PROLONGED INHIBITION OF LUTEINIZING-HORMONE AND TESTOSTERONE LEVELS IN MALE-RATS WITH THE LUTEINIZING-HORMONE-RELEASING HORMONE ANTAGONIST SB-75

被引:23
作者
BOKSER, L
BAJUSZ, S
GROOT, K
SCHALLY, AV
机构
[1] TULANE UNIV,VET ADM MED CTR,SCH MED,NEW ORLEANS,LA 70146
[2] TULANE UNIV,SCH MED,DEPT MED,NEW ORLEANS,LA 70146
关键词
gonadal inhibition; inhibitory analogs of luteinizing hormone-releasing hormone; microgranules;
D O I
10.1073/pnas.87.18.7100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1,4-chloro-D- phenylalanine2,3-(3-pyridyl)-D-alanine3,D-citrulline6, D-alanine10] luteinizing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25, 2.5, 5.0, and 10 μg. Blood samples were taken at different intervals for 48 hr. All doses of SB-75 significantly decreased luteinizing hormone levels for >6 hr (P < 0.01); this inhibition lasted for >24 hr (P < 0.01) with a dose of 5.0 μg and >48 hr with 10 μg(P < 0.05). Serum testosterone levels were also measured in intact male rats injected with SB-75 in doses of 25, 50, and 100 μg. All doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P < 0.01); this inhibition of serum testosterone was maintained for >72 hr, but only the 100-μg dose could keep testosterone in the castration range for >24 hr (P < 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the 'burst' effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P < 0.01) and were maintained at low values for >7 days (P < 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules of the second batch, SB-75 serum levels rose to 33 ng/ml 3 hr after administration and then fell gradually to ≃3.4 ng/ml on day 16, but a second small peak was seen on day 28. Subsequently, the analog levels decreased slowly to 2.9 ng/ml on day 42. At this time, testosterone serum levels were still significantly lower than in controls. These overall results demonstrate the efficacy of SB-75 in the suppression of the pituitary-gonadal axis. This modern luteinizing hormone-releasing hormone antagonist can possibly be used for treating sex hormone-sensitive cancers and other disorders.
引用
收藏
页码:7100 / 7104
页数:5
相关论文
共 21 条
  • [1] BAJUSZ S, 1988, INT J PEPT PROT RES, V32, P425
  • [2] HIGHLY POTENT ANTAGONISTS OF LUTEINIZING-HORMONE-RELEASING HORMONE FREE OF EDEMATOGENIC EFFECTS
    BAJUSZ, S
    KOVACS, M
    GAZDAG, M
    BOKSER, L
    KARASHIMA, T
    CSERNUS, VJ
    JANAKY, T
    GUOTH, J
    SCHALLY, AV
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (05) : 1637 - 1641
  • [3] DELAYED RELEASE FORMULATION OF THE SOMATOSTATIN ANALOG RC-160 INHIBITS THE GROWTH-HORMONE (GH) RESPONSE TO GH-RELEASING FACTOR-(1-29)NH2 AND DECREASES ELEVATED PROLACTIN LEVELS IN RATS
    BOKSER, L
    SCHALLY, AV
    [J]. ENDOCRINOLOGY, 1988, 123 (04) : 1735 - 1739
  • [4] BOKSER L, 1989, J REPROD FERTIL, V85, P569
  • [5] PROTECTIVE EFFECTS OF D-TRP6-LUTEINIZING HORMONE-RELEASING HORMONE MICROCAPSULES AGAINST CYCLOPHOSPHAMIDE-INDUCED GONADOTOXICITY IN FEMALE RATS
    BOKSER, L
    SZENDE, B
    SCHALLY, AV
    [J]. BRITISH JOURNAL OF CANCER, 1990, 61 (06) : 861 - 865
  • [6] CSERNUS VJ, 1990, INT J PEPT PROT RES, V35, P557
  • [7] CSERNUS VJ, 1990, ARZNEIMITTEL-FORSCH, V40-1, P111
  • [8] SUSTAINED INHIBITORY ACTIONS OF A POTENT ANTAGONIST OF GONADOTROPIN-RELEASING-HORMONE IN POSTMENOPAUSAL WOMEN
    DAVIS, MR
    VELDHUIS, JD
    ROGOL, AD
    DUFAU, ML
    CATT, KJ
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1987, 64 (06) : 1268 - 1274
  • [9] DUTTA A S, 1988, Drugs of the Future, V13, P761
  • [10] GONADOTROPIN-RELEASING-HORMONE ANALOG DESIGN - STRUCTURE-FUNCTION STUDIES TOWARD THE DEVELOPMENT OF AGONISTS AND ANTAGONISTS - RATIONALE AND PERSPECTIVE
    KARTEN, MJ
    RIVIER, JE
    [J]. ENDOCRINE REVIEWS, 1986, 7 (01) : 44 - 66