United States Patent (19) 11 Patent Number: 5,026,692 Kuno et al. (45) Date of Patent: Jun. 25, 1991 (54) USE OF SEX HORMONE 56) References Cited U.S. PATENT DOCUMENTS 75 Inventors: Sachiko Kuno, Ibaraki; Ryuji Ueno; Osamu Hayaishi, both of Kyoto, all 4,701,450 10/1987 Kelder ................................. 514/177 of Japan FOREIGN PATENT DOCUMENTS 73 Assignees: Research Development Corporation of 159739 10/1985 European Pat. Off. Japan; Ueno Seiyaku 2204237 11/1988 United Kingdom. Kabushikikaisha, both of Osaka, OTHER PUBLICATIONS Japan Grossman, C.J., Science 227, No. 4684, 257-261 (1985). Kuhl, H., et al, Contraception 28, No. 6, 587-601 (1983). (21) Appl. No.: 361,687 Markham, Phillip, D., et al, Int. J. Cancer, 37, No. 1, 67-72 (1986). 22 Filed: Jun. 5, 1989 Hirota, Y., et al, Immunology, 29, No. 1, 37-46 (1980). Verheul, H. A. M., et al., Clin. Exp. Immunol., 44, 11-17 (1981). Related U.S. Application Data Samuelson, B., J. Biol. Chem. 238 (10), 3229-3234 63 Continuation of Ser. No. 923,791, Oct. 27, 1986, aban (1963). doned. Primary Examiner-Shep K. Rose 30 Foreign Application Priority Data 57) ABSTRACT Nov. 13, 1985 JP Japan ................................ 60-255791 Method of treatment of immunodeficiency disease which comprises administering therapeutically effec 51 Int. Cl. ...................... A61K 9/02; A61K 31/565 tive amount of sex hormone to a subject in need of such 52 U.S. Cl. .................................... 514/178; 514/182; treatment. 514/966 58) Field of Search ........................ 514/178, 182,966 1 Claim, 2 Drawing Sheets U.S. Patent June 25, 1991 Sheet 1 of 2 5,026,692 Afg. / 2 O V O (9 U O OL E o M Control PGE2 PGD2 PGE2 / PGD2 numberonimos of to lo 5 5 4 5 O 6 U.S. Patent June 25, 1991 Sheet 2 of 2 5,026,692 O S E 5 x V O oC Cl W Ee W E W 5 W. O 9> W 9 92O % oC O W/ Control none TES EST -- PGE 2 5,026,692 1. 2 which comprises administering an effective amount of USE OF SEX HORMONE sex hormone to a subject in need of such treatment. In another aspect, the present invention provides a This application is a continuation of application Ser. use of sex hormone for the manufacture of a medica No. 06/923,791, filed Oct. 27, 1986 now abandoned. 5 ment for treatment of immunodeficiency disease. In a further aspect the present invention provides a pharma BACKGROUND OF THE INVENTION ceutical composition comprising a sex hormone as an The present invention relates to a use of sex hormones active ingredient in association with a pharmaceutically for prevention and therapy of immunodeficiency dis acceptable carrier, dilument or excipient. eaS, O Immunodeficiency disease refers to a deficiency in DETAILED DESCRIPTION AND PREFERRED immunological response, either in that mediated by EMBODIMENT humoral antibodies or in that mediated by immune lym The term treatment herein is intended to cover pre phoid cells. Including AIDS (acquired immunological vention and therapy. deficiency syndrome) as a typical example, im 15 The immunodeficiency disease to be treated includes munodeficiency disease is attracting many people's in the lowering of cellular immunological competence, terest due to its unfavorable prognosis. AIDS is known especially the lowering of immunological competence to occur frequently in homosexuals, being characterized by T-cell, e.g., helper T-cell, of which typical ones are by the clinical conditions such as pneumonia, sarcoma, the lowering of immunological competence induced by etc., and to incur a high rate of death of more than 70% 20 because of the destruction of the immune response. It is prostaglandins and the lowering of immunological com also known that the helper T cells are specifically put petence seen in homosexual males. into disorder. The sex hormones usable in the present invention As a result of the search into the causes for the fre include androgen, estrogen, and gestagen, e.g., testos quent occurrences of AIDS among the homosexuals, 25 terone, testosterone propionate, methyl testosterone, the present inventors have found out the following facts estradiol, ethynyl estradiol, norethisterone, androster as the causes: one, progesterone, mestanolone, metenolone enanthate, (1) As shown in the following Table 1, human semen androstanolone, metandienone, nandrolone phenpro contains large amount of prostaglandin E2, pionate, oxandrolone, bolandiol dipropionate, estrradiol (2) In vivo animal experiments reveals that prosta benzoate, estradiol cypionate,fluorxymesterone, stano glandin E2 causes lowering of cellular immunological 30 Zoloi, thiomesterone, negestrol acetate, norethynodrel, competence of male lymphocyte, but prostaglandin E2 allylestrenol, lynestrenol, dimethisterone, estriol, cy does not cause lowering of cellular immunological com proterone acetate, diethylstilbestrol (all being generic petence of female lymphocyte, names), etc. (3) The cause for the aptitude for the homosexual 35 As described above, the sex hormones have an action male to be affected by the pathogens such as AIDS to improve the lowered immunological competence. virus is that prostaglandin E2 which is contained in a This action is seen in both the male hormone and the large amount in semen is injected into rectum by homo female hormone, but is stronger in the female hormone. sexual act and absorbed into body to cause lowering of Based on such action, the sex hormones can be used for cellular immunological competence. 40 recovery of the immunological competence in the pa They have further found out: tient who has shown lowering of immunological com (4) that prostaglandin D2, A2 and J2 have the actions petence and for prevention of lowering of the immuno to lower cellular immunological competence on both logical competence in the patient who is for example male and female, and under treatment with prostaglandin. Especially the sex (5) that lowering of the immunological competence 45 hormones can be used for recovery of the immune-dys caused by prostaglandins in both male and female can function of homosexual males. Further, it can be used be recovered by administration of male or female ste for treatment of the disease such as ARC on AIDS roid hormone. caused by lowering of immunological competence or The present invention has been made on the basis of accompanied with lowering of immunological compe the above findings. 50 tence. TABLE 1. The amount of the sex hormones to be administered Concentration of prostaglandin in human semen for the above purpose is approximately the same as that 1st time (ug/ml) 2nd time (ig/ml) used generally in the sex hormone therapy. For exam PGE2 66, 78.1 ple, the dosage to the human being may be made at the PGF2, 7.8 9. 55 rate of 0.01-20 mg (preferably 0.05-5 mg) (in case of PGD 0.7 0.19 estrogen) or 0.5-50 mg (preferably 1-10 mg) (in case of (NOTE): determined by radioimmunoassay. Samples were collected from two men. gestagen) or 100 mg (preferably 10-50 mg) (in case of androgen) a day in 1-4 times, or as a preparation having sustained effect. The administration method is optional RELATED DISCLOSURES 60 such as peroral, intrarectum, injection, etc. but prefera A comprehensive review on sex hormones can be bly peroral administration or intramuscular injection. found in Kirk-Othmer Encyclopedia of Chemical Tech Administration may be made in the form of ordinary nology, 3rd Edition, Volume 12, Pages 618-657 (John pharmaceutical preparation containing sex hormone as Wiley and Sons, New York, U.S.A., 1980). an active ingredient mixed with pharmaceutical carriers 65 such as organic or inorganic solid or liquid vehicles SUMMARY OF THE INVENTION suitable for the administration method such as peroral, In one aspect, the present invention provides a intrarectum, injection, etc. Such preparation includes method of treatment of immunodeficiency disease solid state tablets, granules, dusts, capsules, and liquid 5,026,692 3 4. state solutions, suspensions, emulsifiers, etc. As the car riers, there may be used starch, lactose, glucose, Su EXAMPLE 7 (CELLULAR IMMUNITY OF crose, dextrin, cellulose, paraffin, fatty acid glyceride, LYMPHOCYTE) water, alcohols, etc. Adjuvant, stabilizer, humidifier, Prostaglandin (PG)E2 and/or D2 (0.5 mg/kg) were 5 intrarectally administered to rats (Wistar strain, SPF, 8 emulsifier, lubricant, binder, and other conventional weeks old, male and female) at the rate of once a day for additives may be added if necessary. 7 days. Three hours after the final administration, blood The present invention is illustrated in more detail by was collected to separate the lymphocytes. The blasto way of the example and its effect clarified by way of the genesis of T lymphocytes against PHA (phytohemag test examples. 10 glutinin) was investigated by measuring labeled thymi dine incorporation. The results are shown in FIG. 1. EXAMPLE 1. It can be observed from FIG. 1 that by the anal ad ministration of prostaglandin E2 the immunological Estradio 10 mg competence in male rats only is lowered, that by the Vegetable oil q.s. to 10 ml 15 anal administration of prostaglandin D2 the immunolog ical competences in both male and female rats are low ered. Human semen contains a large amount of prosta EXAMPLE 2 glandin E derivatives (Table I). Therefore, the lowering of immunological competence in homosexual males 20 may be due to the absorption of seminal prostaglandins Estradio 100 mg through sexual activities. To make aqueous suspension (10 ml) by an ordinary EXAMPLE 8 (EFFECT OF SEX HORMONE) procedure. Male rats (Wister strain, 3 weeks old, male, n = 3) 25 were intrarectally administered with prostaglandin E2 EXAMPLE 3 at the rate of 0.5 mg/kg once a day for 7 days. Prior to this, they were dermatologically injected for seven days with testosterone (TES) or estradiol (EST) suspended Testosterone propionate 250 mg in olive oil at the rate of 1 mg/day.