. Oncol., Vol. 25, No. 4, pp. 691-701, 1989; H. Michna et al., Breast Cancer Research and Treatment 14:275-288, 1989; H. Michna, J. Steroid. Biochem. Vol. 34, Nos 1-6, pp. 447-453, 1989). However, due to low activity and adverse side effects involved with e.g. mifepristone these compounds could not be recommended as a single agent in the management of breast cancer (D. Perrault et al., J. Clin. Oncol. 1996 October, 14(10), pp. 2709-2712).
RU 486 is causing severe side effects because of its strong anti-glucocorticoidially activity. This prohibits long term use.
When using RU 486, a further problem is for instance the poor bioavailability when administered orally. Thus, the compound generally had to be administered in high doses, giving rise to possible unfavorable side effects. Moreover, oral administration is desirable with respect to patient convenience and compliance.
Furthermore, there is still a need for combinations that are active not only in the treatment, but also in the prophylaxis of breast cancer and other hormone-dependent diseases.
It has been found that the growth of hormone-dependent tumors depend, among others, e.g. on estrogens, progesterones and even testosterones. For example, most mammary carcinomas exhibit estrogen as well as progesterone receptors. Thus, a combination of progesterone-receptor antagonists together with aromatase inhibitors may be effective in the therapy of pre- and postmenopausal mammary carcinomas.
One further advantage is the inhibition of proliferative effects of tamoxifen on the uterus by the combination with the progesterone antagonist. The combination of an aromatase inhibitor anastrozole with tamoxifen has been profen to be less effective than the monotherapy with one of these compound (Ref. ATAC Trial results 2005). Our findings provide evidence that combination of aromatase inhibitors may have in contrast positive additive effects on tumor growth inhibition and survival.
It is thus the object of the present invention to provide a highly efficient tool for prophylaxis and treatment of especially breast cancer development and other diseases dependent upon progesterone in BRCA1- or BRCA2 mutations bearing women, such as ovarian cancer, endometrial cancer, colorectal cancer, gastric cancer, endometriosis, myeloma, myoma and meningioma.
It has now surprisingly been found that 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one in combination together with at least one aromatase inhibitor can be used for the prophylaxis and treatment of BRCA1- or BRCA2-mediated breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, gastric cancer, endometriosis, myeloma, myoma and meningioma.
It has now further most surprisingly been found that the combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one together with an aromatase inhibitor shows a synergistic effect when compared to the inhibition of the progesterone-receptor antagonist, or the aromatase inhibitor alone.
Aromatase inhibitors which can be combined together with the compound 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one are for example aminoglutethimide, fadrozole, anastrozole, letrozole, vorozole, formestane, exemestane and atamestane.
It has further been found that 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one, or the combination with an aromatase inhibitor were accompanied by increased apoptosis of tumor cells, a particularly advantageous mechanism of action for the prevention or treatment of mammary carcinoma and other hormone-dependent diseases, where an indicator of high risk is an increased amount of tumor cells in the S-phase of the cell cycle. Such other hormone-dependent diseases may include ovarian cancer, endometrial cancer, myeloma, lung cancer, meningioma, i.e., diseases which substantially originate or are influenced by the presence of hormone receptors and/or hormone-dependent pathways.
The invention furthermore relates to the use of the combination for the preparation of a medicament for prophylaxis and treatment of cancer in BRCA1 and BRCA2 mutation bearing women, as well as for the treatment of other hormone-dependent conditions. In particular the combination of 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one together with an aromatase inhibitor has been shown to effectively inhibit the growth of such tumors as compared to the progesterone-receptor antagonist, or aromatase inhibitor alone.
In another aspect, the present invention provides a method for prophylaxis and treatment of breast cancer and other hormone-dependent diseases in a mammal, in particular a human, in need of such treatment because of mutations in the BRCA1 or BRCA2 gene, said method comprising administering a pharmaceutically effective amount of a composition comprising the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one or a pharmaceutically acceptable derivative or analogue thereof, and at least one aromatase inhibitor to a mammal in need thereof.
11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one or a pharmaceutically acceptable derivative or analogue thereof can be used according to the present invention in combination with at least one aromatase inhibitor.
Although progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one is the preferred progesterone-receptor antagonist for purposes of the present invention, this does not exclude the possibility to use other suitable progesterone-receptor antagonists as well.
With regard to the superiority of the inventive combination over the prior art, it is especially favorable that the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one shows only very weak or no endocrine side effects, such as e.g. androgen, estrogen or antiglucocorticoid activity.
Due to the high bioavailability of the combination according to the present invention comprising the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and the aromatase inhibitor, including their pharmaceutically acceptable derivatives or analogues thereof, it is possible that the combination can be administered orally.
The oral administration has the advantage of improved convenience and patient compliance. As a further favorable consequence, the combination of the present invention is well tolerated. Partial agonism is commonly associated with undesirable side effects, such as for example in the case of the partial antiestrogen tamoxifen an increase in the incidence of endometrial cancers (see I. N. White, Carcinogenesis, 20(7):1153-60, 1999; L. Bergman et al., The Lancet, Vol. 356, Sep. 9, 2000, 881-887) as well as the antiglucocorticoid effects and certain toxic side effects related to the administration of the prior art progesterone-receptor antagonist mifepristone (see D. Perrault et al., J. Clin. Oncol. 1996 October, 14(10), pp. 2709-2712; L. M. Kettel et al., Fertil. Steril. 1991 September, 56(3), pp. 402-407; X. Bertagna, Psychoneuroendocrinology 1997, 22 Suppl. 1; pp. 51-55).
Optionally, the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and the aromatase inhibitor can additionally be combined with further pharmacologically active agents, such as cytotoxic agents.
The manufacture of the medicaments/pharmaceutical compositions may be performed according to methods known in the art. Commonly known and used adjuvants, as well as further suitable carriers or diluents may be used.
Suitable carriers and adjuvants may be such as recommended for pharmacy, cosmetics and related fields in: Ullmann's Encyclopedia of Technical Chemistry, Vol. 4, (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918ff; H.v.Czetsch-Lindenwald, “Hilfsstoffe für Pharmazie und angrenzende Gebiete”; Pharm. Ind. 2, 1961, p. 72ff; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Cantor K G, Aulendorf in Württemberg, 1971.
The inventive combination also comprises pharmaceutical compositions, which can be prepared by known methods of preparing galenics for oral, parenteral, e.g. intraperitoneal, intramuscular, subcutaneous or percutaneous application. The inventive combination can also be implanted into tissue.
The inventive combination can also be administered in the form of tablets, pills, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams, gels, patches for transdermal administration, formulations suitable for administration by inhalation, for instance nasal sprays or by intravaginal (e.g. vaginal rings) or intrauterine systems (diaphragms, loops).
For the preparation of the pharmaceutical compositions for oral administration, the active agents suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and carriers such as for example, gum arabic, talcum, starch, sugars like e.g. mannitose, methyl cellulose, lactose, gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous excipients, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, conserving agents and flavoring agents (e.g., ethereal oils). In the pharmaceutical composition, the progesterone-receptor antagonist and the aromatase inhibitor may be dispersed in a microparticle, e.g. a nanoparticulate, composition.
In order to further enhance the bioavailability of the active agents, the active agents suitable for the purposes of the present invention as defined above can also be formulated as cyclodextrin clathrates by reacting them with α-, β- or γ-cyclodextrines or derivatives thereof according to the method as disclosed in PCT/EP95/02656.
For parenteral administration the active agents suitable for the purposes of the present invention as defined above can be dissolved or suspended in a physiologically acceptable diluent, such as e.g., oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
The pharmaceutical compositions according to the present invention can also be administered via a depot injection or an implant preparation, optionally for sustained delivery of the active agent(s).
Implants can comprise as inert materials e.g. biologically degradable polymers or synthetic silicones such as e.g. silicone rubber.
For percutaneous applications, the active agent(s) may also be formulated into adhesives.
The preferred mode of administration is oral administration. The combination according to the present invention are particularly suitable for oral administration.
The inventive combination can be administered by applying the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one together with the aromatase inhibitors, or applying the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one separately from the aromatase inhibitors, for example the progesterone-receptor 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one can be administered subcutaneously or i.m. and the aromatase inhibitors, can be administered orally or vice versa.
The amounts (a “pharmaceutically effective amount”) of the combined active agents to be administered vary within a broad range and depend on the condition to be treated and the mode of administration. They can cover any amount efficient for the intended treatment. Determining a “pharmaceutically effective amount” of the combined active agent is within the purview of a person skilled in the art.
The weight ratio of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one to the aromatase inhibitor(s), as defined above, can vary within a broad range. They can either be present in equal amounts or one component can be present in excess of the other components. Preferably, 0.1 to 200 mg of the aromatase inhibitor and 0.1 to 100 mg of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one are administered in a unit dose, more preferably in a unit dose of 10 to 150 mg of each of the aromatase inhibitor and progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one. In special cases up to 200 mg of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one may be administered. The aromatase inhibitor and progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one are preferably present in ratios from 100:1 to 1:100. More preferably, they are present in ratios from 4:1 to 1:4.
The progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and the aromatase inhibitor(s) can be administered either together or separately, at the same time and/or sequentially. Preferably they are administered combined in one unit dose. In case they are administered sequentially, preferably the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one is administered before the aromatase inhibitor(s), as defined above.
The combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and an aromatase inhibitor, or pharmaceutically acceptable derivatives or analogues of these components exerts very strong tumor-inhibiting effects in a panel of hormone-dependent breast cancer models (cf. Example 1). The inhibition is synergistic when compared to the inhibition achieved by these compounds alone.
Medicaments, such as the combination in the various aspects of the invention, that induce apoptosis in cells, for example, in the case of tumor cells, by blocking progression in the G0G1-phase, have potential applications for treating and preventing numerous conditions.
Without limitation to any theory, the results provided in the example indicate that the main mechanism of the antitumor action of a combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and the aromatase inhibitors, according to the present invention in the tested model is a direct estrogen-receptor and/or progesterone-receptor-mediated antiproliferative effect at the level of the tumor cells, via the induction of terminal differentiation associated with terminal cell death. In this manner, the combination according to the invention appears to be capable of eliminating the intrinsic block in terminal differentiation inherent in malignant tumor cells in progesterone receptor-positive and estrogen-receptor positive tumors.
Using cell cultures it was revealed that the progesterone receptor is degraded less when BRCA1- or BRCA2 activity is knocked down. As a result, the transcriptional activity of progesterone receptor by progesterone is longer and also stronger.
We showed that we could reduce the accelerated PR signaling in BRCA1- or BRCA2 knocked down cells by prophylactic treatment with the instand compounds and combinations. This results in an reduced proliferation of these breast cells.
The loss in control of PR transcription may be one explanation why tumors occur specifically in the breast, ovaries and endometrium meningio organs that specifically dependent on PR, even though the BRCA1- or BRCA2 gene is mutated in cells throughout the body.
Mammary tissue of female mice bearing a similar to human BRCA1- or BRCA2 mutation (and in which p53 gene has been knocked out, showed increased cell proliferation and progesterone receptors expression and develop mammary cancers. Mice treated with the instant compounds, respectively combinations, however, were tumor free.
The effects of the instant compounds, respectively combinations may not only be restricted to tumor tissue but rather to tissue adjacent to <human> breast tumors with BRCA1- or BRCA2 mutations which also shows elevated progesterone expression compared to tissue from normal breast.
The invention is further illustrated in the Examples. The following Examples are, however, not to be understood as a limitation.
MCF-7 and T47D mammary cells were stabely transfected with the aromatse gene. These cells grow with androstenedione stimulus. These cells were treated with siRNA knocking down the BRCA1 and BRCA2 gene.
Cell growth in comparison to untransfected and mock transfected cells was compared.
In a second step cells were stimulated either with progesterone and/or with androstenedione. An increased proliferation was seen in the BRCA1 and BRCA1 ko cells in the presence of progesterone. The co-treatment with 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one alone or in combination with an aromatase inhibitor was able to antagonize the effects of BRCA1 knock down. The effects on progesterone receptor protein expression were further investigated. By using siRNA for knock down of BRCA1 an increased stability of progesterone receptor which could be antagonized by the progesterone receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one was found.
Thus, the results show that the combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one in combination with an aromatase inhibitor results in a potent inhibition of the growth of BRCA1 knock down cells.
Combination of the progesterone receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one together with the aromatase inhibitor Letrozole
MXT mammary tumors obtained from donor mice are implanted in fragments of about 2 mm diameter in the inguinal region of female BDF1 mice (Charles River). Treatment is started when tumors are 25 mm2 in size with
The results are shown in FIG. 1/1.
The tumor area is determined by caliper measurements. The tumor weight is determined at the end of the experiment.
Compared to the rapid growth of the control, the combination of progesterone-receptor antagonist 11β-(4-acetylphenyl)-17βhydroxy-17α(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one and letrozole according to the present invention exerts an antitumor effect significantly superior to that of the letrozole alone.
The combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17βhydroxy-17α(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one with the letrozole according to the present invention proves to be potent in inhibition of the growth of MXT mouse mammary tumors.
MCF-7 and T47D mammary cells stabely transfected with the aromatse gene. These cells grow with androstenedione stimulus in vivo. These cells were stabely transfected with shRNA knocking down the BRCA1 and BRCA2 gene. Cell growth in vivo in comparison to untransfected and mock transfected cells was compared. In a second step cells were implanted in immunodeficient nude mice and stimulated either with progesterone and/or with androstenedione. An increased proliferation was seen in the BRCA1 ko cells in the presence of progesterone. The co-treatment with 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one alone or in combination with an aromatase inhibitor was able to antagonize the effects of BRCA1 knock down. The effects on progesterone receptor protein expression were further investigated. By using siRNA for knock down of BRCA1 an increased stability of progesterone receptor which could be antagonized by the progesterone receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one was found.
Thus, the results show that the combination of the progesterone-receptor antagonist 11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)-estra-4,9-dien-3-one in combination with an aromatase inhibitor, according to the present invention, results in a potent inhibition of the growth of BRCA1 knock down cells.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 07090081.6, filed Apr. 23, 2007, and U.S. Provisional Application Ser. No. 60/914,373, filed Apr. 27, 2007, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 07090081.6 | Apr 2007 | EP | regional |
This application claims the benefit of the filing date of European Application Serial No. 07090081.6 filed Apr. 23, 2007 and U.S. Provisional Application Ser. No. 60/914,373 filed Apr. 27, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 60914373 | Apr 2007 | US |
