Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) in the rhesus monkey

R. H. Asch, J. P. Balmaceda, M. Neves De Castro, Andrew V Schally

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: (1) subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and (2) i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.

Original languageEnglish
Pages (from-to)109-117
Number of pages9
JournalAdvances in Contraception
Volume1
Issue number2
DOIs
StatePublished - Jun 1 1985
Externally publishedYes

Fingerprint

Hormone Antagonists
Intranasal Administration
Macaca mulatta
Gonadotropin-Releasing Hormone
Gonadotropins
Hormone-Dependent Neoplasms
Biological Availability
Precocious Puberty
Nasal Mucosa
Endometriosis
Serum
Contraception
Haplorhini
Hydrolysis
Injections

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) in the rhesus monkey. / Asch, R. H.; Balmaceda, J. P.; De Castro, M. Neves; Schally, Andrew V.

In: Advances in Contraception, Vol. 1, No. 2, 01.06.1985, p. 109-117.

Research output: Contribution to journalArticle

@article{adb9006adfdd46bd9f68b5ba69578017,
title = "Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) in the rhesus monkey",
abstract = "Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: (1) subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and (2) i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41{\%} (0.2 mg dose) and 41 and 58{\%} (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40{\%} (1 mg) and 32 and 53{\%} (5 mg), respectively. These decreases were dose-related and lasted for up to 12h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26{\%}. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1{\%}) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.",
author = "Asch, {R. H.} and Balmaceda, {J. P.} and {De Castro}, {M. Neves} and Schally, {Andrew V}",
year = "1985",
month = "6",
day = "1",
doi = "10.1007/BF01849792",
language = "English",
volume = "1",
pages = "109--117",
journal = "Advances in Contraception",
issn = "0267-4874",
publisher = "Kluwer Academic Publishers",
number = "2",

}

TY - JOUR

T1 - Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) in the rhesus monkey

AU - Asch, R. H.

AU - Balmaceda, J. P.

AU - De Castro, M. Neves

AU - Schally, Andrew V

PY - 1985/6/1

Y1 - 1985/6/1

N2 - Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: (1) subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and (2) i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.

AB - Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: (1) subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and (2) i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-d-p-Cl-Phe1,2, d-Trp3, d-Arg6, d-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.

UR - http://www.scopus.com/inward/record.url?scp=0022414215&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022414215&partnerID=8YFLogxK

U2 - 10.1007/BF01849792

DO - 10.1007/BF01849792

M3 - Article

VL - 1

SP - 109

EP - 117

JO - Advances in Contraception

JF - Advances in Contraception

SN - 0267-4874

IS - 2

ER -