Development of Therapeutic Agents Handbook E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Pharmaceutical Development
• Sprache: Englisch

Seitenzahl: 4051

Veröffentlichungsjahr: 2011

Beschreibung

A comprehensive look at current drug discovery and development methods--and the roadmap for the future Providing both understanding and guidance in characterizing potential drugs and their production and synthesis, Development of Therapeutic Agents Handbook gives professionals a basic tool to facilitate research and development within this challenging process. This comprehensive text brings together, in one resource, a compendium of concepts, approaches, methodologies, and limitations that need to be considered in the formulation of therapeutic agents across a range of therapeutic fields. Both a reference and a call to action for the pharmaceutical industry, Development of Therapeutic Agents Handbook examines recent innovations taking shape in the various medical disciplines involved in drug discovery, and shows why these advances need to be embraced universally among researchers to improve their solution strategies. Additional subject matter includes: * Extensive coverage and in-depth look into novel treatments and therapeutics * Discussion of hot topics like new drugs and nutraceuticals, the discovery and development of vaccines, cancer therapeutics, and market overviews * Coverage of therapeutic drug development for specific disease areas, such as cardiology, oncology, breast cancer, and kidney diseases As research in biology, chemistry, medicine, and technology rapidly progresses, it is becoming increasingly important for medical researchers to maintain an up-to-date knowledge base of emerging trends directing promising new therapies. Development of Therapeutic Agents Handbook serves this purpose, acting as both a one-stop reference rich in valid science, and a tool to carve out new pathways in the pursuit of bringing safer and more effective drugs to the marketplace.

Leseprobe

Table of Contents

Cover

Title page

Copyright page

PREFACE

CONTRIBUTORS

PART I: FUNDAMENTALS AND CONCEPTS

1 CURRENT NEEDS FOR NEW THERAPEUTIC AGENTS AND DISCOVERY STRATEGIES—A SYSTEMS PHARMACOLOGY APPROACH

1.1 INTRODUCTION: A BRIEF HISTORY OF DRUG DISCOVERY

1.2 CURRENT STATE OF THERAPEUTIC AGENTS AND THE NEED FOR NEW AGENTS

1.3 APPROACHES FOR DRUG DISCOVERY

1.4 CONCLUDING REMARKS

ACKNOWLEDGMENTS

2 TARGET SELECTION IN DRUG DISCOVERY

2.1 INTRODUCTION

2.2 CRITERION 1: TARGET LINKAGE TO DISEASE

2.3 CRITERION 2: POTENTIAL THERAPEUTIC INDEX

2.4 CRITERION 3: CHEMICAL TRACTABILITY

2.5 CRITERION 4: ECONOMIC CONSIDERATIONS

ACKNOWLEDGMENTS

3 NEW DRUG APPLICATIONS

3.1 INTRODUCTION TO THE U.S. DRUG APPROVAL PROCESS

3.2 INVESTIGATIONAL NEW DRUG APPLICATIONS

3.3 FULL NEW DRUG APPLICATIONS

3.4 SECTION 505(B)(2) APPLICATIONS

3.5 ABBREVIATED NEW DRUG APPLICATIONS (ANDAS)

4 FROM CONCEPT TO THE CLINICS: DEVELOPMENT OF CANCER THERAPEUTICS

4.1 INTRODUCTION

4.2 BEVACIZUMAB (AVASTIN)

4.3 PROTEASOME INHIBITORS

4.4 INTERFERON-Α

4.5 ONCOLYTIC VIRUS

5 DEVELOPMENT OF COUNTERMEASURES FOR BIOTERRORISM IN THE UNITED STATES

5.1 INTRODUCTION

5.2 INCENTIVES TO CONDUCT RESEARCH AND DEVELOPMENT (R&D) OF BIOTERRORISM COUNTERMEASURES

5.3 ADVANCED DEVELOPMENT, PRODUCT PROCUREMENT, AND MARKETING

5.4 REGULATORY RESTRICTIONS AFFECTING RESEARCH

5.5 CONCLUSION

ACKNOWLEDGMENT

6 DEVELOPMENT AND APPLICATION OF CONFORMATION-SELECTIVE INTEGRIN ANTIBODIES

6.1 INTRODUCTION

6.2 INTEGRIN STRUCTURE OVERVIEW

6.3 CONFORMATION-SELECTIVE ANTI-INTEGRIN MABS

6.4 CONFORMATIONALLY SELECTIVE MAB AS THERAPEUTICS: PROGRESS AND PROSPECTS

6.5 APPENDIX

7 PAIN MANAGEMENT MARKET OVERVIEW

7.1 INTRODUCTION

7.2 ANALGESIC USE

7.3 ANALGESIC EFFICACY

7.4 SELECTION OF ANALGESICS

7.5 DRUG DEVELOPMENT

8 ANTIVIRAL MARKET OVERVIEW

8.1 INTRODUCTION

8.2 ANTIVIRAL DRUGS FOR HUMAN IMMUNODEFICIENCY VIRUS INFECTIONS

8.3 ANTIVIRALS FOR HEPATITIS B AND C INFECTIONS

8.4 ANTIVIRALS FOR HUMAN HERPESVIRUS INFECTIONS

8.5 ANTIVIRALS FOR HUMAN PAPILLOMAVIRUS (HPV)

8.6 ANTIVIRALS FOR POXVIRUS INFECTIONS

8.7 ANTIVIRALS AGAINST INFLUENZA VIRUS INFECTIONS

8.8 CONCLUSION

PART II: METHODS AND TECHNIQUES IN DRUG DISCOVERY AND DEVELOPMENT

9 HIGH-THROUGHPUT SCREENING FOR SMALL-MOLECULE DRUG DISCOVERY

9.1 INTRODUCTION

9.2 TYPES OF HTS ASSAYS

9.3 ASSAY DEVELOPMENT AND VALIDATION FOR HTS

9.4 SCREEN DESIGN, PROCESS, AND INSTRUMENTATION

9.5 DATA HANDLING AND ANALYSIS

9.6 EMERGING TRENDS

ACKNOWLEDGMENTS

10 MASS SPECTROMETRY

10.1 INTRODUCTION

10.2 INSTRUMENTATION

10.3 SAMPLE PREPARATION

10.4 ROLE OF PROTEOMICS IN PHARMACEUTICAL ANALYSIS

10.5 DRUG METABOLITES

10.6 EMERGING FIELDS FOR DRUG ANALYSIS BY MS

10.7 CONCLUSIONS AND FUTURE OUTLOOK

11 MOLECULAR SCREENING FOR THERAPEUTIC AGENTS

11.1 INTRODUCTION

11.2 MOLECULAR SCREENING

11.3 TARGET DISCOVERY AND HIT VALIDATION FOR NCEs

11.4 DATA MANAGEMENT

11.5 CONCLUSION

ACKNOWLEDGMENTS

12 ACCELERATOR MASS SPECTROMETRY AND POSITRON EMISSION TOMOGRAPHY IN HUMAN MICRODOSING

12.1 INTRODUCTION

12.2 DEFINITIONS

12.3 HUMAN MICRODOSING

12.4 ACCELERATOR MASS SPECTROMETRY

12.5 POSITRON EMISSION TOMOGRAPHY

12.6 EXAMPLES OF HUMAN MICRODOSING

12.7 CONCLUSIONS

13 DEVELOPMENT OF ANTIMICROBIAL PEPTIDES AS THERAPEUTIC AGENTS

13.1 INTRODUCTION

13.2 NATIVE AMPHIPATHIC α-HELICAL ANTIMICROBIAL PEPTIDES

13.3 MECHANISM OF ACTION

13.4 STRUCTURE-ACTIVITY RELATIONSHIPS IN AMPHIPATHIC α-HELICAL ANTIMICROBIAL PEPTIDES

13.5 THERAPEUTIC DEVELOPMENT (PRECLINICAL AND CLINICAL STUDIES)

ACKNOWLEDGMENT

14 ANTIBODIES FOR HUMAN DISEASES

14.1 PRINCIPLE OF MONOCLONAL ANTIBODY THERAPY

14.2 HISTORY OF ANTIBODY THERAPEUTICS

14.3 ANTIBODY TECHNOLOGY

14.4 ANTIBODY ENGINEERING

14.5 ANTIBODIES IN CLINICS

16.6 MONOCLONAL ANTIBODIES UNDER CLINICAL DEVELOPMENT

15 COMBINATORIAL COMPOUNDS AND DRUG DISCOVERY

15.1 INTRODUCTION

15.2 CHEMICAL DIVERSITY

15.3. PRINCIPLES OF COMBINATORIAL CHEMISTRY

15.4 SOLID-PHASE SYNTHESIS

15.5 ENCODING

15.6. FUTURE OF COMBINATORIAL CHEMISTRY AND DRUG DISCOVERY

15.7 KEY POINTS

15.8 REVIEW QUESTIONS

16 LOCOREGIONAL CHEMORADIOTHERAPY OF CANCER USING HYDROGEL

16.1 INTRODUCTION

16.2 MATERIALS AND METHODS

16.3 RESULTS

16.4 DISCUSSION

ACKNOWLEDGMENTS

17 RNAi-MEDIATED THERAPEUTICS

17.1 INTRODUCTION

17.2 MECHANISMS OF GENE SILENCING

17.3 OFF-TARGET AND UNSPECIFIC EFFECTS

17.4 CHEMICALLY SYNTHESIZED SMALL INTERFERING RNA (siRNA)

17.5 EXPRESSION OF SHORT HAIRPIN RNA (shRNA) CONSTRUCTS

17.6 APPLICATIONS

ACKNOWLEDGMENTS

18 CRYSTALLOGRAPHY

18.1 INTRODUCTION

18.2 PRACTICAL MATTERS

18.3 BRIEF HIGHLIGHTS OF NECESSARY THEORY

18.4 DETAILED APPLICATIONS AND CASE STUDIES

19 PEGYLATION

19.1 PEGYLATION

19.2 PEGYLATION OF THERAPEUTIC AGENTS

19.3 POLYETHYLENE GLYCOL

19.4 ACTIVE SITE PROTECTION IN PEGYLATION

19.5 IDENTIFICATION OF PEGYLATION SITE

19.6 SITE-SPECIFIC PEGYLATION

19.7 CHEMISTRY OF PEGYLATION

19.8 LYOPHILIZATION OF PEGYLATED PROTEINS

19.9 CHARACTERIZATION OF PEGYLATED PRODUCT

19.10 BIOPEGYLATION

19.11 PEGYLATION IN NOVEL DRUG DELIVERY SYSTEMS

19.12 RESEARCH UNDER PROGRESS

20 GOLD STANDARD ANIMAL MODELS

20.1 INTRODUCTION: IMPORTANCE OF AND DANGERS IN USING ANIMAL MODELS FOR DRUG DEVELOPMENT

20.2 IMMUNOMODULATION

20.3 RELAPSING REMITTING EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

20.4 BLOCKADE OF T-CELL CO-STIMULATION USING ANTI-B7 MONOCLONAL ANTIBODIES IN R-EAE

20.5 BLOCKADE OF T-CELL CO-STIMULATION WITH CTLA4-IG (ABATACEPT AND BELATSCEPT)

20.6 THEILER’S MURINE ENCEPHALOMYELITIS VIRUS–INDUCED DEMYELINATING DISEASE

20.7 BLOCKADE OF CD154/CD40 SIGNALING IN R-EAE AND TMEV-IDD

20.8 BLOCKADE OF CD154/CD40 SIGNALING IN NONOBESE DIABETIC MICE (NOD)

20.9 ANTI-CD3 (TCR) IN EAE AND NOD

20.10 A SUPERAGONISTIC ANTI-CD28 MONOCLONAL ANTIBODY (VISILIZUMAB) IN LEWIS RAT EAE AND ADJUVANT ARTHRITIS ANIMAL MODEL

20.11 T-CELL MIGRATION BLOCKADE WITH ANTI-VLA-4 (NATALIZUMAB)

20.12 MODELS OF CARDIOVASCULAR DISEASE AND METABOLISM

20.13 KNOCKOUT AND TRANSGENIC ANIMALS AS ANIMAL MODELS OF HUMAN DISEASE

20.14 ARE ANIMAL MODELS USEFUL?

21 DISCOVERY OF VACCINE ADJUVANTS

21.1 INTRODUCTION

21.2 HISTORY OF ADJUVANT DISCOVERY

21.3 REQUIREMENTS OF ADJUVANTS

21.4 IMMUNOLOGICAL REQUIREMENTS OF VACCINES

21.5 ACTIVATION OF INNATE AND ADAPTIVE IMMUNITY BY ADJUVANTS: STRANGER AND DANGER MODELS

21.6 TYPES OF ADJUVANTS

21.7 IMMUNOSTIMULATORY ADJUVANTS

21.8 FUTURE OF ADJUVANT RESEARCH AND DEVELOPMENT

22 ORAL DELIVERY OF MACROMOLECULES FOR THE DEVELOPMENT OF THERAPEUTIC AGENTS

22.1 INTRODUCTION

22.2 FACTORS AFFECTING ORAL PROTEIN ABSORPTION

22.3 APPROACHES FOR ORAL DELIVERY

22.4 FUTURE WORK

22.5 CONCLUDING REMARKS

23 AEROSOL DRUG DELIVERY TO THE LUNGS

23.1 INTRODUCTION

23.2 RESPIRATORY TRACT DEPOSITION OF INHALED PARTICLES

23.3 PARTICLE SIZING

23.4 AEROSOL DELIVERY DEVICES

23.5. CONCLUDING REMARKS

24 RESISTANCE TO ANTIPLATELET THERAPY

24.1 INTRODUCTION

24.2 ROLE OF PLATELETS IN THROMBOTIC EVENTS

24.3 RATIONALE FOR ANTIPLATELET THERAPY

24.4 RESISTANCE TO ANTIPLATELET DRUGS

24.5 CLOPIDOGREL RESISTANCE

24.6 PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES

24.7 LABORATORY EVALUATION OF CLOPIDOGREL RESPONSIVENESS

24.8 CLOPIDOGREL RESPONSIVENESS AND TIME OF TREATMENT

24.9 CLOPIDOGREL RESPONSIVENESS AND EFFECT OF DOSE

24.10 RELATION OF CLOPIDOGREL NONRESPONSIVENESS TO ADVERSE CLINICAL EVENTS

24.11 MECHANISM OF CLOPIDOGREL RESISTANCE

24.12 MANAGEMENT OF CLOPIDOGREL RESISTANCE

CONCLUSIONS

24.13 ASPIRIN RESISTANCE

24.14 CONCLUSIONS

25 ANTIBIOTIC DEVELOPMENT

25.1 BIRTH OF THE ANTIBIOTIC ERA

25.2 WHY DO WE NEED NEW ANTIBIOTICS?

25.3 ANTIMICROBIAL DISCOVERY

25.4 THE SCREEN DOOR

25.5 PHARMACOKINETICS

25.6 PHARMACODYNAMICS

25.7 PHARMACOGENETICS

25.8 DEVELOPMENT AS A CHANGING NEED

PART III: THERAPEUTICS TOPICS

26 ANTIMICROBIAL RESISTANCE IN BIOFILMS: A STICKY SITUATION

26.1 BIOFILMS—A CLINICAL AND INDUSTRIAL PERSPECTIVE

26.2 ANTIMICROBIAL RESISTANCE IN BIOFILMS DIFFERS FROM THAT IN PLANKTONIC CULTURE

26.3 RESTRICTIVE BARRIER TO ANTIMICROBIALS

26.4 A GRADIENT OF GROWTH

26.5 PHYSIOLOGICALLY DISTINCT POPULATION

26.6 CONTRIBUTIONS OF THE PERSISTERS

26.7 NOVEL APPROACHES TO THE “STICKY PROBLEM”

26.8 CONCLUDING REMARKS

ACKNOWLEDGMENT

27 DROTRECOGIN ALFA ACTIVATED (RECOMBINANT HUMAN ACTIVATED PROTEIN C, XIGRIS)

27.1 INTRODUCTION

27.2 EPIDEMIOLOGY OF SEPSIS

27.3 PATHOPHYSIOLOGY OF SEPSIS

27.4 MANAGEMENT OF SEVERE SEPSIS

27.5 INTENSIVE INSULIN THERAPY

27.6 USE OF STEROIDS

27.7 ENDOTOXIN-NEUTRALIZING PREPARATIONS

27.8 ANTI-INFLAMMATORY/IMMUNOMODULATING AGENTS

27.9 ANTICOAGULANTS

27.10 ACTIVATED PROTEIN C

27.11 CONCLUSION

28 ANTI-INFLAMMATORY THERAPEUTICS

28.1 INTRODUCTION

28.2 IMMUNOBIOLOGY OF INFLAMMATION

28.3 MOLECULAR TARGETS OF ANTI-INFLAMMATORY HERAPEUTICS

28.4 EXPERIMENTAL METHODS FOR IDENTIFYING ANTI-INFLAMMATORIES

28.5 PIPELINE NOVEL ANTI-INFLAMMATORIES

28.6 NATURAL ANTI-INFLAMMATORY COMPOUNDS IN FOODS AS DIETARY THERAPEUTICS

28.7 FUTURE PROSPECTS

ACKNOWLEDGMENT

29 ANTI-INFLAMMATORY/ANALGESICS: AN IN-DEPTH LOOK AT P38 MAP KINASES

29.1 INTRODUCTION

29.2 P38 MAP KINASE FAMILY

29.3 EFFECTS MEDIATED BY P38 MAP KINASES

29.4 P38 MAPK AS A THERAPEUTIC TARGET

29.5 CONCLUDING REMARKS

Abbreviatizons

ACKNOWLEDGMENTS

30 CARDIOVASCULAR DISEASE: IN-DEPTH LOOK

30.1 INTRODUCTION

30.3 HEART FAILURE

30.4 ARRHYTHMIAS

30.5 CONCLUSION

31 EZETIMIBE AND CHOLESTEROL ABSORPTION

31.1 INTRODUCTION

31.2 INTESTINAL CHOLESTEROL ABSORPTION

31.3 PHARMACOLOGICAL PRINCIPLE OF CHOLESTEROL ABSORPTION INHIBITION BEFORE EZETIMIBE

31.4 DISCOVERY AND DEVELOPMENT OF EZETIMIBE

31.5 EZETIMIBE—A PORTRAIT

31.6 NPC1L1—THE REAL TARGET OF EZETIMIBE?

31.7 DRUGS OF THE FUTURE

31.8 CONCLUSIONS

32 CARDIOLOGY—IN-DEPTH LOOK: KINASES AS THERAPEUTIC TARGETS IN THE HEART

32.1 KINASES AS PHARMACOLOGICAL TARGETS IN THE HEART—A NEW ERA IN MOLECULAR CARDIOVASCULAR THERAPEUTICS

32.2 PROTEIN KINASE-MEDIATED SIGNALING IN CARDIAC PATHOLOGY: A NOVEL THERAPEUTIC TARGET?

32.3 STRUCTURAL AND FUNCTIONAL BIOLOGY OF PROTEIN KINASES IN THE HEART AND VASCULATURE: MODULATION IN CARDIOVASCULAR DISEASE

32.4 OBSTACLES AND OPPORTUNITIES IN THE CLINICAL DEVELOPMENT OF TARGETED THERAPEUTICS

32.5 CONCLUSIONS AND FUTURE PERSPECTIVES

33 STATINS IN THE REDUCTION OF CARDIOVASCULAR EVENTS

33.1 DISCOVERY OF STATINS

33.2 STATINS: BIOCHEMISTRY AND MECHANISMS OF ACTION

33.3 STATINS: EXPERIMENTAL AND CLINICAL STUDIES

33.4 STATINS: NEW ISSUES

33.5 WITHDRAWAL PHENOMENON

33.6 OTHER DISEASE STATES

33.7 CONCLUSION

34 CARDIOLOGY—IN-DEPTH LOOK: ADVANCES IN ANTIPLATELET THERAPY

34.1 PLATELET PHYSIOLOGY IN CARDIOVASCULAR DISEASE

34.2 THERAPEUTIC TARGETS FOR PLATELET INHIBITION

34.3 THROMBOXANE A2 (TXA2) INHIBITORS

34.4 ADP RECEPTOR ANTAGONISTS: THIENOPYRIDINES

34.5 GLYCOPROTEIN IIB/IIIA INHIBITORS

34.6 NOVEL ADP RECEPTOR ANTAGONISTS

34.7 OTHER ANTIPLATELET AGENTS

34.8 EFFICACY VS. SAFETY

34.9 SPECIAL CONDITIONS

34.10 MONITORING PLATELET FUNCTION AND ANTITHROMBOTIC THERAPY

34.11 CONCLUSIONS AND FUTURE PERSPECTIVES

35 GASTROINTESTINAL DISORDERS: A FOCUS ON ACID-SUPPRESSIVE AGENTS

35.1 INTRODUCTION

35.2 NEED FOR ACID-SUPPRESSIVE AGENTS: AN OVERVIEW OF ACID-RELATED DISEASES

35.3 FROM BENCH TO BEDSIDE: THE RISE OF HISTAMINE-2 RECEPTOR ANTAGONISTS (H2RAS)

35.4 UNMET NEEDS IN ACID SUPPRESSION: THE DEVELOPMENT OF PROTON PUMP INHIBITORS

35.5 NEXT STEPS IN THE USE AND DEVELOPMENT OF ACID-SUPPRESSIVE AGENTS

35.6 CONCLUSION

36 PHARMACOLOGY OF VASOPRESSIN AND THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

36.1 ADH ANTAGONISTS

36.2 RENIN–ANGIOTENSIN SYSTEM

36.3 ACE INHIBITORS

36.4 ANGIOTENSIN II RECEPTOR BLOCKERS

36.5 RENIN INHIBITORS

37 NEW DRUGS AND NUTRACEUTICALS IN THE TREATMENT OF OSTEOARTHRITIS

37.1 INTRODUCTION

37.2 OA PATHOPHYSIOLOGY: IDENTIFICATION OF NEW BIOCHEMICAL TARGETS

37.3 REQUIREMENT FOR REGISTRATION OF DRUGS IN OA

37.4 WHAT’S A NUTRACEUTICALS?

37.5 GLUCOSAMINE SULFATE (GS) AND CHONDROITIN SULFATE (CS)

37.6 HYALURONIC ACID

37.7 LIPIDS

37.8 VITAMINS AND MINERALS

37.9 PHYTOCHEMICALS AND PLANT EXTRACTS

37.10 METHYLSULFONYLMETHANE

37.11 MISCELLANEOUS

37.12 CONCLUDING REMARKS

38 DEVELOPMENT OF ANTICYTOKINE AGENTS FOR RHEUMATOID ARTHRITIS

38.1 INTRODUCTION

38.2 CASE STUDY: ANTI-TNF AGENTS

38.3 NOVEL THERAPIES TARGETING CYTOKINES

38.4 INTERLEUKIN-15

38.5 INTERLEUKIN-18

38.6 INTERLEUKIN-6

38.7 INTERLEUKIN-23/INTERLEUKIN-17 PATHWAY

38.8 OTHER THERAPEUTIC STRATEGIES

39 OVERVIEW OF CNS NEUROPHARMACEUTICALS

39.1 INTRODUCTION

39.2 NEUROPROTECTION AND CNS DISORDERS

39.3 CRUCIAL ROLE OF THE BLOOD–BRAIN BARRIER (BBB)

39.4 DESIGN OF ANTISENSE NEUROPHARMACEUTICALS

39.5 NEUROTROPHIC FACTORS—A PROMISING THERAPEUTIC STRATEGY

39.6 NEUROTRANSMITTER SYSTEMS AS THERAPEUTIC TARGETS

39.7 NEW TARGETS AND APPROACHES FOR CNS THERAPY

39.8 DEVELOPMENT OF NEUROPHARMACEUTICALS FOR ALZHEIMER’S DISEASE

40 THINKING OUTSIDE THE BOX IN ALZHEIMER DISEASE TREATMENT

40.1 INTRODUCTION

40.2 AMYLOID-β

40.3 OXIDATIVE STRESS

40.4 LIPID METABOLISM

40.5 INFLAMMATION

40.6 HORMONAL CHANGES WITH AGE

40.7 CELL CYCLE

40.8 PHOSPHORYLATED TAU

40.9 EXCITOTOXICITY

40.10 CHOLINERGIC DEFICITS

40.11 CONCLUSION

ACKNOWLEDGMENTS

41 NEUROTROPHIC FACTORS AS NOVEL THERAPEUTIC TARGETS

41.1 INTRODUCTION

41.2 NEUROTROPHINS AND THEIR RECEPTORS

41.3 NEUROTROPHIC PROTEINS AS THERAPEUTIC AGENTS

41.4 FUNCTIONAL MIMETICS OF NEUROTROPHINS ACTING AT TRK RECEPTORS

41.5 TARGETING THE P75NTR AS A STRATEGY TO PROMOTE NEURON SURVIVAL

41.6 SMALL-MOLECULE NONPEPTIDE NEUROTROPHIN RECEPTOR AGONISTS

41.7 BDNF–SEROTONIN INTERACTIONS

41.8 NEUROIMMUNOPHILINS

41.9 INHIBITION OF INTRACELLULAR SIGNALING PATHWAYS

41.10 CONCLUDING REMARKS

42 ONCOLOGY

42.1 INTRODUCTION

42.2 NATURAL PRODUCTS

42.3 COMBINATORIAL CHEMISTRY

42.4 HIGH-THROUGHPUT SCREENING

42.5 BIOINFORMATICS

42.6 GENOMICS AND PROTEOMICS

42.7 CURRENT CLASSES OF ANTICANCER AGENTS

42.8 DRUG FORMULATION AND DELIVERY SYSTEMS

42.9 IN VITRO CELL LINES

42.10 NCI 60 CANCER CELL LINES

42.11 IN VIVO STUDIES

42.12 CLINICAL TRIALS

42.3 FUTURE DIRECTIONS

42.14 CONCLUSION

43 TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA

43.1 IMATINIB

43.2 SECOND-GENERATION TYROSINE KINASE INHIBITORS

43.3 THIRD-GENERATION TYROSINE KINASE INHIBITORS

43.4 SUMMARY

44 AROMATASE INHIBITORS FOR BREAST CANCER

44.1 INTRODUCTION

44.2 BIOCHEMISTRY

44.3 CLASSIFICATION

44.4 CLINICAL PHARMACOLOGY

44.5 DESCRIPTION OF AI IN BRIEF

44.6 AROMATASE INHIBITORS IN POSTMENOPAUSAL PATIENTS

44.7 CONCLUSION ON AIS IN BREAST CANCER THERAPY

44.8 LACK OF CROSS RESISTANCE

44.9 SIDE EFFECTS

44.10 SKELETAL EVENTS

44.11 TREATMENT OF SKELETAL-RELATED EVENTS WITH AIS

44.12 CONTRAINDICATION OF AI

44.13 DRUG INTERACTIONS

44.14 NUTRITION AND HERB INTERACTIONS

44.15 PREGNANCY IMPLICATIONS

44.16 FUTURE DIRECTIONS

45 EVOLUTION OF SELECTIVE ESTROGEN AND ANDROGEN RECEPTOR MODULATORS: STATUS OF CURRENT THERAPY AND NEW DRUG DEVELOPMENT

45.1 BACKGROUND

45.2 CLINICAL TARGETS OF SERMS AND SARMS

45.3 AGENTS UNDER DEVELOPMENT AND THEIR POTENTIAL CLINICAL TARGETS

45.4 FUTURE OF SERMS AND SARMS

45.5 CONCLUSIONS

46 IN-DEPTH LOOK: ANTI-TNF-α THERAPIES

46.1. INTRODUCTION

46.2 INFLAMMATION AND CANCER—THE TNF-α LINK

46.3 ANTI-TNF-α THERAPY FOR CANCER

46.4 CONCLUSIONS AND FUTURE PROSPECTS

ACKNOWLEDGMENTS

47 DEVELOPMENT OF THERAPEUTIC AGENTS: THE MATERNAL–FETAL PERSPECTIVE

47.1 INTRODUCTION

47.2 PLACENTAL PHYSIOLOGY

47.3 PHYSIOLOGICAL CHANGES IN PREGNANCY

47.4 EXPERIMENTAL TECHNIQUES

47.5 DRUG DEVELOPMENT PROCESS

47.6 SELECTED CASES OF DRUGS DESIGNED FOR USE PARTICULARLY DURING PREGNANCY

47.7 FUTURE DIRECTION: ORPHAN DRUG STATUS

47.8 CONCLUSION

48 HISTORY OF ANTIPSYCHOTIC DRUG DEVELOPMENT

48.1 HISTORICAL PERSPECTIVE

48.2 DEVELOPMENT OF PHARMACOTHERAPY OF SCHIZOPHRENIA

48.3 NEUROPHARMACOLOGY OF ANTIPSYCHOTIC DRUGS

48.4 ADVERSE EFFECTS OF ANTIPSYCHOTICS

48.5 CURRENT DEVELOPMENTS AND FUTURE PROSPECTS

48.6 CONCLUSION

49 RADIOPHARMACEUTICALS AND MEDICAL IMAGING: DEVELOPMENT OF RADIOIMMUMOCONJUGATES FOR RADIOIMMUNOIMAGING AND RADIOIMMUNOTHERAPY OF MALIGNANT DISEASES

49.1 INTRODUCTION

49.2 RADIONUCLIDES

49.3 ANTIBODY AND ANTIBODY FRAGMENTS

49.4 ANTIBODY LABELING

49.5 PRETARGETING

49.6 RII AND RIT OF MALIGNANT DISEASES

49.7 OUTLOOK AND PERSPECTIVES

50 THERAPEUTIC DRUG DEVELOPMENT FOR KIDNEY DISEASES

50.1 INTRODUCTION

50.2 DRUG DEVELOPMENT FOR ACUTE KIDNEY INJURY

50.3 DRUG DEVELOPMENT FOR POLYCYSTIC KIDNEY DISEASE

50.4 THERAPEUTIC AGENTS TO SLOW THE PROGRESSION OF CHRONIC KIDNEY DISEASE

50.5 TREATING THE COMPLICATIONS OF CKD: VITAMIN D ANALOGS

50.6 TREATING THE COMPLICATIONS OF CKD: CALCIMIMETICS

50.7 SUMMARY

51 TARGETING CHEMOKINES AND ANGIOGENESIS IN RHEUMATOID ARTHRITIS

51.1 INTRODUCTION

51.2 CHEMOKINES AND CHEMOKINE RECEPTORS IN ARTHRITIS

51.3 ANGIOGENESIS IN ARTHRITIS

51.4 CHEMOKINES AND CHEMOKINE RECEPTORS IN ANGIOGENESIS

51.5 TARGETING OF CHEMOKINES AND CHEMOKINE RECEPTORS

51.6 TARGETING OF ANGIOGENESIS

51.7 SUMMARY

52 DEVELOPMENT OF THERAPEUTIC AGENTS: METHODS AND APPROACHES IN THE DEVELOPMENT OF VACCINES AGAINST PROTOZOAN PARASITES

52.1 INTRODUCTION

52.2 PARASITE LIFE CYCLES AND VECTORS

52.3 HOST IMMUNITY AND PARASITE ANTIGENIC VARIATION

52.4 MULTIPLE STRATEGIES, DIFFERENT OUTCOMES

52.5 ENTAMOEBA HISTOLYTICA: THE IDEAL PARASITE?

52.6 IMMUNITY TO E. HISTOLYTICA

52.7 PATHOGENESIS OF AMEBIASIS

52.8 PREVALENCE OF DISEASE AND TARGET POPULATION

52.9 VACCINE DESIGN

52.10 CONTINUING RESEARCH EFFORTS

53 TOXICOLOGY

53.1 INTRODUCTION

53.2 BASIC PRINCIPLES

53.3 DOSE–EFFECT AND DOSE–RESPONSE RELATIONSHIPS

53.4 CHEMICAL INTERACTIONS

53.5 SAFETY ASSESSMENT

53.6 CLASSIFICATION AND LABELING

53.7 TOXICITY TESTING

53.8 SHORT-TERM (ACUTE) TESTS

53.9 MEDIUM-TERM (SUBCHRONIC) TESTS

53.10 LONG-TERM (CHRONIC) TESTS

53.11 SCREENING FOR MUTAGENICITY AND POSSIBLE CARCINOGENICITY—THE AMES TEST

53.12 OTHER IN VITRO TESTS

53.13 TIERED TOXICITY TESTING

53.14 ESTABLISHING SAFE EXPOSURE LEVELS

53.15 TOXICOKINETICS

53.16 INTERACTION OF GENES AND TOXICITY

53.17 ECOTOXICOLOGY

53.18 ECOSYSTEMS

53.19 ECOSYSTEM HEALTH AND TOXICITY

53.20 ECOSYSTEM PATHOLOGY

53.21 ECOSYSTEM HEALTH AND HUMAN HEALTH

53.22 ANTIBIOTIC RESISTANCE AND AGRICULTURAL PRACTICE

53.23 ECOSYSTEM RESTORATION

53.24 PREVENTION OF ECOSYSTEM DAMAGE

54 DEVELOPMENT OF PHOSPHODIESTERASE 4 INHIBITORS FOR ALLERGIC AND NONALLERGIC INFLAMMATORY DISEASES OF THE AIRWAYS

54.1 INTRODUCTION

54.2 GLUCOCORTICOIDS AND THE TREATMENT OF ASTHMA AND COPD

54.3 PHOSPHODIESTERASE INHIBITORS

54.4 STANDARDIZED NOMENCLATURE

54.5 ROLIPRAM: A PROTOTYPE PDE4 INHIBITOR

54.6 PDE4 INHIBITORS BEYOND ROLIPRAM

54.7 PHOSPHODIESTERASE 4

54.8 ANTI-INFLAMMATORY EFFECTS OF PDE4 INHIBITORS IN VIVO

54.9 CLINICAL PHARMACOLOGY OF PDE4 INHIBITORS

54.10 OPTIMIZING THE EFFICACY OF PDE4 INHIBITORS

54.11 CONCLUDING REMARKS

ACKNOWLEDGMENTS

Index

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Development of therapeutic agents handbook / [edited by] Shayne Cox Gad.

p. cm.

 ISBN 978-0-471-21385-7 (cloth)

 1. Drugs–Research–Handbooks, manuals, etc. 2. Drugs–Design–Handbooks, manuals, etc. 3. Pharmaceutical chemistry–Handbooks, manuals, etc. 4. Drug development–Handbooks, manuals, etc. I. Gad, Shayne C., 1948-

 RM301.25.D47 2011

 615'.19–dc22

ePDF ISBN: 978-1-118-07710-8

ePub ISBN: 978-1-118-07711-5

PREFACE

The Development of Therapeutic Agents Handbook represents a collective attempt to present the broad range of areas of therapeutic needs and classes of potential new therapeutic moieties, assembled in the context of the Wiley pharmaceutical development handbook series, which covers the entire process of pharmaceutical discovery and development. This volume, in fact, is the eighth in this series, which, in its entirety, is intended to be comprehensive in its coverage.

This volume is unique in that it seeks to cover the entire range of significant therapeutic areas and their underlying causes and then proceeds to overview specific classes of agents over a wide range of disease claims. The 54 chapters cover introductory and regulatory issues, disease mechanisms, and potential thera­peutic targets, as well as new classes of therapy in development.

This book would not have occurred without the dedicated efforts of Wiley’s managing editors, Monika Laszkowska and Michael Leventhal. Their persistence in the recruitment of contributors and ensuring follow-through was essential.

While like all textbooks, this one presents the state of the practice and field at a specific period in time. I hope that it will become a frequently consulted friend.

SHAYNE COX GAD

CONTRIBUTORS

Jame Abraham

Breast Cancer Program

Section of Hematology/Oncology

West Virginia University School of Medicine

Morgantown, West Virginia

Mazen S. Abu-Fadel

Section of Cardiovascular Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma

Muhammad Mansoor Alam

University of Michigan School of Medicine

Ann Arbor, Michigan

Charles F. Albright

Bristol-Myers Squibb

Neuroscience Discovery

Research and Development

Wallingford, Connecticut

Anita Arora

Center for Clinical Studies

Houston, Texas

Nathan S. Astrof

Immune Disease Institute

Children’s Hospital Boston

Harvard Medical School

Boston, MA

and

Laboratory of Nanomedicine

Dept. of Cell Research and Immunology

George S. Wise Faculty of Life Sciences

Tel Aviv University

Tel Aviv, Israel

Ali Azhdarinia

Division of Diagnostic Imaging

The University of Texas

M.D. Anderson Cancer Center

Houston, Texas

Ankur Bansal

UGC Centre of Advanced Studies

University Institute of Pharmaceutical Sciences

Panjab University

Chandigarh, India

Robert L. Bettiker

Temple University School of Medicine

Philadelphia, Pennsylvania

James C. Bigelow

Department of Biomedical and Pharmaceutical Sciences

College of Pharmacy

Idaho State University

Pocatello, Idaho

F. Garcia Bournissen

Hospital for Sick Children

Toronto, Ontario, Canada

Elizabeth J. Brant

Renal Division

Brigham and Women’s Hospital

Bostons, Massachusetts

Kelly L. Brown

Department of Rheumatology and Inflammation Research

Göteborg University

Göteborg, Sweden

Jerry Bryant

Division of Diagnostic Imaging

The University of Texas

M.D. Anderson Cancer Center

Houston, Texas

Christopher D. Buckley

Rheumatology Research Group

MRC Centre for Immune Regulation

University of Birmingham

Birmingham, United Kingdom

Gemma Casadesus

Department of Neuroscience

Case Western Reserve University

Cleveland, Ohio

Carol Castaneda

Indiana University Northwest

Gary, Indiana

Rudy J. Castellani

Department of Pathology

University of Maryland

Baltimore, Maryland

Kris Chadee

Faculty of Medicine

Department of Microbiology and Infectious Diseases

University of Calgary

Calgary, Alberta, Canada

Marion M. Chan

Department of Microbiology and Immunology

Temple University School of Medicine