Acidic non-steroidal anti-inflammatory agents represent a large group of closely related compounds prescribed for the many patients suffering from rheumatic diseases. The mode of action of this group of drugs has been related to prostaglandin synthetase inhibition. This action is non- specific and may also be responsible for the gastric irritation and bleeding which constitute a major side effect. It is important therefore for patients being treated with such non-specific high dosing agents to be far better controlled than they are at present. Methods providing simple, rapid analysis of body fluids must be developed and adapted for routine use in clinical situations. These techniques are also necessary for an investigation into possible reasons for disparate drug activities observed in patients with rheumatic disease responding differently to different acidic drugs. The technique of High Pressure Liquid Chromatography (HPLC) has been explored as a means to these ends. The novel procedure of 'ionic suppression' in HPLC employing a reversed phase column and aqueous acidic solvent, based upon the physico-chemical properties of the acidic anti-inflammatory agents studied, has been developed for routine use. The procedure has been found to afford flexibility, selectivity, load capacity, sensitivity, speed and convenience over previously reported analytical methods. It is also capable of being exploited in the analysis of newly developed related drugs. The results obtained from the application of the HPLC procedure developed have been:- (1) the determination of ten non-steroidal anti-inflammatory agents in plasma and urine, (2) the application in a clinical trial of Benoxa-profen, (3) the assistance to clinicians at the Royal National Hospital for Rheumatic Diseases in providing rapid evaluation of patient compliance, (4) the simultaneous determination of four nonsteroidal anti-inflammatory agents and their metabolites in plasma and urine, (5) the profile study of levels of Sulindac and its metabolites in the plasma of a healthy volunteer after a single oral dose over 24 hours, (6) the examination of clinical urine and plasma samples of a patient treated with Clinoril and naproxen, (7) the separation of the glucuronide conjugates of ketoprofen and benoxaprofen, (8) the detection of hydroxyketoprofen as a metabolite of ketoprofen in rabbit. HPLC techniques have thus been established by this study as a most valuable aid to the modern therapy of rheumatic diseases. Improvements in detector technology will afford greater sensitivity and should extend the scope of its therapeutic applications.
|Date of Award||1979|