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Methods for treating FSH related conditions with GnRH antagonists

a technology of gnrh and fsh, which is applied in the direction of drug compositions, extracellular fluid disorders, peptide/protein ingredients, etc., can solve the problems of lh no longer being produced, histamine-releasing activity, and worsening the condition, so as to and reduce the plasma fsh and lh levels

Inactive Publication Date: 2009-08-06
GARNICK MARC B +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]In another aspect, the invention features a method for treating prostatic intraepithelial neoplasia in a male subject, preferably a human male. The method includes administering to the subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a male subject, in an amount or in a formulation effective to reduce plasma FSH levels in the male subject, e.g., to a symptom alleviating level, thereby treating prostatic intraepithelial neoplasia in the male subject.
[0017]In yet another aspect, the invention features a method for contraception in a male subject, preferably a human male. The method includes administering to the subject an GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a male subject, in an amount or in a formulation effective to reduce plasma FSH levels in the male subject, e.g., to a symptom alleviating level, and administering testosterone to the male subject in an amount or in a formulation effective to restore libido and potency in the male subject. In one embodiment, the testosterone is administered to the male subject after the GnRH antagonist is administered. In another embodiment, the testosterone is administered to the male subject before the GnRH antagonist is administered. In yet another embodiment, the testosterone is administered to the male subject simultaneously with the GnRH antagonist.
[0021]In another aspect, the invention features a method for reducing FSH levels in a subject. The method involves administering to the subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a subject, in an amount or in a formulation effective to reduce plasma FSH levels in the subject, thereby reducing FSH levels in the subject.

Problems solved by technology

However, such GNRH superagonists initially act to stimulate LH release (and, frequently, testosterone or estrogen production) and only after prolonged treatment act to desensitize GnRH-R such that LH is no longer produced.
Additionally, each successive administration of the superagonist can cause a small LH surge (known as the “acute-on chronic” phenomenon) that again can worsen the condition.
A typical problem, however, that is frequently encountered with GnRH antagonist peptides is the occurrence of histamine-releasing activity.
This histamine-releasing activity represents a serious obstacle to the clinical use of such antagonists because histamine release results in adverse side effects such as edema and itching.
Many GnRH antagonist peptides also suffer from poor water-solubility, which complicates formulation of the antagonist for administration in vivo.

Method used

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  • Methods for treating FSH related conditions with GnRH antagonists
  • Methods for treating FSH related conditions with GnRH antagonists
  • Methods for treating FSH related conditions with GnRH antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0105]The following example describes the results of a multicenter, open-label Phase II study that enrolled 242 men (prospective concurrent control, N=33; abarelix depot, N=209). The groups were well matched for age, weight, height, race, body mass, stage of disease, and Gleason score (Table 4).

TABLE 4Demographic Characteristics Of Study Populationabarelix depotConcurrent controls(N = 209)(N = 33)Age (years)Mean (SD)72 ± 8.673 ± 6.2Range49-9359-84Weight (lbs)Mean (SD)188 ± 36.2185 ± 28.0Range104-315135-256No. (%) nonwhitea51 (24)11 (33)ECOG status (%)0201 (96)  33 (100)15 (2)023 (1)0Categories of disease (%)Stage D1 / D2b25 (12) 6 (18)Increasing PSA after53 (25) 8 (24)definitive local therapyNeoadjuvant / intermittent therapy131 (63) 19 (58)aAfrican American, Hispanic, Asian, othersbD1 = evidence of pelvic lymph note metastases; D2 = extrapelvic soft tissue or bone metastases

[0106]The institutional review boards of all participating institutions approved the study protocol, and all men ...

example 2

[0109]The following example describes results of experiments examining levels of FSH in plasma of human subjects treated with the GnRH antagonist abarelix, obtained from a Phase III clinical trial involving administration of abarelix to prostate cancer patients.

Study Design and Schema

[0110]The following Phase III clinical studies A and B (using the abarelix depot) were blinded, randomized, parallel-group, multicenter phase 3 trials conducted in adult male patients with prostate cancer who were candidates for initial hormonal therapy, including patients with local or regional disease who were candidates for neoadjuvant hormonal therapy; patients with metastatic disease (stage D1 or D2); patients with rising prostate specific antigen (PSA) levels after radical prostatectomy, radiation therapy, or other local therapy; and patients scheduled for their initial course of intermittent therapy.

[0111]Patients were randomized to receive either abarelix depot 100 mg or active control medicatio...

example 3

[0118]The effect of abarelix depot on FSH levels was further evaluated in phase III multicenter studies and compared to the effect of leuprolide±bicalutamide (L±B) on FSH levels. FSH levels were measured throughout the study in patients treated with injections of 100 mg abarelix depot and 7.5 mg leuprolide±oral daily bicalutamide 50 mg. Avoidance of FSH surge (50% over baseline FSH) on day 2 and maintenance of FSH suppression (≦FSH at baseline) on day 169 were evaluated in 512 patients. Data from the two studies was pooled for abarelix depot treated patients.

TABLE 5Patients (%) with FSH Responseabarelixleuprolide +depotleuprolidebicalutamideAvoidance of345 / 345 (100%)14 / 87 (16%) 8 / 80% (10%)FSH surgeMaintenance of312 / 322 (97%) 66 / 80 (82%)48 / 69 (70%)FSH Suppression(day 169)

[0119]FSH levels were rapidly suppressed with abarelix depot as compared to L±B. None of the abarelix depot treated patients versus 84% of the leuprolide (Lupron Depot®) treated and 90% of the L+B treated patients ex...

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Abstract

Methods for treating FSH related conditions, such as prostatic intraepithelial neoplasia, pedophilia, infertility, or vaginal bleeding, with GnRH antagonists are disclosed. The methods of the invention generally feature administering to a subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a subject, in an amount or in a formulation effective to reduce plasma FSH levels in the subject to a symptom alleviating level. In vitro fertilization and male contraceptive methods are also provided.

Description

RELATED APPLICATIONS[0001]This application is a Continuation of U.S. patent application Ser. No. 11 / 343,283 filed on Jan. 30, 2006 which, in turn, is a Continuation of U.S. patent application Ser. No. 09 / 793,669 filed on Feb. 28, 2001, which claims priority to U.S. Provisional Application No. 60 / 185,573, filed on Feb. 28, 2000; U.S. Provisional Application No. 60 / 185,574, filed on Feb. 28, 2000; U.S. Provisional Application No. 60 / 238,337, filed on Oct. 5, 2000; and U.S. Provisional Application No. 60 / 238,338, filed on Oct. 5, 2000. The entire contents of each of the foregoing applications are incorporated herein by this reference.BACKGROUND OF THE INVENTION[0002]Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are hormones released by the pituitary gland. These hormones regulate the functioning of the gonads and the production and maturation of gametes. LH and FSH are generally released by the pituitary gland upon prior release of a triggering hormone from the hypoth...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/08A61K47/48A61K31/568A61K38/04A61K38/09A61K38/12A61K38/22A61K45/00A61K47/46A61P5/02A61P5/04A61P5/06A61P5/14A61P5/24A61P7/04A61P13/08A61P15/00A61P15/02A61P15/08A61P15/16A61P35/00A61P35/02A61P43/00
CPCA61K47/46A61K38/09A61P13/08A61P15/00A61P15/02A61P15/08A61P15/16A61P35/00A61P35/02A61P43/00A61P5/02A61P5/04A61P5/06A61P5/14A61P5/24A61P7/04
Inventor GARNICK, MARC B.MARTHA, JR., PAUL M.MOLINEAUX, CHRISTOPHER J.DEPAOLI, ALEX
Owner GARNICK MARC B
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