Isotopes, stable clinical application

See also Archaeometry and Antique Analysis Dating of Artifacts Metaiiic and Ceramic Objects. Atomic Absorption Spectrometry Principles and Instrumentation. Atomic Mass Spectrometry Inductively Coupled Plasma. Gas Chromatography Mass Spectrometry. Mass Spectrometry Time-of-Flight Stable Isotope Ratio Clinical Applications Environmental Applications Food Applications Forensic Applications. 

Since the 1977 review in Annual Reports, the applications of stable-isotope-labeled compounds to biomedical research have increased dramatically. Three international conferences devoted to the use of stable isotopes in the life sciences and one to synthesis and general applications have been held. Review articles have focused on mass spectrome-tric-based analytical methods, on applications of stable isotopes in clinical and pharmacological research, and on more specific studies concerning problems in drug metabolism, pharmacokinetics and synthesis. The present review covers mainly the literature published since 1981 and focuses on recent developments in the use of stable isotopes for investigations of drug metabolism and disposition. 

The next five chapters deal with pharmaceutical and clinical applications of GC-MS, paying attention to automated sample pretreatment procedures for rapid GC-MS of drugs (Ch. 9), multidimensional detection strategies in the analysis of anesthetics (Ch. 10), the use of stable isotope-ratio GC-MS in clinical applications (Ch. 11), steroid profiling in relation to a variety of diseases... 

Baillie, T.A., Stable Isotopes Application in Pharmacology, Toxicology and Clinical Research, Macmillan, London, 1978. 

De Ridder, J. J., and Koppens, P. C. (1978). Discrimination between endogenous and exogenous testosterone in human plasma after oral treatment with testosterone undecano-ate, using stable-isotope labeled compounds and mass spectrometric analysis. In Stable Isotopes. Applications in Pharmacology, Toxicology and Clinical Research (T. A. Baillie, ed.), pp. 157-165. Mcmillan, New York. 

Krahmer, U. I., and McCloskey, J. (1978). Biomedical applications of mass spectrometry Clinical uses of stable isotopes. Adv. Mass Spectrom. 7B, 1483-1499. 

In principle, the applications of ICP-MS resemble those listed for OES. This technique however is required for samples containing sub-part per billion concentrations of elements. Quantitative information of nonmetals such as P, S, I, B, Br can be obtained. Since atomic mass spectra are much simpler and easier to interpret compared to optical emission spectra, ICP-MS affords superior resolution in the determination of rare earth elements. It is widely used for the control of high-purity materials in semiconductor and electronics industries. The applications also cover the analysis of clinical samples, the use of stable isotopes for metabolic studies, and the determination of radioactive and transuranic elements. In addition to outstanding analytical features for one or a few elements, this technique provides quantitative information on more than 70 elements present from low part-per-trillion to part-per-million concentration range in a single run and within less than 3 min (after sample preparation and calibration). Comprehensive reviews on ICP-MS applications in total element determinations are available. " ... 

A review of cellular mechanisms of insulin resistance has been produced with 46 references. The use of NMR to study glycogen in exercise has been reviewed with many references. The quantification of the contribution of gluconeogenesis to glucose production in fasted human subjects, using stable isotopes and NMR, has been reviewed with 72 references. A review of the use of magnetic resonance imaging and spectroscopy in biomedicine has been produced with 180 references. The beginnings and later applications of NMR for clinical studies has been reviewed with 18 references. 

Quantitative Applications - The use of stable-isotope-labeled compounds as internal standards for the quantitation of drugs and metabolites in biological fluids offers a unique combination of sensitivity and selectivity of detection for pharmacokinetic studies. The principles of the technique have been outlined, and applications up to 1981 have been compiled. Specific aspects of the isotope dilution method, e.g. its utility as a reference technique and associated procedures for handling the data generated from the use of multiple isotope tracers simultaneously, have been discussed. Examples of isotope dilution methods used in clinical psychopharmacology have also been reviewed. ... 

Finally, stable isotopes are frequently used in clinical studies, where their main advantage over radioactive isotopes is that they present no hazard to the patient and can be used quite safely in children. Many applications have been published such as their use to monitor the pharmacokinetics of a single dose of drug diuing chronic therapy or to measure the bioavailabihty of a drug from various formulations. 

It is an interesting question how toxic deuterium or heavy water is to humans. If it is accepted on the basis of animal experiments that the critical deuterium concentration (the double of which would cause severe physiological effects) is about 10%, then one can easily estimate that a person of 70 kg may drink 4.81 heavy water or 1.21 per day for 4 days without serious consequences (Forstel 1978). Thus, heavy water cannot be considered toxic to humans. This is an important conclusion, since stable isotopes (e.g., heavy water for the estimation of total body water) are widely used in clinical research and diagnosis (Krumbiegel 1991). In the literature, one can find also some more conservative estimates as far as the application risk of the deuterium in the form of heavy water is concerned, for example, Jones and Leatherdale (1991) suggest that the threshold for noticeable side-effects exists at the dosage between 70 and 140 g of 100% D2O. 

Symposium on Stable Isotopes Applications in Pharmacology, Toxicology, and Clinical Research, Royal Postgraduate Medical School, London, 1977, to be published. 

Table 25.3 Applications of stable isotope dilution assays (SIDAs) to folates in clinical samples. Reported SIDAs for clinical samples are listed along with the isotopologic standard used.

Applications of folate stable isotope dilution assays are reported for foods with or without fortification by folic acid and for clinical samples such as blood serum, plasma, red blood cells, urine and ileostomy effluents. 

Stable isotope labeled compounds can be obtained by chemical modification of the molecule. Many labeled products can be purchased from commercial suppliers and ordered from the catalog or on special request. Organic compounds of interest for clinical research are labeled with H, C, N, and/or 0 at one or more positions. Multilabeled substrates containing two or three different labels are also available. The choice of the type of label and the position(s) of labeling may be critical for the success of the application for two reasons. First, metabolism of the substrate may lead to loss of label, when the label is in the wrong position. Secondly, unfavorable MS fragmentation may be a cause of loss of... 

Clinical stable isotope studies cover a wide range of applications. Most are related to studies on nutrients and related endogenous compounds (Table 5). The fields of proteins, fats, lipids, and carbohydrates are widely covered. Both GC MS and... 

Table 5. Fields of Application for In Vivo Clinical Stable Isotope Studies...

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