Fred C. Falkner

Ampiroxicam, an anti-inflammatory agent which is a prodrug of piroxicam

Ampiroxicam is a nonacidic ether carbonate prodrug of piroxicam. Our results demonstrate that, in contrast to piroxicam, ampiroxicam does not possess detectable prostaglandin synthesis inhibitory activityin vitro. Ampiroxicam, however, has similarin vivo potency to piroxicam in suppressing paw swelling in rat adjuvant arthritis. In an acute model of paw inflammation in rats, ampiroxicam is less potent than piroxicam itself: the ED50s of ampiroxicam are 9- and 3.5-fold higher than those of piroxicam following a single or multiple (5) daily oral doses, respectively. Using the phenylbenzoquinone stretching test as a method of evaluating acute analgetic activity, the ED50 for ampiroxicam is about 3-fold higher than that of piroxicam. These tests of activity share the property of being partially prostaglandin-dependent. Ampiroxicam itself is not observed in plasma after oral dosing to man [24], nor in the rat, dog, and monkey as reported here. Bioavailability studies show that conversion to piroxicam is about 100%, 90%, 70%, and 50% in these four species, respectively. These results indicate that ampiroxicams anti-inflammatory activity is producedin vivo by conversion to piroxicam and support its credentials as an efficacious prodrug of piroxicam.

Profile of trimazosin: an effective and safe antihypertensive agent.

Trimazosin, a selective alpha-1-adrenoceptor-blocking agent, has been extensively evaluated in over 1000 patients. In hypertensive patients, reduction in elevated blood pressure in both supine and standing positions, consequent to a reduction in systemic vascular resistance, persisted in long-term therapy. Progression of hypertension target organ damage did not occur. Improvement in blood lipids with decreased total serum cholesterol was noted in long-term therapy. In long-term studies, 74% of patients responded at a trimazosin dose of 300 mg/day or less; the maximum dose was 300 mg/day or less in 52% of patients and 200 mg/day or less in 36%. Most patients received twice a day therapy. The side effect profile of trimazosin was comparable to placebo and significantly better than that of either methyldopa or propranolol. Concomitant disease or therapy did not adversely affect the trimazosin safety profile. Hematology, clinical chemistry, and urinary parameters did not indicate deleterious effects. Because of its excellent safety and toleration profile, trimazosin may be particularly suitable in first-line therapy of patients with mild or moderate hypertension.

Metabolism of N-acetyl PGE2 carboxamide in the rat.

After intratracheal administration to rats, the bronchodilator N-acetyl PGE2 carboxamide was converted rapidly to PGE2 and 13,14-dihydro-15-keto-PGE2, the major plasma metabolite. Oxidation of the N-acetyl carboxamide by prostaglandin dehydrogenase and hydrolysis of the imide bond were demonstrated in vitro.

Synthesis of 14C isotopic isomers of tenidap—A novel antiinflammatory agent

Two isotopic isomers of tenidap, a novel antiinflammatory agent, were prepared. Compound 6 (specific activity = 10.24 mCi/mmol), having 14 C in the indole ring, was prepared in three steps (52% overall yield) starting from 1H-[ 14 C]indole-2,3-dione. Compound 11 (specific activity = 57.16 mCi/mmol, radiochemical purity = 99.0%), with 14 C in the C-3 methylene, was prepared in two steps (66% overall yield) beginning with 2-thiophenecarboxylic-[14C-carbonyl] acid.

Radioimmunoassay for sulprostone

The development of a radioimmunoassay for measuring subnanogram amounts of the prostaglandin uterine stimulant, sulprostone (N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 carboxamide), is described. The 9-carboxymethoxime derivative of sulprostone was coupled to keyhole limpet hemocyanin to prepare the immunogen, and to tyramine to yield a precursor suitable for radioiodination. The antiserum generated from rabbits was specific for sulprostone, showing cross reactivities of less than 0.1% against PGE2, PGF2 alpha, and known sulprostone metabolites. The range for routine assay of sulprostone was 10-300 pg which corresponded to 50-1500 pg/ml of plasma. The coefficient of variation for replicate analyses on the same sample was 8-12%. The assay was used to measure the plasma levels of sulprostone in patients who had received the drug intramuscularly.