MEDICINAL PREPARATIONS FOR TREATING SEX HORMONE-DEPENDENT DISEASES
Medicinal preparations for treating sex hormone-dependent diseases which comprise a combination of a compound having a luteinizing hormone-releasing hormone agonistic effect or its salt with a compound having a luteinizing hormone-releasing hormone antagonistic effect or its salt for administering the compound having a luteinizing hormone-releasing hormone agonistic effect or its salt followed by the compound having a luteinizing hormone-releasing hormone antagonistic effect or its salt. By using these preparations, the concentration of a sex hormone (for example, testosterone, LH, FSH, estrogen) can be quickly recovered after the medicable period of a compound having a luteinizing hormone-releasing hormone antagonistic effect or its salt or a preparation containing the same (preferably a sustained-release preparation), which makes it possible to definitely determine the drug cessation period in an intermittent treatment.
1 . A medicinal preparation for treating sex hormone-dependent diseases comprising a combination of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof with a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof, for administering the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
2 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof is a peptide compound or a salt thereof.
3 . The preparation according to claim 2 , wherein the peptide compound is a natural hormone or an analog thereof.
4 . The preparation according to claim 2 , wherein the peptide compound is a peptide represented by the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
wherein Y is a residue selected from DLeu, DAla, DTrp, DSer(tBu), D2NaI and DHis(ImBzl), Z is NH—C 2 H 5 or Gly-NH 2 .
5 . The preparation according to claim 2 , wherein the peptide compound or a salt thereof is a compound or a salt thereof selected from leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and recirelin.
6 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof is used as an injectable preparation.
7 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof is used as a sustained release preparation.
8 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof is used as a preparation for nasal administration.
9 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is a peptide compound or a salt thereof.
10 . The preparation according to claim 9 , wherein the peptide compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is a compound selected from NAcD2NaI-D4ClPhe-D3 Pal-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DAlaNH 2 , N(4H2-furoyl)Gly-D2NaI-D4ClPhe-D3 Pal-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DAlaNH 2 , cetrorelix, ganirelix, antarelix, decirelix, azaline, antide, ramorelix and abarelix, or a salt thereof.
11 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is used as an injectable preparation.
12 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is used as a sustained release preparation.
13 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is used as a preparation for nasal administration.
14 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is a nonpeptide compound or a salt thereof.
15 . The preparation according to claim 14 , wherein the nonpeptide compound or a salt thereof is a compound represented by the formula (I):
wherein each of R 1 and R 2 is hydrogen atom, hydroxy group, a C 1-4 alkoxy group, a C 1-4 alkoxy-carbonyl group or an optionally substituted C 1-4 alkyl group,
R 3 is hydrogen atom, a halogen atom, hydroxy group or an optionally substituted C 1-4 alkoxy group, or the two adjacent R 3 s may link to form a C 1-4 alkylenedioxy group,
R 4 is hydrogen atom or a C 1-4 alkyl group,
R 6 is an optionally substituted C 1-4 alkyl group or a group represented by the formula:
wherein R 5 is hydrogen atom, or R 4 and R 5 may link to form a heterocyclic ring, and
n is an integer of 0 to 5, or a salt thereof.
16 . The preparation according to claim 14 , wherein the nonpeptide compound or a salt thereof is 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione or a salt thereof.
17 . The preparation according to claim 14 , wherein the nonpeptide compound or a salt thereof is a compound represented by the formula (VIII):
wherein R 9 is an optionally substituted C 1-7 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 1-6 alkoxyamino group or an optionally substituted hydroxyamino group,
R 10 is an optionally substituted C 1-7 alkyl group or an optionally substituted phenyl group, or a salt thereof.
18 . The preparation according to claim 14 , wherein the nonpeptide compound or a salt thereof is 3-(N-benzyl-N-methylaminomethyl)-4,7-dihydro-5-isobutylyl-7-(2,6-difluorobenzyl)-2-[4-[(1-hydroxycyclopropyl)-carbonylamino]phenyl]-4-oxothieno[2,3-b]pyridine or a salt thereof.
19 . The preparation according to claim 1 , wherein the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof is administrated before administration, during administration or immediately after administration of the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof.
20 . A method for using a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof and/or a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof for the preparation of a medicinal preparation for treating sex hormone-dependent diseases, said preparation being characterized by administering the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof, followed by the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
21 . A medicinal preparation for treating sex hormone-dependent diseases comprising a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof or a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof, said preparation being characterized by administering the compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof, followed by the compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
22 . An agent for maintaining a hormone therapy comprising a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
23 . A method for determining a drug cessation period comprising using a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
24 . A method for recovering the concentration of a sex hormone in a living body comprising using a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof.
25 . A method for the treatment of sex hormone-dependent diseases comprising administering an effective amount of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof to a mammal.
26 . A method for maintaining hormone therapy comprising administering an effective amount of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof to a mammal.
27 . A method for determining a drug cessation period comprising administering an effective amount of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof to a mammal.
28 . A method for recovering sex hormone concentration in a living body comprising administering an effective amount of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof to a mammal.
29 . A method for treating a sex hormone-dependent disease, comprising administering an effective amount of a compound having a luteinizing hormone-releasing hormone agonistic effect or a salt thereof followed by an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic effect or a salt thereof to a mammal, thereby maintaining sex hormone-dependency.