Clinical Chemistry and Laboratory Medicine (CCLM)

Published by De Gruyter

Volume 42 Issue 11

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)

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Contents
Journal Overview

June 1, 2005

Therapeutic drug monitoring in clinical toxicology: current strategies, thoughts and views on the future

Willy Lambert, Hugo Neels

Page range: 1203-1203

June 1, 2005

Therapeutic monitoring of immunosuppressant drugs. Where are we?

Pierre E. Wallemacq

Page range: 1204-1211

Abstract

The emergence of specific immunosuppressive drugs (cyclosporine, tacrolimus, mycophenolate mofetil and sirolimus) during the last two decades has contributed dramatically to the success of organ transplantation. However, optimum balance between therapeutic efficacy and the occurrence of side effects has been a real challenge for physicians, mainly due to inter- and intra-patient variability arising from pharmacokinetic, pharmacogenetic and pharmacodynamic individual properties. Therapeutic drug monitoring, defined as the measurement and interpretation of concentrations of these drugs in biological fluids, with as a final objective the prediction of organ responses, became an integral part of transplant protocols. New analytical techniques became available with different performances in terms of specificity and sensitivity. In addition, there has been progress in understanding the mechanisms of action of these drugs that have implications for the development of better monitoring strategies and for their coprescription. The purpose of this review is to examine the current strategies in use for the therapeutic drug monitoring of immunosuppressant drugs and to discuss some of the factors that impinge on the monitoring of these drugs.

June 1, 2005

Therapeutic drug monitoring of non-tricyclic antidepressant drugs

Philip B. Mitchell

Page range: 1212-1218

Abstract

Therapeutic drug monitoring (TDM) of many of the tricyclic antidepressants (TCAs) has been demonstrated to be of clear clinical value. This article reviews studies of TDM for the selective serotonin reuptake inhibitors (SSRIs) and other non-tricyclic antidepressants such as venlafaxine, nefazodone, trazodone, mianserin and bupropion. No definitive therapeutic concentrations have been demonstrated for these agents, nor have levels indicative of toxicity been reported. The major benefit of TDM for these agents would appear to be in the assessment of the apparently treatment-refractory depressed patient, to determine whether such lack of response is related to inadequate levels that would suggest either poor compliance, ultra-rapid metabolism, or drug interactions leading to induction of metabolising enzymes. Potential future applications of TDM, in conjunction with genotyping of cytochrome P450 enzymes and pharmacogenomic evaluations, are discussed.

June 1, 2005

The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment

Herlinde Dumez, Gunther Guetens, Gert De Boeck, Martin S. Highley, Robert A. A. Maes, Allan T. van Oosterom, Ernst A. de Bruijn

Page range: 1219-1227

Abstract

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.

June 1, 2005

Therapeutic drug monitoring of old and newer anti-epileptic drugs

Hugo M. Neels, Ann C. Sierens, Kristine Naelaerts, Simon L. Scharpé, George M. Hatfield, Willy E. Lambert

Page range: 1228-1255

Abstract

The aim of the present paper is to provide information concerning the setting up and interpretation of therapeutic drug monitoring (TDM) for anti-epileptic drugs. The potential value of TDM for these drugs (including carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide) is discussed in relation to their mode of action, drug interactions and their pharmacokinetic properties. The review is based upon available literature data and on observations from our clinical practice. Up until approximately 15 years ago anti-epileptic therapeutics were restricted to a very few drugs that were developed in the first half of the 20th century. Unfortunately, many patients were refractory to these drugs and a new generation of drugs has been developed, mostly as add-on therapy. Although the efficacy of the newer drugs is no better, there is an apparent improvement in drug tolerance, combined with a diminished potential for adverse drug interactions. All new anticonvulsant drugs have undergone extensive clinical studies, but information on the relationship between plasma concentrations and effects is scarce for many of these drugs. Wide ranges in concentrations have been published for seizure control and toxicity. Few studies have been undertaken to establish the concentration-effect relationship. This review shows that TDM may be helpful for a number of these newer drugs.

June 1, 2005

Pharmacogenomic genotyping methodologies

Paul J. Jannetto, Elvan Laleli-Sahin, Steven H. Wong

Page range: 1256-1264

Abstract

“Personalized medicine” based on an individual’s genetic makeup is slowly becoming a reality as pharmacogenomics moves from the research setting to the clinical laboratory. Concordance studies between genotype and phenotype have shown that inherited mutations in several key drug-metabolizing enzymes, such as cytochrome P450 ( CYP ) 2D6 , 2C9 , and 2C19 , result in several distinct phenotypes that lead to different individual responses following drug administration. One of the major driving forces behind pharmacogenomics and its ability to be used effectively are the technologies that are available. A beneficial genotyping test must identify most or all of the mutations that have a significant impact on the expression or function of drug-metabolizing enzymes, transporter proteins, and/or drug receptors. Selection of the appropriate technology will be based on several issues, including prior knowledge of the mutation/polymorphism, sensitivity/specificity, sample requirements, and cost. Since the future volume of pharmacogenomic testing is anticipated to be large, automation of pharmacogenomics will also become increasingly important. This paper provides an overview of current technologies available for assessing polymorphisms on a small- to large-scale basis.

June 1, 2005

Hair analysis in toxicology

Marion Villain, Vincent Cirimele, Pascal Kintz

Page range: 1265-1272

Abstract

Morphological, serological and chemical examination of human hair for medical purposes was initiated some decades ago. In the 1960s and 1970s, hair analysis was used to evaluate exposure to toxic heavy metals. At this time, examination of hair for organic substances, especially drugs, was not possible because analytical methods were not sensitive enough. Since the early 1980s, the development of highly sensitive and specific assay methods such as radioimmunoassay or gas chromatography/mass spectrometry has permitted the analysis of organic substances trapped in hair. This, theoretically, offered the possibility of revealing an individual’s recent history of drug exposure beginning at sampling day and dating back over a period of weeks or months. The present review aims to summarise the various applications that have been published.

September 21, 2011

Oral fluid as a diagnostic tool

Robin E. Choo, Marilyn A. Huestis

Page range: 1273-1287

Abstract

Technological advances over the past decades have enabled oral fluid to expand its usefulness in the diagnosis of disease, prediction of disease progression, monitoring of therapeutic drug levels and detection of illicit drugs. The easy non-invasive nature of collection and the relationship between oral fluid and plasma levels make oral fluid a valuable clinical tool. This review describes advances over the past 5 years in the area of oral fluid as a diagnostic tool, its use in therapeutic and illicit drug monitoring, including proposed guidelines for cut-off values, and methods of collection.

September 21, 2011

Position of immunological techniques in screening in clinical toxicology

Steve George

Page range: 1288-1309

Abstract

There is a continuing increase in the use of immunological techniques in the field of clinical toxicology. This is primarily due to the rapidity by which analytical results are now required, and can be obtained, following the testing of individuals for drug use. There has recently been an increase in the repertoire of assays now available to testing laboratories (e.g., buprenorphine and heroin metabolite assays), with the techniques themselves becoming increasingly more specific for the drugs and/or metabolites being monitored (e.g., methadone metabolite assays). The near patient testing (NPT), or point-of-care testing (POCT), devices are now several generations forward from their inception, with some tests now approaching the sensitivity and specificity of automated laboratory-based methods. This review has been collated from the literature to illustrate some of the possible reasons for the move towards the increasing use of immunological techniques, and to highlight some of the advantages and disadvantages associated with such drug screening methods. In particular, it has been shown that it is important to determine, monitor and review the knowledge and training of the individual using the technique. In addition, quality control and quality assessment are paramount to ensure the validity of any drug testing being performed. It has also been shown that it is vital to maintain and develop the relationships between the staff performing the testing, the laboratory (if the testing is performed using NPT devices), and the clinicians utilising the results obtained from drug testing. Without these links, interpretive errors could arise which could adversely affect the diagnosis and management of patients.

September 21, 2011

Position of chromatographic techniques in screening for detection of drugs or poisons in clinical and forensic toxicology and/or doping control

Hans H. Maurer

Page range: 1310-1324

Abstract

This paper reviews chromatographic screening procedures for simultaneous detection of several drug classes relevant to clinical and forensic toxicology or doping control in urine or blood using gas chromatography-mass spectrometry (GC-MS), liquid chromatography coupled with a diode-array detector (LC-DAD) or a mass spectrometer (LC-MS). The pros and cons of the different techniques and procedures are discussed leading to the following conclusions and perspectives. GC-MS, especially in the electron ionization full-scan mode, is still the method of choice for comprehensive screening providing best separation power, specificity and universality, although requiring derivatization. LC-DAD is also often used for screening, but its separation power and its specificity are still inferior to those of GC-MS. Finally, LC-MS has shown to be an ideal supplement, especially for the detection of more polar, thermolabile and/or low-dose drugs, especially in blood plasma. It may become the gold standard in clinical and forensic toxicology and doping control if, at a later date, the costs of the apparatus will be markedly reduced, the current disadvantages like irreproducibility of fragmentation, reduction of ionization by matrix, etc. will be overcome, and finally if one of the increasing number of quite different techniques will become the apparatus standard.

September 21, 2011

Systematic toxicological analysis by high-performance liquid chromatography with diode array detection (HPLC-DAD)

Fritz Pragst, Matthias Herzler, Björn-Thoralf Erxleben

Page range: 1325-1340

Abstract

In recent years, photodiode array detectors (DADs) have been much improved with respect to wavelength accuracy and resolution, sensitivity, linearity and software operation. UV spectra of drugs measured with up-to-date DADs from different manufacturers are in excellent agreement, have the same quality as measured by a conventional UV spectrometer and are highly reproducible. The calculation of similarity parameters by the DAD software includes the entire range of the spectra compared and allows recognition of very small differences. It was shown in a systematic study of more than 2500 toxicologically relevant substances that UV spectra have a very high specificity with respect to substance structure. Therefore, HPLC-DAD in combination with a comprehensive database of UV spectra and retention parameters is one of the most efficient techniques used in systematic toxicological analysis (STA). Furthermore, the method is advantageous for the identification of metabolites, since in many cases they have the same or very similar UV spectra compared with their respective parent substances and their retention times on reversed-phase columns are shifted in a manner typical of the particular biotransformation reaction. Beside these general aspects, practical applications of HPLC-DAD for STA are reviewed with respect to sample preparation and chromatographic conditions. The efficiency of the method is demonstrated for an example of a routine procedure using liquid-liquid extraction with CH 2 Cl 2 and protein precipitation for sample preparation, a system of three isocratic mobile phases with different acetonitrile/phosphate buffer ratios and RP8 columns for chromatography and a database of 2682 UV spectra and relative retention times for substance identification.

September 21, 2011

Analysis of γ-hydroxybutyric acid, DL-lactic acid, glycolic acid, ethylene glycol and other glycols in body fluids by a direct injection gas chromatography-mass spectrometry assay for wide use

Paul Van hee, Hugo Neels, Mireille De Doncker, Nicolas Vrydags, Katinka Schatteman, Wim Uyttenbroeck, Nicole Hamers, Dirk Himpe, Willy Lambert

Page range: 1341-1345

Abstract

Analysis of blood of severely intoxicated patients always requires prompt investigation. Diagnosis of intoxication with ethylene glycol, γ-hydroxybutyric acid or D-lactic acid takes hours, since several different procedures are required. Rapid derivatization of the common hydroxyl function may resolve this analytical problem. Here we describe a fast method for the simultaneous measurement of ethylene glycol, glycolic acid, γ-hydroxybutyric acid and racemic lactic acid. Only 20 µl of serum, plasma or urine are required for immediate derivatization at 70°C with 750 µl of bis-N,O-trimethylsilyl trifluoroacetamide after adding 20 µl of internal standard solution (1,3-propylene glycol) and 20 µl of the catalyst dimethylformamide. After centrifugation an aliquot is transferred to a gas chromatographic system and analyzed with electron-impact mass spectrometry in selective ion monitoring mode. The derivatized acids and ethylene glycol are well separated and detected with a limit of detection ranging from 0.12 mg/l for ethylene glycol to 0.95 mg/l for γ-hydroxybutyric acid, while the limit of quantification ranged from 0.4 mg/l for ethylene glycol to 3.15 mg/l for γ-hydroxybutyric acid. The method is linear from 0.5 to 1800 mg/l blood for ethylene glycol, from 0.7 to 1200 mg/l for lactic acid, from 1.2 to 1800 mg/l for glycolic acid, and from 3.2 to 200 mg/l for γ-hydroxybutyric acid, with analytical recoveries, accuracy, day-to-day and within-day precision well within the required limits. Total analysis time with one calibrator was 30 min, derivatization time included. This method is very suitable for emergency toxicology, since several toxic substances can be quantified simultaneously in a fast and sensitive manner.

About this journal

Objective
Clinical Chemistry and Laboratory Medicine (CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. It is focused on basic and applied research and cutting-edge clinical laboratory medicine. CCLM is one of the leading journals in the field, with an impact factor over 3.5. All contributions submitted for publication in CCLM are single-blind peer reviewed by at least two experts in the field. CCLM is led by a multi-institutional editorial board. It is issued monthly, both in print and electronically. Letters to the Editor and Congress Abstracts are published online only.

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Topics

clinical biochemistry
clinical genomics and molecular biology
clinical haematology and coagulation
clinical immunology and autoimmunity
clinical microbiology
drug monitoring and analysis
evaluation of diagnostic biomarkers
disease-oriented topics (cardiovascular disease, cancer diagnostics, diabetes)
new reagents, instrumentation and technologies
new methodologies
reference materials and methods
reference values and decision limits
quality and safety in laboratory medicine
translational laboratory medicine
clinical metrology

Article formats
Research Articles, Reviews, Mini Reviews and Opinion Papers on all aspects of clinical chemistry and laboratory medicine, Guidelines and Recommendations, Point/Counterpoint Articles, Letters to the Editor, Editorials

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