Synthesis and biological activity of peptidyl aldehyde urokinase inhibitors.

Solid- and solution-phase synthesis of peptidomimetic inhibitors of urokinase-type plasminogen activator based on the sequence dSerAlaArg-al are described. The biological activities of these unique inhibitors are reported herein. Carbonate prodrugs were prepared and tested as potential drug delivery systems.

Quantitation of an orally available thrombin inhibitor in rat, monkey and human plasma and in human urine by high-performance liquid chromatography and fluorescent post-column derivatization of arginine.

An assay for the quantification of plasma and urine levels of CVS 1123, an orally bioavailable thrombin inhibitor, and its desmethyl form. CVS 738, was developed to support clinical and toxicology studies. This assay uses solid-phase extraction, reversed-phase HPLC separation, and post-column fluorescent derivatization with ninhydrin. An internal standard is added to correct for recovery. In aqueous solution, the arginine aldehyde structures of CVS 1123 and CVS 738 exist in multiple forms which can be separated under standard reversed-phase HPLC conditions. HPLC conditions were optimized to give rapid interconversion of the forms on the separation time scale, and consequently a single chromatographic peak. Extraction conditions were modified for quantitative extraction of drug compounds from large volumes of human plasma. The assay was shown to be accurate and precise, with a quantification limit of 17 ng CVS 1123/ml human plasma.

Contrasting presentation and findings between patients with rheumatic complaints taking nonsteroidal anti-inflammatory drugs and a general population referred for endoscopy.

One hundred and fifty patients with various rheumatic complaints who were taking nonsteroidal anti-inflammatory drugs (NSAIDs) and required upper gastrointestinal endoscopy were compared with 150 patients, matched for age and sex, who were also referred for gastroscopy but who did not have rheumatic complaints and were not taking these drugs. A comparison was made between the indications for endoscopy and the endoscopic findings in the two groups. Significant differences were found. Fewer patients with rheumatic complaints had normal findings, more had chronic gastric ulcer, duodenal ulcer, gastritis or mucosal erosions. Patients with rheumatic complaints were referred more frequently for anaemia and less frequently for dysphagia or abdominal symptoms. The increased severity of gastric morbidity in patients with rheumatism is probably due to damage caused by NSAIDs. The frequency and severity of upper gastrointestinal lesions in patients with rheumatic complaints taking NSAIDs cannot be estimated from the patient's complaint rate, anaemia rather than pain being the most frequent finding. Upper gastrointestinal tract endoscopy is required to make a definitive diagnosis. This has important implications for the licensing policies of regulatory authorities when considering the licensing of new nonsteroidal anti-inflammatory drugs.

The influence of cimetidine on peptic ulcer in patients with arthritis taking anti-inflammatory drugs.

Patients with arthritis who take nonsteroidal anti-inflammatory drugs (NSAIDs) often develop peptic ulceration. Withdrawal of the NSAID may lead to increased debility and thus it may be desirable to continue the NSAID while attempting to heal the ulceration by additional therapeutic measures. We have investigated the effect of cimetidine in this role. Patients with gastroscopically-proven peptic ulcer associated with NSAID ingestion were given either cimetidine or placebo treatment while continuing to take their NSAIDs. It was found that the ulceration healed in some patients over a 6-week period even on placebo treatment. There was no statistical difference found between the healing of these ulcers when compared with the cimetidine-treated group. The mechanism of NSAID-induced ulceration and the reason for the above finding is discussed.