The broad, long-range objectives are to develop state-of art mass spectrometric (MS) methodologies for: (i) the specific, sensitive, and rapid monitoring of drug levels in serum and urine samples from patients on ACTG protocols and (ii) the investigation of the effects of disease states and advanced age on the metabolism of drugs used in ACTG protocols. There will be five specific aims: (1) Investigate the utility of electrospray (at atmospheric pressure) ionization, in the single ion monitoring mode, as a """"""""universal"""""""" ionization technique for the quantification of low molecular weight, underivatized drugs and their metabolites using: (i) direct injection (without chromatographic separation) of serum or urine ultrafiltrates, or (ii) effluents from single or switched multiple chromatographic columns capable of handling direct serum or urine injections; (2) Develop quantification techniques of oligonucleotides, interferons, and other high molecular weight drugs of interest in serum and urine using electrospray ionization; (3) Develop MS """"""""referee"""""""" techniques for drugs commonly used in existing ACTG protocols, employing combined liquid or gas chromatography-MS techniques with fast ion bombardment, thermospray, electrospray, or chemical ionization; (4) Explore the use of multiple ion monitoring techniques for the simultaneous quantification of drugs and their metabolites in combination chemotherapy; (5) Use MS or tandem MS (MS/MS) techniques of high specificity to identify in serum and urine samples from patients with renal or hepatic failure, or of advanced age: (i) endogenous constituents the concentration of which drastically changes chromatographic profiles with respect to patients without these conditions, thereby interfering with the chromatographic analysis of drug or metabolite levels; (ii) the effects of these conditions on drug metabolism, i.e., appearance of additional metabolites and/or excessive changes in metabolite concentrations. These new methodologies will be of immediate and direct benefit to patients on ACTG protocols because they will lead to dose and regimen adjustments to increase efficacy and reduce toxicity.
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