Clinical applications of mifepristone (RU 486) and other antiprogestins : assessing the science and recommending a research agenda / Committee on Antiprogestins: Assessing the Science, Division of Health Promotion and Disease Prevention, Institute of Medicine ; Molla S. Donaldson ... [et al.], editors.

Format:

Book

Contributor:

Benet, Leslie Z.

Donaldson, Molla S.

Institute of Medicine (U.S.). Committee on Antiprogestins: Assessing the Science.

Institute of Medicine (U.S.). Division of Health Promotion and Disease Prevention.

Language:

English

Subjects (All):

Mifepristone--Research.

Mifepristone.

Abortifacients--Research.

Abortifacients.

Progesterone--Antagonists--Research.

Progesterone.

Physical Description:

xi, 288 p. : ill.

Edition:

1st ed.

Place of Publication:

Washington, D.C. : National Academy Press, 1993.

Language Note:

English

Summary:

Mifepristone (RU486), the first clinically available antiprogestin, has generated great interest since its discovery in the early 1980s. Today, it is recognized that mifepristone, along with other antiprogestins, has a potentially significant therapeutic role in human health and disease, with likely applicability to a variety of pregnancy-related conditions (e.g., management of labor) and to contraception, endometriosis, and cancer, among others. But because mifepristone has been studied and used most widely as a means of nonsurgical abortion, political issues have thus far limited research on the drug and prevented its introduction into the U.S. market. This book provides an unbiased evaluation of current knowledge about both the fundamental nature of antiprogestins as well as their possible use in treating numerous diseases and conditions, and it contains recommendations for future research.

Contents:

Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins

Copyright

Preface

Contents

Summary

CROSS-CUTTING RECOMMENDATIONS

USES OF ANTIPROGESTINS: THE REPRODUCTIVE CYCLE

Contraception

Post-Coital Contraception

Menses Induction

Pregnancy Termination During the First Trimester

Pregnancy Termination During the Second Trimester

Cervical Ripening

Labor Induction in Late Pregnancy

OTHER POTENTIAL THERAPEUTIC USES OF ANTIPROGESTINS

Endometriosis

Uterine Leiomyomas (Fibroids)

Breast Cancer

Meningioma

ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS

1 Introduction

BACKGROUND AND HISTORICAL PERSPECTIVES

Finding an Antiprogestin

THE IOM REPORT

REFERENCES

2 Uses of Antiprogestins: The Reproductive Cycle (Part I)

CONTRACEPTION

POST-COITAL CONTRACEPTION

MENSES INDUCTION

3 Uses of Antiprogestins: The Reproductive Cycle (Part II)

PREGNANCY TERMINATION DURING THE FIRST TRIMESTER

Health Services Research

PREGNANCY TERMINATION DURING THE SECOND TRIMESTER

CERVICAL RIPENING

LABOR INDUCTION IN LATE PREGNANCY

Fetal Demise

SUMMARY

4 Other Therapeutic Uses of Antiprogestins

ENDOMETRIOSIS

Utility of Mifepristone (RU 486) for Treatment of Endometriosis

UTERINE LEIOMYOMAS (FIBROIDS)

Utility of Mifepristone for Treatment of Uterine Leiomyomas

BREAST CANCER

Mechanism of Action

Clinical Issues

Adjuvant Therapy and Chemoprevention

Resistance

Dose Issues

Conclusions

MENINGIOMAS

5 Antiglucocorticoid Effects of Antiprogestins

GLUCOCORTICOID FUNCTION

THERAPEUTIC USE OF MIFEPRISTONE (RU 486) AS ANANTIGLUCOCORTICOID

ADVERSE ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS

REFERENCES.

6 Animals as Models for Studying Antiprogestins

APPENDIXES

A Agenda for the IOM Workshop ''Antiprogestins: Assessing the Science," April 13-14, 1993

B Background Papers and Presentations (In Order of Presentation at IOM Workshop)

B1 1993: RU 486-A DECADE ON TODAY AND TOMORROW

ANTIHORMONES: THE 20 YEARS BEFORE RU 486

CHEMISTRY: NOVEL MOLECULES

CELLULAR AND MOLECULAR MECHANISMS OF ACTION OF ANTIPROGESTINS: THE RECEPTOR AT THE CENTER

Ligand Binding

Receptor Transconformation

Heat Shock Protein Binding

Receptor Dimerization

Binding to DNA

Studies of Chromatin

Gene Transcription

PHYSIOPHARMACOLOGICAL REPRODUCTIVE EFFECTS

REPRODUCTIVE MEDICINE (TABLE B1.4)

Voluntary Early Pregnancy Interruption

Pregnancy Interruption After Nine Weeks of Amenorrhea

Initiation of Labor

Contragestive and Contraceptive Methods Using RU 486

Emergency Post-Coital Contraception (Contraceptive or Contragestive According to When it is Applied)

Late Luteal Phase Administration (Occasional Use) (Contragestive)

Monthly Premenstrual, Late Luteal Phase Administration (Repeated Use) (Contragestive)

Early Luteal Phase Administration (Once a Month) (Anti-Implantation)

Endometrial Contraception" (Daily Delivery of Very Low Dose) (Contraceptive and Contragestive)

Ovulation Suppression (Daily Delivery of a Low Dose) (Contraceptive)

Male Contraception

MEDICAL APPLICATIONS (TABLE B1.4)

Uterine Diseases

Fibroids

ANTIGLUCOCORTICOSTEROID EFFECTS

CONCLUSIONS

Use for Voluntary Pregnancy Interruption

Cancer

Novel Antiprogestins: Biology and Chemistry

ACKNOWLEDGMENTS

B2 OVERVIEW AND BACKGROUND: MECHANISM OF ACTION OF ANTIPROGESTINS

INTRODUCTION

STRUCTURE AND FUNCTION OF THE PROGESTERONE RECEPTOR.

The Hormone Binding Domain

The DNA Binding Domain

Transactivation Function

Association with Other Proteins

Phosphorylation of the Progesterone Receptor

Progesterone-Receptor Function

MECHANISMS OF ACTION OF PROGESTERONE ANTAGONISTS

Binding of Antagonists to Progesterone Receptors

Formation of Dimers and DNA Binding Complexes

Effects of Antagonists on Transcriptional Activation

Other Effects of Antagonists on Receptors

SUMMARY AND FUTURE AREAS OF STUDY

B3 THE USE OF ANTIPROGESTINS IN THE REPRODUCTIVE CYCLE

USE OF ANTIPROGESTINS IN THE REPRODUCTIVE CYCLE

Basic Concepts and Assumptions

Assessment Issues in Evaluating Antiprogestins

Potential Uses of Antiprogestins

Follicular Phase Administration of RU 486

Other Strategies for Administration of RU 486 During the Menstrual Cycle

TOXICITY

QUESTIONS FOR FUTURE RESEARCH

B4 POTENTIAL CONTRACEPTIVE EFFECTS OF ANTIGESTOGENS

ABSTRACT

PHYSIOLOGICAL STUDIES IN THE MENSTRUAL CYCLE

POSSIBLE CONTRACEPTIVE USES OF MIFEPRISTONE

Inhibition of Ovulation

Endometrial Contraception

Late Post-Coital Contraception

FUTURE DEVELOPMENTS

Basic Research

Mode of Action

Clinical Studies

B5 USE OF ANTIPROGESTINS BEFORE 63 DAYS OF AMENORRHEA

EFFECT OF MIFEPRISTONE DURING EARLY PREGNANCY

TERMINATION OF EARLY PREGNANCY

Mifepristone Alone

Mifepristone in Combination with Prostaglandin

Practical Guidelines for Clinical Use of Mifepristone in Combination with Prostaglandin

FURTHER DEVELOPMENTS IN MEDICAL TERMINATION OF EARLY PREGNANCY

B6 USES OF ANTIPROGESTINS AFTER 63 DAYS OF AMENORRHEA

RU 486 FOR SECOND-TERM PREGNANCY TERMINATION

RU 486 FOR INTRAUTERINE FETAL DEATH (IUFD).

CERVICAL RIPENING WITH RU 486 PRIOR TO SURGICAL ABORTION

RU 486 FOR LABOR INDUCTION

B7 COMMENTS ON SESSION II

USE OF MIFEPRISTONE AND PROSTAGLANDIN FOR FIRST-TRIMESTER ABORTION

Need for Medical Supervision

Acceptability of Medical Versus Surgical Abortion

Number of Visits Required

Appropriate Dose of Mifepristone

Side Effects

SECOND-TRIMESTER ABORTIONS

B8 USE OF ANTIPROGESTINS IN THE MANAGEMENT OF ENDOMETRIOSIS AND LEIOMYOMA

Antiprogestin in the Treatment of Endometriosis

Pilot Study

Long-Term, Low-Dose Studies

LEIOMYOMA (FIBROID TUMOR)

Antiprogestin in the Management of Leiomyoma- Dose-Response Studies

50-mg Dose

25- and 5-mg Doses

Outcome

B9 ANTIPROGESTINS AND THE TREATMENT OF BREAST CANCER

PROGESTERONE AND THE NORMAL BREAST

PROGESTERONE AND BREAST CANCER

Progestin Agonists and Tumor Induction

Progestin Agonists and Growth of Established Tumors

PROGESTERONE ANTAGONISTS AND THE TREATMENT OF BREAST CANCER

Human Breast Cancer Cell Lines

Animal Models of Mammary Cancer

Human Clinical Trials

PROGESTIN RESISTANCE

SUMMARY AND FUTURE PROSPECTS

B10 USES OF RU 486 AS AN ANTIGLUCOCORTICOID

HOW DO GLUCOCORTICOIDS ACT?

PHYSIOLOGIC ROLE OF GLUCOCORTICOIDS

RU 486 AS AN ANTIGLUCOCORTICOID

RESEARCH DIRECTIONS FOR ANTIGLUCOCORTICOIDS

B11 PRIMATE MODELS FOR THE STUDY OF ANTIPROGESTINS IN REPRODUCTIVE MEDICINE

PART I: ACTIVITY EXPRESSIONS OF ANTIPROGESTINS

Progesterone Antagonists

Antiglucocorticoid Activity

Noncompetitive Antiestrogenic (Antiproliferative) Activity

Sources of Antiprogestins.

PART II: NONCOMPETITIVE ANTIESTROGENIC ACTIVITY OF PROGESTERONE ANTAGONISTS

Initial Evidence of Noncompetitive Antiestrogenic Activity of Mifepristone

Dose-Dependent Blockade of the Proliferative Action of Estradiol Endometrium by Mifepristone

Mifepristone-Induced Elevations of Estrogen Receptor in Primate Endometrium

B12 ANTIPROGESTOGENS: PERSPECTIVES FROM A GLOBAL RESEARCH PROGRAM

COMPOUNDS

Progesterone Synthesis Inhibitors

Progesterone-Receptor Blockers

ANIMAL MODELS

Receptor Binding

Plasma Protein Binding

Pregnant Guinea Pig Model

MECHANISMS OF ACTION

Prostaglandin Metabolism

Myometrial Gap Junctions

Estrogen and Progesterone Receptors

POSSIBLE USES

PROSPECTS

ACKNOWLEDGMENT

C Observers at the Workshop on Antiprogestins: Assessing the Science April 13-14, 1993

Index.

Notes:

"Support for this project was provided by a grant from the Henry J. Kaiser Family Foundation, Menlo Park, California."--Verso T.p.

Committee chairman: Leslie Z. Benet.

Includes bibliographical references and index.

ISBN:

9786610196029

9781280196027

1280196025

9780309598354

0309598354

9780585024783

0585024782

OCLC:

923265433