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Dr David W Holt
Research Areas
Biography After an early foray into school teaching, Dr Holt graduated in Biochemistry from London University in 1970. Subsequently, he worked at the Poisons Unit, Guy’s Hospital, where he gained a PhD in Biochemistry and progressed to the position of Consultant Biochemist. In 1989, at the invitation of Professor Camm, he established the Analytical Unit at St George’s Hospital Medical School. The Unit is self-supporting, all running costs being earned from research grants, contract research, and clinical services. It is committed to providing specialist analytical facilities for the diverse research interests of the Department of Cardiological Sciences. The resources of the Unit include high-performance liquid chromatography with mass-spectrometric detection (HPLC/MS/MS). Since 1993 the Unit has been accredited by the Department of Health as compliant with Good Laboratory Practice (GLP). The Unit is also responsible for the Forensic Toxicology Services of the Medical School, offering extensive services for the measurement of drugs to the Histopathology and Forensic Medicine Unit within the Medical School, and to HM Coroners around the UK. As the Director of the Analytical Unit Dr Holt has led a team of scientists involved in basic research on the measurement of markers of myocardial damage, the measurement of markers of atherosclerotic disease progression, the clinical pharmacokinetics of immunosuppressive drugs and phenotypic markers of drug metabolic enzymes. Dr Holt is the author of over 200 peer-reviewed articles and invited contributions. He is also involved in training students in the use of a wide variety of analytical techniques, as well as in undergraduate and postgraduate teaching. Dr Holt is a frequent speaker on a broad range of issues concerning analytical clinical toxicology and he has served on many international consensus panels relating to the optimal prescription of immunosuppressive drugs. Research Interests
Dr Holt’s research has focused on three main areas:
Dr Holt’s doctoral thesis was on the measurement of digoxin in plasma and tissue. It formed the basis of his research career devoted to the measurement of drugs and endogenous compounds. The publications resulting from his thesis were early examples of a field that has become known as therapeutic drug monitoring, i.e. the process of optimising drug therapy on the basis of drug measurements made in blood samples. In response to intense clinical interest in a range of drugs introduced throughout the 1970’s and 1980’s, Dr Holt developed methodology for the measurement of numerous cardio-active drugs and applied these methods to the investigation of clinical pharmacokinetic and clinical toxicological problems. These included determining plasma concentration/response relationships, age-related pharmacokinetic differences, drug interactions, formulation changes and the management of deliberate or accidental overdosage. A key example amongst the drugs studied was amiodarone, for which Dr Holt produced definitive papers relating to its single-dose pharmacokinetics, the discovery of its desethyl metabolite, its tissue distribution and its clinical toxicology. Since 1982 Dr Holt has been involved in clinical studies of immunosuppressive drugs and has established an international reputation for his work on the problems related to the measurement of these drugs. He has advised on several international consensus panels on immunosuppressive drug monitoring, chaired the Association of Clinical Biochemists Task Force on cyclosporin measurement and is the chairman of the International Federation of Clinical Chemistry / International Association of Therapeutic Drug Monitoring and Clinical Toxicology Working Group on Guidelines for Immunosuppressive Drug Monitoring. He has established international proficiency testing schemes for the measurement of all the major immunosuppressive drugs. As a result of his earlier interest in drug pharmacokinetics Dr Holt has provided services for the measurement of these drugs for regulatory studies of their efficacy in a variety of clinical settings. As a natural corollary to his interest in clinical toxicology, Dr Holt went on to explore the measurement of endogenous compounds which could act as markers of myocardial muscle damage. In particular, he pioneered the use of a specific marker of myocardial damage, creatine kinase isoforms, as a marker of minor, rather than overt, myocardial damage. This resulted in investigations into myocardial damage following exposure to drugs and to the use of the marker to investigate the comparative efficacy of strategies to minimise peri-operative myocardial damage. This analyte was also used to investigate the possibility of developing a non-invasive diagnosis of heart allograft rejection. Following from this interest, definitive studies were also performed on the expression of cardiac troponin T in patients with end-stage renal failure. Recently, Dr Holt’s group has extended its interest in drug metabolism into the field of pharmacogenetics. Assays have been developed for phenotypic markers of cytochrome P450 metabolic activity and for genotyping cytochrome P450 enzymes involved in the metabolism of immunosuppressive drugs. In addition, the academic output of the Forensic Toxicology Service is being enhanced by establishing graduate and post-graduate courses in aspects of forensic science and by embarking on a project to detect drugs used in drug-assisted-sexual assault.
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