Potent pituitary-gonadal axis suppression and extremely low anaphylactoid activity of a new gonadotropin releasing hormone (GnRH) receptor antagonist “azaline B”

Campen, Carolyn A.; Lai, Muh-Tsann; Kraft, Pat; Kirchner, Tom; Phillips, A.; Hahn, Do Won; Rivier, Jean

doi:10.1016/0006-2952(95)00027-w

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…The PLA (202H [3]) microspheres released in vivo more than 60% of the drug within 2 weeks and continued to release 0.37% per day ( Figure 10A). In contrast, only 16% release occurred in vitro in 14 days, but subsequently the release rate stabilized at 0.38% per day.…”

Section: Resultsmentioning

confidence: 99%

“…Since the discovery and structural elucidation of luteinizing hormone-releasing hormone (LHRH), numerous analogues have been synthesized and studied for potential application in gynecology and oncology as antigonadotropic agents for ovarian and testicular suppression [1][2][3][4]. Leuprolide acetate, developed and marketed by TAP Pharmaceuticals, Inc. (Deerfield, Ill.) as Lupron Depot®, is one of the most widely used LHRH superagonists in the treatment of sex hormone-dependent tumors, such as prostatic carcinoma in men [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

et al. 2000

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Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 µ were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

et al. 2000

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“…Azaline B, a competitive antagonist of the GnRH receptor (61), was used to test this hypothesis. Treatment with azaline B reduced pCREB in Ovx rats to a level that was similar to that seen in estradioltreated rats.…”

Section: Discussionmentioning

confidence: 99%

“…In the experiments that involved the GnRH receptor antagonist, rats were ovariectomized bilaterally for 10-12 days and the antagonist, azaline B, was injected once (400 g sc/rat in 0.2 ml sesame oil) (61). The control group received sesame oil only.…”

Section: Animal Modelsmentioning

confidence: 99%

Estradiol Suppresses Phosphorylation of Cyclic Adenosine 3′,5′-Monophosphate Response Element Binding Protein (CREB) in the Pituitary: Evidence for Indirect Action via Gonadotropin-Releasing Hormone

Duan

Shin

Jameson

1999

Molecular Endocrinology

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Estradiol acts on the hypothalamus and pituitary gland to modulate the synthesis and secretion of gonadotropins. We recently reported that GnRH-induced transcription of the human gonadotropin alpha-gene promoter is increased markedly in transfected pituitary cells derived from animals treated with estradiol. Because the cAMP response element binding (CREB) protein plays an important role in the transcriptional regulation of this promoter and is highly regulated by posttranslational phosphorylation, we hypothesized that it might serve as a target for estradiol-induced sensitivity to GnRH. In this study, we assessed the roles of estradiol and GnRH in the regulation of CREB phosphorylation in the rat pituitary. Using an antibody that specifically recognizes phosphorylated CREB (pCREB), we found that the pituitary content of pCREB was inversely related to the level of estradiol during the estrous cycle. Ovariectomy increased the level of pCREB, and treatment with estradiol for 10 days decreased the content of pCREB dramatically (93% inhibition). A similar reduction of pCREB was seen when ovariectomized rats were treated with a GnRH receptor antagonist for 10 days. This result indicates that the ovariectomy-induced increase in pCREB is GnRH-dependent. In alphaT3 gonadotrope cells, estradiol had no direct effect on CREB phosphorylation, whereas GnRH increased CREB phosphorylation 4- to 5-fold within 5 min. We conclude that estradiol inhibits CREB phosphorylation in the gonadotrope, probably by inhibiting GnRH production. The estradiol-induced decrease in CREB phosphorylation is proposed to lower basal alpha-promoter activity and increase its responsiveness to GnRH.

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“…GnRH agonists and antagonists have been used in the treatment for various clinical conditions such as breast cancer, prostate cancer, endometriosis, premenstrual syndrome, infertility (Karten and Rivier, 1986; Tarlatzis and Bili, 2003), precocious puberty (Mul and Hughes, 2008; Schultze-Mosgau et al, 2005). Azaline B is a synthetic GnRH receptor antagonist that has very low anaphylactic properties (Campen et al, 1995; Rivier et al, 1995a). The effectiveness of GnRH antagonists in vivo in the context of gonadotropin-induced folliculogenesis or ovarian steroidogenic enzyme expression in laboratory rodents, particularly in the golden hamster, warrants further study.…”

Section: Introductionmentioning

confidence: 99%

Effect of azaline B on follicular development and functions in the hamster

Chakraborty¹,

Roy²

2015

Molecular and Cellular Endocrinology

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The usefulness of azaline B, a GnRH antagonist, in suppressing gonadotropin secretion in the golden hamster was examined by examining follicular development, steroidogenesis and expression of steroidogenic enzymes. Serum levels of P and E declined significantly, while FSH or LH was undetectable in azaline B-treated hamsters. FSH significantly increased serum E levels, whereas LH upregulated serum P levels. The formation of antral follicles ceased in azaline-treated hamsters, but was reversed by FSH with or without LH supplement. FSH also activated the primordial follicle pool resulting in increased formation of primary and preantral follicles. Further, an increasing trend in the formation of preantral follicles in response to E or E + P, and the formation of antral follicles in response to E + P treatment was evident. The level of Cyp11a1 mRNA increased markedly in LH− or LH + FSH-treated hamsters, whereas FSH with or without LH upregulated Cyp17a1, Cyp19a1 and Fshr mRNA expression. E without or with P also upregulated ovarian Cyp19a1 mRNA expression. The expression of enzyme protein corroborated the mRNA data. In summary, azaline B is an efficient GnRH antagonist in the hamster, and will be useful in studying the selective effect of gonadotropins on ovarian functions without disrupting the physiological functions of other hormones in ovarian cells.

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Potent pituitary-gonadal axis suppression and extremely low anaphylactoid activity of a new gonadotropin releasing hormone (GnRH) receptor antagonist “azaline B”

Cited by 14 publications

References 24 publications

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

Estradiol Suppresses Phosphorylation of Cyclic Adenosine 3′,5′-Monophosphate Response Element Binding Protein (CREB) in the Pituitary: Evidence for Indirect Action via Gonadotropin-Releasing Hormone

Effect of azaline B on follicular development and functions in the hamster

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