METHODS OF TERMINATING PREGNANCY

Abstract: A method of terminating pregnancy in mammals is described by a novel application of the common fertility-promoting hormone known as human menopausal gonadotropin. A single injection of this gonadotropic hormone as early as the first day of conception can terminate pregnancy.

Description: METHODS OF TERMINATING PREGNANCY This application is a continuation-in-part of application Serial No. 07/819,830 filed January 13, 1992, now abandoned. FIELD OF THE INVENTION This invention relates to a novel use of the common fertility-promoting hormon hMG (human menopausal gonadotropin) as an agent to terminate the fertile state pregnancy in female mammals. This invention also relates to the use of hMG for terminating pregnancies in humans. BACKGROUND OF THE INVENTION It is common scientific knowledge that fertility in mammals is the stage of life during which the ovaries and testes produce eggs and sperm, respectively. In the female gender this process involved the periodic development of ovarian follicles which contain the eggs. In the human species, for example, a pair of ovaries possesses an estimated 300,000 egg-bearing primordial follicles at the time of puberty. When an individual reaches sexual maturity, some of these follicles periodically develop and release their eggs (a phenomenon called ovulation). In all mammalian species that have been studied, the processes of follicular development and ovulation are regulated by two important hormones that are rhythmically secreted from the pituitary gland at the base of the brain. The activejhormones are follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These two gonadotropic hormones are secreted by pituitary cells when the pituitary gland itse is stimulated by gonadotropin-releasing hormone (GnRH), a small peptide hormon that is produced by nerve cells in a portion of the forebrain known as the hypothalamus. Thus, mammalian fertility is controlled by both nervous and hormonal activities (Espey, L.L., and LA. BenHalim, Obstet. Gynecol. Clin. N. Amer. 17:275, 1990) FSH and LH are large glycoprotein molecules that belong to a group of hormones collectively referred to as "gonadotropins" because they stimulate the gonads. When one or more ovarian follicles reaches maturity by the actions of thes hormones, there is a surge in GnRH secretion from the hypothalamus, and this surge promotes a sharp increase in FSH and LH release from the pituitary glan This sudden increase in gonadotropins stimulates the mature ovarian follicles to enter what is called the "ovulatory process". The ovulatory process requires approximately 10 to 40 hours, depending on the species of mammal. At the end of this metabolic process, the mature ovarian follicles rupture and release fertile eggs into the oviduct (Espey, L.L., and LA. BenHalim, Obstet. Gynecol. Clin. N. Amer 17:275,_1990) K an egg is fertilized and the developing embryo becomes implanted in the uterus, special embryonic cells called trophoblasts begin secreting a hormone called chorionic gonadotropin (CG). (In humans this hormone is called human chorionic gonadotropin and is abbreviated as hCG.) CG circulates from the uterus back to th ovaries and stimulates any ruptured follicles (which are now called corpora lutea) to produce large amounts of the steroid hormone progesterone (Espey, L.L., and LA. BenHalim, Obstet. Gynecol. Clin. N. Amer. 17:275, 1990). Progesterone has two principal functions; (1) it maintains the uterine lining in the nutritive state that is required to support a developing embryo, and (2) it circulates back to the hypothalamus and the pituitary gland and inhibits further secretion of GnRH, FSH, and LH. This inhibitory action of progesterone prevents a second ovulatory process from occurring in a gravid animal. That is to say, a second pregnancy cannot occur "on top of an existing pregnancy. Thus, progesterone functions as a natural contraceptive during pregnancy. This steroid hormone is the basis of the oral contraceptive pills that are commonly used today. Syntheti progestins (along with some estrogens) are used in "the pill" to block ovulation b inhibiting the normal preovulatory surge in GnRH, FSH, and LH (Espey, L.L., a LA. BenHalim, Obstet. Gynecol. Clin. N. Amer. 17:275, 1990). At the time of menopause, the ovaries lose their capacity to produce signific amounts of progesterone and other sex steroids like estradiol. The reduction in t ovarian steroid hormones causes an abatement in the negative feedback action t they normally have on the hypothalamus and the pituitary gland. The result of decline in inhibitory action is a significant increase in the secretion of FSH and from the pituitary glands of menopausal women. These two "menopausal gonadotropins" (i.e., FSH and LH) are filtered by the kidneys from the blood into urine. Thus, human menopausal gonadotropin (hMG) is a urinary extract that contains substantial amounts of both FSH and LH, two gonadotropic hormones similar origins and similar molecular configurations. Since menopausal urine contains a high concentration of hMG, extracts of human urine are the most com source of commercial preparations of hMG that are used to induce ovulation and fertility in women (Harlin, J., S.A. Khan, and E. Diczfalusy, Fertil. Steril. 46:1 1986; Cook, A.S., B.W. Webster, P.F. Terranova, and B.A. Keel, Fertil. Steril. 49:704, 1988; Corsan, G.H., and E. Kemmann, Fertil. Steril. 55:468, 1991). SUMMARY OF THE INVENTION This invention relates to a method of terminating pregnancy in mammals by administration of hMG, or equivalent hormone preparations. The novelty of this invention is that hMG has been used heretofore to induce ovulation and fertility non-pregnant women. This invention reveals that a single injection of hMG can als induce follicular maturation and ovulation in pregnant laboratory animals. Such treatment has an abortifacient effect and terminates the gravid state of the animals DESCRIPTION OF THE INVENTION Human menopausal gonadotropin (hMG) (also called menotropin) is commonly used to treat infertility in women (Corsan, G.H., and E. Kemmann, Fertil. Steril. 55:468, 1991; Gougeon, A., and J. Testart, Fertil. Steril. 54:848, 1990). This extra from menopausal urine has both follicle-stimulating hormone (FSH) andluteinizing hormone (LH) activities. Therefore, hMG can induce ovarian follicular maturation and cause ovulation. While this fertihty-promoting action of hMG is well known, there is negligible information about the effect of this hormone on pregnant individuals. This invention teaches that hMG can also induce follicular maturation and ovulation in pregnant animals. The supporting experiments show that a single dose of hMG can stimulate ovarian folhcular development and ovulation when it is injected subcutaneously into pregnant laboratory rats. The experiments also assess the effect of these hMG-induced events on the gravid state of the experimental animals. The results show that hMG will terminate an existing pregnancy when th hormone is administered during the first one-third of the gestation period. The hMG utilized in the experimental section of this patent was purchased from Sigma Chemical Company (St. Louis, MO). As stated above, hMG is a urinary extract from menopausal women that contains both FSH and LH activities. Other commercial sources for these hormones also exist, as well as methods for their purification from natural sources by chemical and recombinant technology. The hormone amounts may be, in general, expressed in international units (E.U.), or by weight. These units are described in The United States Pharmacopeia, as revised and published by the Board of Trustees of the United States Pharmacopeial Convention, Inc., on January 1, 1990. Typically, a single milligram of hMG suppli by Sigma Chemical Company contains approximately 50 I.U. of FSH activity and I.U. of LH activity. Wistar laboratory rats for the experiments were selected from a breeding colo on the basis of their age and weight. When the young females reached approximately 55 days of age, vaginal smears were performed each morning to confirm sexual maturity of the animals and to monitor their sexual cycles. Mature rats weighing 180-220 grams were caged with adult males for 24 hours beginning noon on the day of proestrus. At the end of this 24-hour period, a final vaginal smear was performed to confirm that the animals were in estrus and that sperm were present in their vaginal tracts. This simple routine is a reliable method of establishing the first day of pregnancy. EXAMPLE 1 In the first experiment, three groups of pregnant rats were used to assess whether hMG could induce follicular development and ovulation during pregnancy (TABLE 1): hMGDav-6 0.5 mg/rat + CGDav-8 50 IU/rat 22 19 13 13 9 15.0 + 2.8 The control group was not treated with any hormones. The two experimental groups were injected subcutaneously with 0.5 mg hMG (Sigma Chemical Compan product G-8760) in 0.5 ml distilled water on Day-6 of pregnancy. The latter experimental group was treated subsequently 2 days later with human chorionic gonadotropin (hCG), a common substitute for LH to induce ovulation. The hCG (Sigma Chemical Company product CG-5) was injected subcutaneously in a single dose of 50 I.U. in 0.5 ml distilled water. Twenty-four hours later (i.e., on Day-9 of pregnancy) the oviducts were removed from all of the animals in the three groups, and the number of ova in the oviducts were counted in order to tabulate the ovulation rates. The results in TABLE 1 show that there were no ovulations in th control animals, a mean ovulation rate of 1.6 ± 1.2 ova/rat in the hMG-treated animals, and a mean ovulation rate of 15.0 ±2.8 ova rat in the hMG/hCG-treated animals. Statistical analysis of the data by the t-test for the difference between tw independent means confirms that the mean values of both experimental groups we significantly different (p < 0.05) from the control group. Thus, the data show that follicles which develop in pregnant animals in response to hMG treatment have ability to ovulate. Also, the data show that exogenous hCG significantly enhanc the ovulation rate of such follicles. The pregnant state of all the animals was confirmed by counting the number of fetuses in the uteri at the time the oviducts were removed to tabulate ovulation rates. There were 11.4 ± 1.6 fetuses in the control group, 10.8 ± 1.1 fetuses in the hMG-treated group, and 11.2 ± 0.7 fetuse the hMG/hCG-treated group. These values are all in the range of the normal litt size of an adult rat. EXAMPLE 2 In the second experiment, nine groups of pregnant rats were used to assess t effects of hMG on pregnancy (TABLE 2): TABLE 2. Termination of pregnancy bv treatment with hMG GROUP DOSE LITTER SIZES (per rat) MEAN hMG/DAY-6.7 0.5 mg/rat 0 0 7 11 died 4.5 + 2.7 hMG/DAY-6 1.0 mg/rat 0 0 0 0 2* 0 hMG DAY-6 0.5 mg/rat + hMG/DAY-8 50 IU/rat 0 0 0 3 5* 0.6 + 0.6 In this study, the effect of hMG on litter size was determined after the hormone wa administered (1) on different days of the gestation period, (2) in multiple doses, (3) in different amounts, and (4) in conjunction with hCG. Day-1 of pregnancy is defined as the day of estrus during which the female mated with a male rat. The data show that hMG terminated pregnancy in all of the rats when 0.5 mg of the hormone were injected in a single dose on either Day-1 or Day-2 of gestation. Pregnancy was also terminated when a double dose of 0.5 mg hMG was administered to the animals on both Day-3 and Day-4 of pregnancy. In addition, th mean number of animals in the litters were statistically lower (p < 0.05) than the control value of 11.8 ± 1.3 when the pregnant animals were (1) treated with 0.5 mg hMG/rat on Day-3 or Day-6, (2) treated with 0.5 mg hMG/rat on Days-6,7, (3) treate with 1.0 mg hMG/rat on Day-6, or (4) treated with 0.5 mg hMG/rat on Day-6 followed by 50 I.U. hCG/rat on Day-8. When hMG was given on both days 6 and 7, one of the animals died. This event was associated with excessive vaginal bleeding. Also, in two instances (see asterisks in TABLE 2), the litters were stillborn several days after the normal arturition date. The data in EXAMPLE 2 show that a single dose of 0.5 mg hMG/rat is more effective (p < 0.05) in terminating pregnancy when the hormone preparation is administered on Day-1 or Day-2 of pregnancy compared to an equivalent injection Day-3 or Day-6. This information demonstrates that the method is more efficient when it is administered during the earlier stages of gestation. Nevertheless, the data show that pregnancy can also be terminated by hMG when the hormone is administered as late as 6 to 7 days after conception. Therefore, since the normal gestation period in the rat is 21 to 22 days, the data in EXAMPLE 2 demonstrate that hMG can be administered at least during the first one-third of the gestation period, and preferably during the first one-tenth of gestation. In comparison, in th 266-day gestation period of a human being, the equivalent intervals would be duri the first trimester, and preferably during the first four weeks of gestation, respectively. The data in EXAMPLE 2 also show that the efficiency of pregnancy terminatio was significantly greater (p < 0.05) when hCG was injected on Day-8 (i.e., on the second day after treatment with hMG) compared to when no hCG was administere In comparison, the data in EXAMPLE 1 show that the frequency of ovulation is significantly greater (p < 0.05) when hCG was injected on Day-8, 2 days after the hMG treatment. Therefore, taken together, EXAMPLES 1 and 2 reveal a correlatio between the induction of ovulation in the pregnant animals and the frequency of pregnancy termin ation following hormonal treatment. That is to say, a hormonal regimen that induces ovulation in a pregnant mammal is more likely to terminate the gravid state of the animal. Since urinary extracts of hMG consist of both FSH and LH (Stone, B.A., K. Quinn, P. Quinn, J.M. Vargyas, and .P. Marrs, Fertil. Steril. 52:745 r 1989; Harlin, J., S.A. Khan, andE. Diczfalusy, Fertil. Steril. 46:1005, 1986) the abortifacient action of this hormonal extract is based on the combined effects of the two pituitary hormones. The ratio of FSH and LH in different hMG preparations is dependent in part on the extraction procedures that are used to obtain the hormone from urine samples (Harlin, J., S.A Khan, andE. Diczfalusy, Fertil. Steril. 46:1005, 1986; Cook, A.S., B.W. Webster, P.F. Terranova, and B.A. Keel, Fertil. Steril. 49:704, 1988; Corsan, G.H., and E. Kemmann, Fertil. Steril. 55:468, 1991) The FSH and LH activities in suchjpreparations of hMG are biologically standardized in terms of the Second International Reference Preparation for Huma Menopausal Gonadotropins established in September, 1964, by the Expert Committee on Biological Standards of the World Health Organization (Physicians' Desk Reference, 46th Edition, published by Medical Economics Data, Oradell, NJ, 1992, p. 2184). In the commercial preparations used in the experiments described i EXAMPLES 1 and 2 above, 1.0 mg hMG contained approximately 50 I.U. each of FSH and LH activities. Therefore, treatment of a 250 g rat with 0.5 mg hMG amounts to a dose of 2.0 mg hMG/kg rat weight, which is equivalent to approximately 100 I.U. each of FSH and LH per kg of body weight (with hMG preparations from Sigma Chemical Company). However, the dosage of hMG (and hCG) that would be adequate to terminate pregnancy in a human being has not ye been confirmed by actual tests. In fact, there is negligible information about the effects of hMG when it is administered to a pregnant human being (Physicians' Desk Reference, 46th Edition, pubHshed by Medical Economics Data, Oradell, N 1992, p. 2184). As stated above, the data in EXAMPLES 1 and 2 indicate that the efficiency of pregnancy-termination is greater when the regimen of gonadotropin treatment induces ovulation in the treated animal. Therefore, the amount of hMG (and hCG) that would be required to terminate pregnancy in a human being would probably b equivalent to an amount that is adequate to induce ovulation. In a non-pregnant, infertile human being, ovulation can be induced by a variety of hormonal regimens which utilize one or more common commercial sources of hMG, FSH, LH, and/or hCG (Gougeon, A., and J. Testart, Fertil. Steril. 54:848, 1990; Dodson, W.C., C.L. Hughes, Jr., and A.F. Haney, Am. J. Obstet. Gynecol. 159:382, 1988; Martinez, A.R., R.E. Bernardus, F. J. Voorhorst, J.P.W. Vermeiden, and J. Schoemaker, Ferti Steril. 55:258, 1991; Chaffkin, L.M., J.C. Nulsen, A.A. Luciano, and D.A. Metzger, Fertil. Steril. 55:252, 1991; Stone, B.A., K. Quinn, P. Quinn, J.M Vargyas, and R. Marrs, Fertil. Steril. 52:745, 1989; Harlin, J., S.A. Khan, and E. Diczfalusy, Ferti Steril. 46:1005, 1986; Tanbo, T., P.O. Dale, E. Kjekshus, E. Haug, and T. Abyholm, Fertil. Steril. 53:798, 1990; Anderson, R.E., J.M. Cragun, R.J. Chang, F.Z. Stanczyk, and R. A. Lobo, Fertil. Steril. 52:216, 1989). It is reasonable to expect any of the protocols that induce follicular maturation and ovulation in infertile women to represent approximately the same hormone dosages that would be required to induce follicular maturation and ovulation and cause an abortion in a pregnant woman. In brief, the more common protocols for inducing ovulation in infertile women consist of individual daily doses of hMG (comprising about 75 to 30 I.U. each of FSH and LH activities) for about seven consecutive days, beginning 3 t 5 days after the start of any one menstrual cyde. Also, hormonal preparations that consist mainly of FSH can be substituted for hMG in the above protocols (Gemzell, C.A., E. Diczfalusy, and G. Tfflinger, J. Clin. Endocr. Metab. 18:1333, 1958; Tanbo, T., P.O. Dale, E. Kjekshus, E. Haug, andT. Abyholm, Fertil. Steril. 53:798, 1990; Anderson, R.E., J.M. Cragun, R.J. Chang, F.Z. Stanczyk, and . A Lobo, Fertil. Steril. 52:216, 1989). The last daily dosage of hMG (or FSH) is normally followed 24 to 48 hours later by an ovulation-inducing dose of hCG, amounting to about 5,000 to 10,000 I.U. of hCG. It is reasonable to expect these same protocols to induce follicular maturation and owdation in pregnant human beings and to thereb cause termination of the gravid state. In the above examples, it is sdentifically reasonable to expect the same biological responses if LH is used as a substitute for hCG, or vice versa. Such a substitution is possible because it is common knowledge that LH and hCG are members of the same family of hormones. Both LH and hCG are heterodimeric glycoproteins composed of a common α-subunit and a dosely related β-subunit. The similarity in these molecular configurations allows both hormones to bind to the same membrane receptors on the surface of target cells in the body, and therefore LH and hCG elicit identical biological responses (Roche, P.C., and R.J. Ryan, J. Biol. Chem. 264:4636, 1989; McFarland, K.C., R. Sprengel, H.S. Phillips, M. Kohler, N. Rosemblit, K. Nikolics, D.L. Segaloff, andP.H. Seeburg, Science 245:494, 1989). It is common sdentific knowledge that most hormones have similar functions in all vertebrate animals (Biology, 3rd Edition, by P.H. Raven and G.B. Johnson, pubHshed by Mosby Year Book, Inc., St. Louis, MO, 1992, p. 965). In the class of vertebrates known as mammals, it is even more likely that common hormones such as the gonadotropins each have the same specific functions in different spedes of mammals. Therefore, it is reasonable to expect the abortifadent action of the gonadotropic hormones described in EXAMPLES 1 and 2 above involving laborator rats to also be appHcable to other mammafian spedes. Comparable abortifacient action in human beings is espedaHy feasible, in view of the fact that the hMG and hCG preparations that were used in the experiments described in EXAMPLES 1 an 2 above were, by definition, hormones of human origin. Although the hormones in EXAMPLES 1 and 2 above were dissolved in distille water, it is scientificaHy reasonable to expect them to exert the same abortifacient action if they are dissolved and administered in other pharmacologicaUy inert solutions such as physiological salines and/or physiological buffers. Also, although the hormones were administered via subcutaneous injections, it is equaUy reasonable to expect them to exert the same abortifadent action if they are administered intramuscularly, intravenously, or by any other route that does not alter the normal molecular composition of the hormones. The pregnancy-terminating action of hMG (and hCG) is different from that of the abortifacient agent RU486. RU486 (also caUed mifeprestone) is a.synthetic steroid that blocks target ceH receptors for progesterone and thereby terminates pregnancy (BauHeu, E.E., Endocrinology 127:2043, 1990). During the past decade, this progesterone antagonist has been used more and more extensively as a abortifacient agent (Silvestre, L., C. Dubois, M. Renault, Y. Rezvani, E.E. BauHeu, and A. Ulmann, New Engl. J. Med. 322:645, 1990). RU486 also reportedly inhibit ovulation and the formation of corpora lutea (BauHeu, E.E., Endocrinology 127:2043, 1990). Thus, the mechanism of action of this agent is quite different from that of hMG, even though both compounds share the abifity to terminate pregnancy Also, in_regard to RU486, it is weH known that analogs of prostaglandin E increase the pregnancy-terminating abiHty of this drug from about 80% effectiveness to abo 96% (BauHeu, E.E., Endocrinology 127:2043, 1990; Silvestre, L., C. Dubois, M. Renault, Y. Rezvani, E.E. BauHeu, and A. Ulmann, New Engl. J. Med. 322:645,1990). The enhancing action of prostaglandin E is based on the abiHty of this substance to induce musde contractions in the myometrial tissue of the uterus. This observation makes it sdentificaHy reasonable to expect the abortifadent action of hMG to be enhanced by concomitant treatment of pregnant animals with hMG (and hCG) and prostaglandin E. For example, on the basis of existing knowledge about enhancement of the abortifadent action of RU486 in humans by supplementary treatment with prostanoids, prostaglandin E£ (or an equivalent analog) would be administered either as a vaginal suppository containing about 0.5 to 1.0 mg of the active prostaglandin, or as an intramuscular injection consisting of total of 0.125 to 0.5 mg of the active prostaglandin, at approximately 24 to 48 hours after administration of the final daily dose of hMG, or after the single dose of hCG when this latter gonadotropin is given in conjunction with hMG (Silvestre, L., C. Dubois, M. Renault, Y. Rezvani, E.E. BauHeu, and A. Ulmann, New Engl. J. Med. 322:645,1990; Guillebaud, J., Brit. Med. J. 301:352, 1990). In sum ry, the invention is a method of terminating pregnancy by the administration of single or multiple doses of hMG to induce ovarian folHcular maturation and ovulation during the first one-third of the gestation period of any given spedes of mammal. Since hMG is a human urinary extract that contains both FSH and LH as the two active ingredients, it is reasonable to expect combinations of FSH and LH to exert the same abortifadent action as hMG. It is also reasonable to expect the abortifadent action of hMG (and/or FSH andLH) to be enhanced when such hormone preparations are_admini tered in conjunction with hCG or prostaglandin E2, as described above. Since hMG and hCG are hormones of huma origin, the method should be particularly effective in human beings. The novelty o this invention is that the described protocols have been used heretofore as methods of inducing fertOity in non-pregnant women, rather than as pregnancy-terminating procedures.

Claims: I aim: 1. The method of terminating pregnancy in mammals by the injection into the mammalian body of dosages of one or more of the group of fertOity promoting hormones induding hMG, hCG, FSH and LH in amounts that induce ovarian folficular maturation and ovulation during the period from the first day of conception to the end of the first trimester of the normal gestation period for a given spedes of mammal. 2. The method of claim 1 wherein said injection is administered subcutaneously. 3. The method of claim 1 wherein said injection is administered intramuscularly. 4. The method of daim 1 wherein said injection is administered intravenously. 5. The method of daim 1 wherein said dosage comprises substantiaUy equal quantities of FSH and LH. 6. The method of daim 1 wherein the pregnant mammal is a woman. 7. The method of daim 6 wherein the amount of hMG injected in the pregnant woman comprises from 75 to 300 I.U. each of FSH and LH activities for about seven consecutive days. 8. The method of daim 7 wherein the last daily dosage of hMG is foUowed within 24 to 48 hours by injection of an ovulation inducing dosage of hCG in the range of 5,000 to 10,000 I.U. 9. The method of daim 1 wherein prostaglandin E in the amount of 75 to 150 1.U./kg of body weight is introduced into the mammalian body substantiaUy concurrently with the last dosage of said fertOity promoting hormones. AMENDED CLAIMS [received by the International Bureau on 4 June 1993 (04.06.93) original claims 1 , 6-9 amended ; other claims unchanged(2 pages) ] 1. A method of terminating pregnancy in mammal by inducing ovarian folficular maturation and ovulation during the period from the first day of conception to the end of the first trimester of the normal gestation period for the mammal, the method comprising: injecting into the mammal a dosage of fertOity promoting hormone selected from the group consisting of hMG and a combination of FSH and LH. 2. The method of claim 1 wherein said injection is administered subcutaneously. 3. The method of daim 1 wherein said injection is administered intramuscularly. 4. The method of daim 1 wherein said injection is administered intravenously. 5. The method of daim 1 wherein said dosage comprises substantiaUy equal quantities of FSH and LH. 6. The method of daim 1 wherein the mammal is a woman. 7. The method of daim 1 wherein the fertOity promoting hormone is injected for up to seven consecutive days and wherein the fertOity promoting hormone has an FSH activity of from 75 to 300 I.U. and an LH activity of from 75 to 300 I.U. 8. The method of daim 7 further comprising injecting an ovulation inducing dosage of hCG in the range of 5,000 to 10,000 I.U. 24 to 48 hours after the last injection of the fertOity promoting hormone. 9. The method of daim 7 further comprising administering to the mammal prostaglandin E in an amount of from 75 to 150 I.U./kg of body weight substantiaUy concurrently with the last injection of said fertOity promoting hormone.

Inventors: ESPEY LAWRENCE L, ESPEY, LAWRENCE, L.
Applicants: UNIV TRINITY, TRINITY UNIVERSITY
Application year: 1992
Main classification: A61K43
IPC codes: A61K38, A61P3