Analytical techniques for clinical chemistry methods and applications

ANALYTICAL
TECHNIQUES FOR
CLINICAL CHEMISTRY


ANALYTICAL
TECHNIQUES FOR
CLINICAL CHEMISTRY
METHODS AND APPLICATIONS

Edited by

Sergio Caroli
National Institute of Health, Viale Regina Elena, Rome, Italy

Gyula Za´ray
Eo¨tvo¨s Lora´nd University, Budapest, Hungary


Copyright Ó 2012 by John Wiley & Sons, Inc. All rights reserved
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Library of Congress Cataloging-in-Publication Data:
Analytical techniques for clinical chemistry : methods and applications /
edited by Sergio Caroli, Gyula Za´ray.
p. cm.
Includes index.
ISBN 978-0-470-44527-3 (cloth)
1. Clinical chemistry–Analysis. I. Caroli, Sergio, 1943- II. Za´ray, Gyula.
RB40.A53 2012
616.07’9–dc23
2011043320
Printed in the United States of America
ISBN: 9780470445273
10 9 8 7 6 5 4 3 2 1


In memory of Karoly Zimmer, our beloved friend Karcsi, who always stimulated us to
do well what we had to do, taught us that work can be a source of real fun, and lives

forever in our hearts.
Sergio Caroli and Gyula Z
aray


CONTENTS

FOREWORD

xxiii

PREFACE

xxv

CONTRIBUTORS

xxvii

PART I Exploring Fundamentals
1. Good Clinical Practice Principles: Legal Background
and Applicability
Umberto Filibeck, Angela Del Vecchio, and Fabrizio Galliccia
Summary

1

3
3

1.1. Introduction

4

1.2. Good Clinical Practice
1.2.1. ICH E6: Guidelines for Good Clinical Practice
1.2.2. WHO Guidelines for Good Clinical Practice
for Trials on Pharmaceutical Products
1.2.3. WHO Handbook for Good Clinical Research
Practice Guidance for Implementation
1.2.4. WHO Good Clinical Laboratory Practice

4
4

7
7

1.3. Good Clinical Practice: Legal Background in the European Union

8

1.4. Good Clinical Practice: Applicability in the European Union
1.4.1. EU 2007 Conference on the Implementation and
Applicability in the European Union of Legislation on
Clinical Trials of Medical Products
1.4.2. Directives 2001/20/EC, 2005/28/EC, and Good Clinical
Practice in Case of Noncommercial Clinical Trials

10

1.5. Good Clinical Practice and Bioequivalence Trials: GCP
Inspections and Laboratories
1.5.1. General Aspects
1.5.2. EMA Guidelines on Bioequivalence Studies
1.5.3. EMA Reflection Paper for Applicants Who Want
to Submit Bioequivalence Performed Outside the
European Union

7

10
11
13
13
14

15


viii

CONTENTS

1.5.4. Good Clinical Practice Bioequivalence Inspections
1.5.5. Good Clinical Practice Clinical Laboratory Inspections
1.5.6. Good Clinical Practice Inspections on Phase I Units
1.6. Good Clinical Practice for Clinical Trials with Advanced
Therapy Medicinal Product
1.7. Good Clinical Practice and Clinical Trials in Developing

Countries
1.7.1. The Increase of Clinical Trials in Developing
Countries
1.7.2. European Union Legislation and Clinical Trials
in Developing Countries
References
2. Clinical Chemistry and the Quest for Quality
Sergio Caroli
Summary

16
19
20
20
22
22
23
25
29
29

2.1. Introduction

30

2.2. Quality Today
2.2.1. General Aspects
2.2.2. Major Quality Systems and Their Scope

31

31
32

2.3. Conclusions

55

References
3. Uncertainty in Clinical Chemistry Measurements Including
Preanalytical Variables
Marit Sverresdotter Sylte, Tore Wentzel-Larsen, and Bjørn J. Bolann
Summary

55
59
59

3.1. Introduction

60

3.2. Analytical Uncertainty in Laboratory Results
3.2.1. General Aspects
3.2.2. Control Materials
3.2.3. Estimating Analytical Precision
3.2.4. Within-Run Precision (Repeatability)
3.2.5. Total Analytical Precision (Reproducibility)
3.2.6. Estimating Precision Using Duplicates

62

62
62
64
65
66
66

3.3. Trueness and Traceability
3.3.1. Basic Concepts

67
67


CONTENTS

3.3.2.
3.3.3.
3.3.4.
3.3.5.
3.3.6.
3.3.7.

Reference Methods and Materials
Estimating the Trueness
Factorizing the Patients’ Results
Changing Reagent Lot
Analytical Specificity
Method Validation

ix

69
70
70
71
72
73

3.4. Proficiency Testing
3.4.1. Background Information
3.4.2. Choice of EQA Schemes
3.4.3. Interpretation and Actions

74
74
75
76

3.5. Biological Variations and Quality Goals

77

3.6. Reference Intervals
3.6.1. Establishing Reference Intervals
3.6.2. Transferring Reference Intervals

80
80
83

3.7. Estimating Preanalytical Uncertainty
3.7.1. Setting the Stage
3.7.2. Preanalytical Variables
3.7.3. The Model for an Uncertainty Budget
3.7.4. Statistical Analysis
3.7.5. Assumptions and Modeling Details

83
83
86
88
89
90

3.8. Conclusions

92

References
4. The Role and Significance of Reference Values in the
Identification and Evaluation of Trace Elements from Diet
Pietro Apostoli and Maria Cristina Ricossa
Summary
4.1. Reference Values

93

97
97

97

4.2. Reference Values in Specific Groups of Population: The
Children Case

100

4.3. Trace Elements and Diet

106

4.4. Arsenic

108

4.5. Mercury

110

4.6. Lead

112

4.7. Chromium

114


x

CONTENTS

4.8. Cadmium

115

4.9. Conclusions

116

References

117

5. Sample Collection, Storage, and Pretreatment in Clinical Chemistry 127
Andrew Taylor
Summary

127

5.1. Introduction

128

5.2. Collection Procedures
5.2.1. Sample Types
5.2.2. Practical Issues

129
129

130

5.3. Storage

132

5.4. Pretreatment

133

5.5. Conclusions
References
6. Metal Toxicology in Clinical, Forensic, and Chemical Pathology
Jose A. Centeno, Todor I. Todorov, Gijsbert B. van der Voet,
and Florabel G. Mullick
Summary

136
137
139

139

6.1. Introduction

140

6.2. Biological Markers

140

6.3. Methodology for Trace Metal Ion Analysis in Clinical,
Forensic, and Chemical Pathology
6.3.1. Clinical Chemistry Implications
6.3.2. Forensic Toxicology Implications
6.3.3. Chemical Pathology Implications

141
141
143
143

6.4. Case Studies of Relevance to Research and Diagnosis on
Clinical Chemistry, Forensic Toxicology, and Chemical
Pathology
6.4.1. Case Study No. 1: Copper Levels in Placental
Tissues as a Biomarker for Menkes Disease
6.4.2. Case Study No. 2: Cd, Fe, Se, and Zn in Prostate
Tissue as Biomarkers for Prostate Disease
6.4.3. Case Study No. 3: Measurement of Dental
Implant Corrosion Products and Histological
Correlation in Periimplant Tissues

144
144
145

146

CONTENTS

6.4.4. Case Study No. 4: Skin Pigmentation after
Exposure to Topical Hg from Skin Ointment
6.4.5. Case Study No. 5: Analysis of U Isotope Ratios by
using ICP-MS for the Assessment of Natural U or
DU Exposures

xi

148

149

Disclaimer

152

References

152

PART II Selected Applications

157

7. Elemental Speciation in Clinical Sciences
Douglas M. Templeton
Summary

159
159

7.1. Introduction
7.1.1. General Aspects
7.1.2. Definitions
7.1.3. Levels of Speciation

159
159
160
161

7.2. Selected
7.2.1.
7.2.2.
7.2.3.

167
167
167
170

Elements
Background Concepts
Biological Speciation of Essential Elements
Biological Speciation of Toxic Elements

7.3. Conclusions
References

8. The Role of Analytical Chemistry in
the Safety of Drug Therapy
Sa´ndor Go¨ro¨g
Summary

172
173

179
179

8.1. Drug Quality and Analysis: Their Role in Drug Safety
8.1.1. Introductory Remarks
8.1.2. The Role of Pharmacopoeias in Assuring Drug Quality

180
180
181

8.2. Methodological Aspects
8.2.1. Historical Overview
8.2.2. Spectroscopic Techniques
8.2.3. Chromatography and Related Techniques
8.2.4. Hyphenated Techniques
8.2.5. Miscellaneous Methods

189
189
190
192

195
198

8.3. The Role of Analytical Chemistry in Drug Research,
Development, and Production

200


xii

CONTENTS

8.3.1.
8.3.2.
8.3.3.
8.3.4.

QC of Drugs
Drug Impurity Profiling
Drug Stability Issues
Contribution of Analytical Chemistry to
Drug Research
8.3.5. Chiral Issues
8.4. Future Trends
References
9. Analytical Techniques and Quality Control
of Pharmaceuticals
Fedele Manna, Francesca Rossi, and Rossella Fioravanti
Summary

200
202
214
215
223
227
227
245
245

9.1. Introduction

245

9.2. Sources of Impurities in Medicines

246

9.3. Validation of Analytical Methods
9.3.1. Specificity
9.3.2. Linearity
9.3.3. Precision
9.3.4. Trueness
9.3.5. Accuracy
9.3.6. Dosing Range
9.3.7. Quantification Limit

247
248

248
248
249
249
249
250

9.4. Analytical Approaches
9.4.1. General
9.4.2. TLC
9.4.3. HPLC
9.4.4. CE

250
250
251
251
253

9.5. Conclusions

253

References
10. Detection of Drugs in Biological Fluids for
Antidoping Control
Sabina Strano Rossi and Marcello Chiarotti
Summary

253

257
257

10.1. Introduction

257

10.2. Doping Control and Analytical Requirements

258


CONTENTS

xiii

10.3. Confirmation Techniques

262

10.4. Conclusions

264

References
11. The Applicability of Plasma-Based Techniques
to Biological Monitoring
Ilse Steffan and Goran Vujicic
Summary

264

269
269

11.1. Introduction

269

11.2. ICP as a Spectrochemical Source

271

11.3. Element Analysis in Environmental and
Biological Materials
11.3.1. General
11.3.2. Method Development
11.3.3. Reference Materials
11.3.4. Environmental Applications
11.3.5. Studies on Human Subjects
11.3.6. Studies on Animals
11.3.7. Studies on Drugs
11.3.8. Studies on Food

276
276
277
278
279

281
287
291
291

11.4. Conclusions

292

References
12. Atomic Spectrometric Techniques for the Analysis of
Clinical Samples
Pilar Bermejo Barrera, Antonio Moreda Pi~
neiro, and
Marı´a del Carmen Barciela Alonso
Summary

293

319

319

12.1. Introduction

320

12.2. Analytical Techniques
12.2.1. Atomic Absorption Spectrometry
12.2.2. Atomic Emission Spectrometry

12.2.3. Atomic Fluorescence Spectrometry
12.2.4. Inductively Coupled Plasma Mass Spectrometry
12.2.5. State of the Art

320
320
336
341
342
345

12.3. Sample Preparation

347


xiv

CONTENTS

12.3.1. Precautions During Sampling and Contamination
Control
12.3.2. Storage of Samples
12.3.3. Methods for Sample Preparation
12.3.4. Direct Analysis of Solid Samples

347
348
348
350

12.4. Speciation Analysis

351

12.5. Quality Control in Trace Element Determination

355

12.6. Conclusions

358

References
13. Applications of ICP-MS in Human Biomonitoring Studies
Peter Heitland and Helmut D. K€
oster
Summary

359
367
367

13.1. Introduction

367

13.2. Advantages and Limitations of Inductively Coupled
Plasma Mass Spectrometry

368

13.3. Sample Collection and Storage

370

13.4. Sample Preparation

371

13.5. Human Biomonitoring by Inductively Coupled
Plasma Mass Spectrometry
13.5.1. General
13.5.2. Potentially Toxic Elements: Cadmium,
Mercury, Lead
13.5.3. Essential Trace Elements: Copper,
Selenium, Zinc
13.5.4. Nonmetals: Bromine and Iodine
13.5.5. Precious Metals: Silver, Gold, Iridium, Palladium,
and Platinum
13.5.6. Actinides: Uranium and Thorium
13.5.7. Multielemental Determinations

377
378
378

13.6. Trace Element Speciation and Metallomics

382

13.7. Determination of Stable Isotopes

384

13.8. Method Validation and Quality Assurance

384

13.9. Conclusions

387

References

374
374
374
375
376

387


CONTENTS

14. Molybdenum in Biological Samples and Clinical Significance
of Serum Molybdenum
Munehiro Yoshida
Summary

14.1. Introduction
14.2. Analysis of Molybdenum in Biological Samples by
Inductively Coupled Plasma Mass Spectrometry
14.2.1. General
14.2.2. Sample Preparation
14.2.3. Determinations by Inductively Coupled Plasma
Mass Spectrometry

xv

397
397
397
398
398
398
399

14.3. Molybdenum in Food
14.3.1. Molybdenum Concentration in Food
14.3.2. Speciation of Molybdenum in Food
14.3.3. Molybdenum Intake in Human Population

400
400
400
401

14.4. Molybdenum in Human Samples
14.4.1. Molybdenum in Urine

14.4.2. Molybdenum in Blood
14.4.3. Molybdenum in Milk

401
401
403
403

14.5. Clinical Significance of Serum and Plasma Mo
14.5.1. Index of Dietary Molybdenum Intake
14.5.2. Index of Molybdenum Exposure
14.5.3. Index of Various Diseases

404
404
405
405

14.6. Conclusions

406

References
15. Application of Organometallic Speciation in
Clinical Studies
Bin He, Chungang Yuan, Jing Sun, and Guibin Jiang
Summary

406

409
409

15.1. Introduction

409

15.2. Arsenic
15.2.1.
15.2.2.
15.2.3.
15.2.4.

410
410
410
411
412

Arsenic Pollution and Arsenicosis
Arsenic Biotransformation and Metabolism
Clinical Application of Arsenicals
Analytical Techniques and Clinical Applications


xvi

CONTENTS

15.2.5. Arsenic Speciation

15.2.6. Application of Arsenic Speciation Techniques
in Clinical Analysis

414
416

15.3. Mercury
15.3.1. Introduction
15.3.2. Sample Pretreatment
15.3.3. Gas Chromatography and its Hyphenated
Methods
15.3.4. High-Performance Liquid Chromatography and
its Hyphenated Methods

422
422
423

15.4. Tin
15.4.1.
15.4.2.
15.4.3.
15.4.4.

432
432
434
435

Introduction

Analytical Techniques and Clinical Applications
Developments in Analytical Techniques
Significance of Speciation Analysis of Organo-Tin
Compounds in Clinical Applications

15.5. Conclusions
References
16. Biosensors for Drug Analysis
Daniela Deriu and Franco Mazzei
Summary

426
430

439
441
441
455
455

16.1. Introduction

455

16.2. Basic Concepts

456

16.3. Electrochemical Biosensors
16.3.1. First-Generation Biosensors

16.3.2. Second-Generation Biosensors
16.3.3. Third-Generation Biosensors

460
460
460
461

16.4. Surface Plasmon Resonance

462

16.5. Biosensors for Drugs Analysis
16.5.1. Biosensors for Catecholamines Detection
16.5.2. Polyphenol Oxidase/Tyrosinase-Based
Biosensors
16.5.3. Biosensors for Hormones Analysis

465
465

16.6. Conclusions

471

References

469
469

471


CONTENTS

17. Bioimaging of Metals and Proteomic Studies of Clinical Samples
by Laser Ablation Inductively Coupled Plasma Mass
Spectrometry (LA-ICP-MS)
J. Sabine Becker and J. Susanne Becker
Summary

xvii

479
479

17.1. Introduction

480

17.2. Analytical Approaches

481

17.3. Experimental Aspects of Imaging Laser Ablation
Inductively Coupled Plasma Mass Spectrometry
17.3.1. General
17.3.2. Bioimaging of Metals and Quantification
Strategies
17.3.3. Single Hair Strand Analysis by Line Scan

Measurement
17.3.4. Bioimaging of Metals in Biological Tissues by
Laser Ablation Inductively Coupled Plasma
Mass Spectrometry
17.4. Conclusions

485
485
486
488

489
498

Acknowledgment

499

References

499

18. Applications of LC-MS/MS in Clinical Laboratory Diagnostics
Uta Ceglarek, Georg Martin Fiedler, and Joachim Thiery
Summary

507
507

18.1. Introduction

18.1.1. Methods in Laboratory Medicine
18.1.2. Tandem Mass Spectrometry in the Clinical
Laboratory
18.1.3. Pre-Analytical Aspects of Clinical Laboratory
Testing
18.1.4. Sample Preparation of Human Body Fluids for
Liquid Chromatography-Mass Spectrometry
Analysis

507
507

18.2. Current Applications and Future Perspectives
18.2.1. Mass Spectrometry Concepts
18.2.2. MS Instrumentation
18.2.3. Coupling of Liquid Chromatography with Mass
Spectrometry

513
513
515

508
509

510

518

xviii

CONTENTS

18.2.4. Development of Liquid Chromatography-Tandem
Mass Spectrometry Methods for Clinical Laboratory
Diagnostics
18.3. Liquid Chromatography-Tandem Mass Spectrometry
Applications in Clinical Laboratories
18.3.1. Determination of Amino Acids and Acylcarnitines
for Inherited Metabolic Diseases
18.3.2. Therapeutic Drug Monitoring of Immunosuppressives
18.3.3. Sterol Lipids
18.3.4. Steroid Hormones
18.3.5. Eicosanoid Profiling with Quadrupole-Trap Mass
Spectrometry
18.4. Conclusions
References
19. Metabolomics Using UPLC/HPLC-Tandem Mass Spectrometry
in Diagnosis and Research of Inherited Metabolic Diseases
Willem Kulik and Andre B. P. van Kuilenburg
Summary

519
520
520
523
524
525
526

528
528

535
535

19.1. Introduction

536

19.2. Acylcarnitines
19.2.1. General
19.2.2. Carnitine Biosynthesis

537
537
538

19.3. Acyl-Coenzyme A Thioesters

538

19.4. Amino Acids

540

19.5. Organic Acids

542

19.6. Purines and Pyrimidines

542

19.7. Bile Acids

544

19.8. Lipidomics
19.8.1. General
19.8.2. Very Long Chain Fatty Acids, Pristanic Acid,
Phytanic Acid
19.8.3. Sterols
19.8.4. Isoprenoid Biosynthesis
19.8.5. Phospholipids

545
545

19.9. Carbohydrates

548

545
547
547
547


CONTENTS

xix

19.10. Neurotransmitters

548

19.11. Conclusions

549

Further Reading

549

References

549

20. Biomarkers of Oxidative Stress in Plasma and Urine
Papasani V. Subbaiah
Summary

555
555

20.1. Introduction

556

20.2. Antioxidant Mechanisms and Assays
20.2.1. Total Antioxidant Capacity of Plasma
20.2.2. Measurement of Ratios of Reduced/Oxidized
Antioxidants (Plasma)
20.2.3. Markers of Protein Oxidation
20.2.4. Markers of DNA Oxidation (Blood and Urine)
20.2.5. Markers of Lipid Oxidation
20.2.6. Primary Oxidation Products
20.2.7. Degradation Products of Lipid Oxidation
20.2.8. Acrolein (Urine)
20.2.9. Oxidized Low Density Lipoprotein Assays (Plasma)
20.2.10. Ex Vivo Oxidizability of Low-Density Lipoproteins
(Plasma)
20.2.11. Enzyme Markers (Plasma)

558
558

578
579

20.3. Concluding Remarks and Perspectives

583

References
21. The Use of X-Ray Techniques in Medical Research
Imre Szal
oki, Gyula Z
aray, and Norbert Szoboszlai

Summary

561
562
564
566
568
569
576
576

584
595
595

21.1. Introduction

595

21.2. Physical Basis of XRF Analytical Methods

596

21.3. Basic Equipment and Setup for X-Ray Fluorescence
Analysis
21.3.1. X-Ray Sources
21.3.2. X-Ray Optics
21.3.3. Mirrors and Multilayers
21.3.4. Detectors

597
597
600
603
603


xx

CONTENTS

21.3.5. Setup for Total Reflection X-Ray Fluorescence and
X-Ray Fluorescence Microanalysis

605

21.4. Quantification Approaches

606

21.5. Sample Preparation Techniques

609

21.6. Applications
21.6.1. General
21.6.2. Blood
21.6.3. Urine
21.6.4. Cerebrospinal Fluid
21.6.5. Amniotic Fluid

21.6.6. Tissues
21.6.7. Cells–Cell Lines

610
610
611
613
613
614
614
615

21.7. Conclusions

617

PART III

References

617

Future Trends

625

22. A New Tool Based on the Use of Stable Isotopes and Isotope
Pattern Deconvolution (IPD)-ICP-MS for
Nutritional and Clinical Studies
Hector Gonza´lez Iglesias, Maria Luisa Ferna´ndez-Sa´nchez,

and Alfredo Sanz-Medel
Summary

627

627

22.1. Introduction

627

22.2. Milk as Source of Trace Elements

628

22.3. Stable Isotopes and Trace Elements Metabolism

629

22.4. Isotope Pattern Deconvolution

631

22.5. Selenium Metabolism in Lactating Rats by Means of
Stable Isotopes and Isotope Pattern Deconvolution

631

22.6. Determination of Selenium in Urine, Faeces, Serum,
and Erythrocytes by Isotope Pattern Deconvolution

Inductively Coupled Plasma Mass Spectrometry
22.6.1. Determination of Endogenous and Exogenous
Total Selenium in Urine and Feces
22.6.2. Determination of Endogenous and Exogenous
Total Selenium in Serum and Red Blood Cells
22.7. Quantitative Speciation of Selenium in Urine, Serum, and
Erythrocytes by High Performance Isotope Pattern Deconvolution
Inductively Coupled Plasma Mass Spectrometry

634
634
636

637


CONTENTS

22.7.1. General
22.7.2. High-Performance Isotope Pattern Deconvolution
Inductively Coupled Plasma Mass Spectrometry
Quantification of Natural and Exogenous
Selenospecies in Urine
22.7.3. Quantification of Endogenous (Natural) and
Exogenous Selenospecies in Erythrocytes
22.7.4. Quantification of Natural and Exogenous
Selenospecies in Serum

xxi

637

637
640
642

22.8. An Application of Isotope Pattern Deconvolution to
Clinical Studies

643

22.9. Conclusions

645

References
23. Breath Analysis: Analytical Methodologies and Clinical
Applications
Alessio Ceccarini, Fabio Di Francesco, Roger Fuoco,
Silvia Ghimenti, Massimo Onor, Sara Tabucchi,
and Maria Giovanna Trivella
Summary

646

651

651

23.1. Introduction

652

23.2. Sampling Methods

655

23.3. Analytical Techniques
23.3.1. General
23.3.2. Gas Chromatography Mass Spectrometry
23.3.3. Selected Ion Flow Tube Mass Spectrometry
23.3.4. Proton Transfer Reaction Mass Spectrometry
23.3.5. Ion Mobility Spectrometry
23.3.6. Laser Spectroscopy
23.3.7. Sensor-Based Systems

658
658
658
660
660
662
662
663

23.4. Application of Breath Analysis
23.4.1. General
23.4.2. Tests Approved by the US Food and Drug
Administration
23.4.3. Diagnostic Challenges

23.4.4. Breath Markers and Pathological Conditions

664
664
665
669
671

23.5. Exposure Assessment

675

23.6. Exhaled Breath Condensate

677


xxii

CONTENTS

23.7. Conclusions
References
24. Proteo-Metabolomic Strategies in the Future of Drug Development
Uwe Christians, Volker Schmitz, Jost Klawitter,
and Jelena Klawitter
Summary

677
678

691

691

24.1. Introduction

692

24.2. The Principles of Molecular Marker Development
24.2.1. General Aspects
24.2.2. Discovery
24.2.3. Qualification
24.2.4. Validation
24.2.5. Regulatory Aspects

699
699
699
701
707
710

24.3. Technologies for Molecular Marker Development
24.3.1. Nontargeted Discovery Technologies
24.3.2. General Strategies
24.3.3. Targeted Strategies

718
718
719

734

24.4. Molecular Markers in Drug Development
and Clinical Monitoring
24.4.1. Introductory Comments
24.4.2. Kidney Dysfunction Markers

737
737
743

24.5. Current Challenges

749

References
25. Basics in Laboratory Medicine: Past, Present, and Future
Lor
and A. Debreczeni, Anna Kov
acsay, and Sandor Nagy
Summary

752
775
775

25.1. Introduction

776

25.2. Informatics

777

25.3. Global Standardization

778

25.4. Focus on the Individual

782

25.5. A Look into the Future

783

References
INDEX

784
787


FOREWORD

The quality and reliability of data generated during the conduct of clinical trials
represent a very critical aspect in the development of pharmaceutical products. The
latter must meet all the regulatory and legislative requirements established at an
international level in order to protect the health and well being of the patients exposed
to these new drugs. Analytical techniques represent a very important aspect in

producing the supporting data required by clinical research protocols. In this context,
analytical work performed in research and control laboratories must comply with
current legislation and guidelines, especially with the requirements of the International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. This fact represents a real challenge in the conduct
of clinical investigations and, in particular, the development of appropriate analytical
techniques, due to the fact that the actors in this field are faced with ever-changing
regulations that attempt (but do not always succeed) to keep pace with the rapid
technological advancements in developing instrumentation for use in research and
control laboratories.
This multiauthored book aims at underlining the role played by analytical
techniques in supporting and promoting research and control in the various fields
of clinical activity, starting from the very early stages of clinical research to the
attainment of marketing authorizations as well as in practical applications. The book
also elicits the progress made in developing instrumentation that is fit-for-purpose
as well as to identify outstanding problems that deserve further investigation,
investment, and improvement in both research and routine laboratories.
The 25 chapters of this book have been written by prominent scientists and cover
primary issues which include three main parts Fundamentals, Selected Applications,
and Future Trends. The first area provides a survey of the current legal framework (in
particular the EC Directive 2005/28 of April 2005 on the principles of Good
Laboratory Practice), the major challenges of clinical investigations and the availability of analytical techniques for research and routine work. In this section the reader
will encounter topics such as uncertainty in clinical chemistry measurements, the role
and significance of reference values in the identification of trace elements from diet,
sample collection, storage and pretreatment in clinical chemistry, metal toxicology in
clinical, forensic and chemical pathology, elemental speciation in clinical sciences,
and detection of drugs in biological fluids for antidoping control, which are discussed
in detail. The book then goes on to illustrate the applicability of the most popular and
successful analytical techniques as well as the relevant quality systems and their
implementation. Here the reader can find information such as the applicability of

xxiv

FOREWORD

plasma-based techniques to biological monitoring, atomic spectrometry, organometallic speciation, the clinical meaning of molybdenum, bioimaging of metals and
proteomic studies of clinical samples by laser ablation inductively coupled plasma
mass spectrometry, application of liquid chromatography combined with tandem
mass spectrometry in clinical laboratory diagnostics, metabolomics using highperformance liquid chromatography-tandem mass spectrometry, biomarkers of stress
in plasma and urine, X-ray techniques in medical research, and analytical examination of drugs in the forensic science laboratory. The third part gives the reader a look at
promising innovative approaches and their possible exploitation, e.g., for breath
analysis, development of proteo-metabolic strategies and optimization of laboratory
medicine.
This book greatly benefits from the enthusiastic participation and support of all
authors who greatly collaborated with the editors and to whom the editors express
their sincere gratitude.
VALENTINE ANTHONY SFORZA


PREFACE

The first idea of a multiauthored book devoted to the role played by analytical
chemistry in fostering clinical research was conceived by the Editors some four years
ago during a lively conversation had in the aftermath of the publication by Wiley of
another book of ours.1 It was perhaps the enthusiasm sparked by the fact that this work
was well received by the readers, or perhaps the exciting atmosphere of the Hungarian
tavern where we were dining (not to speak of a bottle of excellent red wine which made
us rather loquacious), or perhaps—and most likely—the synergistic action of these
factors altogether, that fertilized our minds and led us to plan a new book in the belief
that it would meet the needs of the scientific community. Greatly inspired by optimism

and self-confidence (never out of place under such circumstances), the more we
debated this issue, the more the project became a fascinating challenge. Deliberately
minimizing all the difficulties that we knew by personal experience would thwart the
progress of the work and make our professional lives uneasy for quite a long period of
time, a list of key topics was promptly drafted and a tentative list of potential
contributors was jotted down. A new adventure was starting. . .
Now that the book has finally reached completion in spite of an endless number of
technical problems, delays, withdrawal of manuscripts, and all kinds of unexpected
events, we wish to express our sincere gratitude to all contributing authors for their
valuable competence, their willingness to cooperate at all stages of preparation of
their chapters, and their infinite patience in tackling all our often complex, always
time-consuming, and certainly tedious requests. Needless to say, we do hope that they
will be happy with the outcome of their unremitting efforts.
The sponsorship of PerkinElmer, Inc. to the making of this book is gratefully
acknowledged. Without their generosity, constant support, and firm trust in our
project, it would never be possible for us to accomplish it. If the result of our
commitment pleases them, this will also significantly add to our satisfaction.
SERGIO CAROLI

GYULA ZARAY

1
Sergio Caroli (Editor), The Determination of Chemical Elements in Food—Applications for Atomic and
Mass Spectrometry, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2007.


CONTRIBUTORS

Marı´a del Carmen Barciela Alonso, Trace Elements, Spectroscopy and Speciation
Group, Department of Analytical Chemistry, Nutrition and Bromatology, Faculty

of Chemistry, University of Santiago de Compostela, Spain
Pietro Apostoli, Department of Experimental and Applied Medicine, Section of
Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy
Pilar Bermejo Barrera, Trace Elements, Spectroscopy and Speciation Group,
Department of Analytical Chemistry, Nutrition and Bromatology, Faculty of
Chemistry, University of Santiago de Compostela, Spain
J. Sabine Becker, Central Division of Analytical Chemistry, Forschungszentrum
J€
ulich, J€
ulich, Germany
J. Susanne Becker, Aeropharm, Francois-Mitterrand-Allee 1, Rudolstadt, Germany
Bjørn J. Bolann, Laboratory of Clinical Biochemistry, Haukeland University
Hospital, Helse Bergen HF, Bergen, Norway; and Institute of Medicine, University
of Bergen, Bergen, Norway
Sergio Caroli, National Institute of Health (Istituto Superiore di Sanita), Rome, Italy
Alessio Ceccarini, Department of Chemistry and Industrial Chemistry, University of
Pisa, Pisa, Italy
Uta Ceglarek, University Hospital Leipzig, Institute of Laboratory Medicine,
Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany
Jose A. Centeno, Biophysical Toxicology, The Joint Pathology Center, 606 Sitter
Stephen Ave., Silver Spring, MD, USA
Marcello Chiarotti, Institute of Forensic Medicine, Catholic University of the
Sacred Heart, Rome, Italy
Uwe Christians, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO, USA
Lor
and A. Debreczeni, Department of Laboratory Medicine, St. Imre Hospital of
Budapest Metropolis, Budapest, Hungary
Daniela Deriu, Department of Chemistry and Drug Technologies, La Sapienza
University, Piazzale Aldo Moro Roma, Italy
Fabio Di Francesco, Department of Chemistry and Industrial Chemistry, University

of Pisa, Pisa, Italy


xxviii

CONTRIBUTORS

Angela Del Vecchio, Italian Medicine Agency (Agenzia Italiana del Farmaco,
AIFA), Rome, Italy
Maria Luisa Fern
andez-S
anchez, Department of Physical and Analytical
Chemistry, University of Oviedo, Oviedo, Spain
Georg Martin Fiedler, Institute of Laboratory Medicine, Clinical Chemistry and
Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
Umberto Filibeck, Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA),
Rome, Italy
Rossella Fioravanti, Department of Chemistry and Drug Technologies, Faculty of
Pharmacy, La Sapienza University, Rome, Italy
Roger Fuoco, Department of Chemistry and Industrial Chemistry, University of
Pisa, Pisa, Italy
Fabrizio Galliccia, Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA),
Rome, Italy
Silvia Ghimenti, Department of Chemistry and Industrial Chemistry, University of
Pisa, Pisa, Italy
Sandor G€
or€
og, Gedeon Richter Plc., Budapest, Hungary
Bin He, State Key Laboratory of Environmental Chemistry and Ecotoxicology,
Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences,

Beijing, P.R. China
Peter Heitland, Medical Laboratory Bremen, Bremen, Germany
Hector Gonz
alez Iglesias, Department of Physical and Analytical Chemistry,
University of Oviedo, Oviedo, Spain
Guibin Jiang, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, P.R. China
Jelena Klawitter, iC42 Clinical Research & Development, Department of
Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO,
USA
Jost Klawitter, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO, USA
Anna Kov
acsay, Department of Laboratory Medicine, St. Imre Hospital of Budapest
Metropolis, Budapest, Hungary
Helmut D. Ko¨ster, Medical Laboratory Bremen, Bremen, Germany
Willem Kulik, Academic Medical Center, University of Amsterdam, Laboratory
of Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam,
The Netherlands