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Twelve normal subjects each received single 300-, 600-, and 1200-mg oral doses of oxaprozin according to a three-period crossover design. Total drug plasma concentrations did not increase in proportion to the dose administered. Total clearance (CIo) and volume of distribution (Vd) increased with dose, though elimination t1 2 remained unchanged. The fraction of unbound oxaprozin in plasma (fup) varied linearly with total plasma concentration: it increased from 0.068 per cent at 10 micrograms/ml to 0.180 per cent at 170 micrograms/ml. A parameter fup was therefore introduced to express the average degree of unbound drug plasma for a given dose, and to allow the calculation of unbound volume of distribution (Vdu) and intrinsic clearance (CIi) as if binding were constant. Even though fup increased with dose, the overall binding in the body (fub approximately 0.52 per cent) was relatively stable. Neither Vdu nor CIi changed with dose; hence, unbound oxaprozin kinetics can be considered to be linear. Protein binding had no effect on unbound oxaprozin plasma levels within the given dose range, and there was a one-to-one proportionality between the dose administered and the unbound drug concentration in plasma.

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Twelve healthy volunteers received single 1200-mg oral doses of oxaprozin while fasting and immediately after a standard breakfast in a two-period crossover design with three weeks between administrations. Oxaprozin plasma concentrations were monitored during a 10-day period after each dose. No statistically significant differences were noted between kinetic parameters obtained in the fasting and post-prandial states for mean peak plasma concentrations (Cmax, 103 vs. 109 micrograms/ml), absorption rate constants (ka, 1.1 vs. 0.8 h-1), or total AUC (7042 vs. 7066 micrograms/ml X hr). Compared with doses administered during fasting, postprandial doses led to a delay in the onset of absorption in the gastrointestinal tract (lag time t0, 24 vs. 9 min), but not in the peak time (tmax approximately 5 hours). Oxaprozin's mean residence time t was slightly shorter for subjects in the postprandial state (72 hours) than for those in fasting state (73 hours), probably because of the intrasubject variability in half-life (48 vs. 50 hours). The results of this study indicate that the ingestion of food has no effect on the bioavailability of oxaprozin.

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Oxaprozin, a new nonsteroidal antiinflammatory agent, was studied alone and in combination with aspirin for its effects on hemostasis and protein binding in 10 healthy adults. When both oxaprozin and aspirin were given separately for seven days and in combination for five days, both drugs prolonged bleeding time and inhibited collagen- and epinephrine-induced platelet aggregation to a similar degree. The effects of the combination of oxaprozin and aspirin were not additive. The data from the protein binding study showed that oxaprozin was more than 99 per cent bound to plasma proteins. Aspirin displaced oxaprozin from its binding sites. As a result, the rate of plasma clearance of oxaprozin significantly increased from 20 to 26 ml/min/kg (P less than 0.05), and the plasma half-life decreased from 45 to 40 hours. Platelet count and the humoral clotting mechanism were not affected by either drug alone or in combination. There was no clinical evidence of bleeding. One subject who received oxaprozin for 12 days and, in addition, aspirin for the last five days developed a rash that subsided after both drugs were discontinued; one subject treated with aspirin experienced tinnitus. These data suggest that oxaprozin, like aspirin and other nonsteroidal antiinflammatory drugs, should be used with caution when administered to patients who have suffered trauma, who undergo surgery, or who have known defects in hemostasis.

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Oxaprozin, a new long-acting, antiinflammatory agent, and aspirin were compared utilizing gastroscopic evaluation and photography of the gastric mucosa in a double-blind, crossover study in normal volunteers. Submucosal hemorrhages or mucosal bleeding was observed in seven of eight subjects on aspirin and in only two of eight on oxaprozin (P = 0.061). Adverse effects were experienced by seven of eight subjects after the aspirin treatment period--tinnitus in five and gastrointestinal symptoms in four. Only one patient had mild diarrhea on oxaprozin. The incidence of adverse effects was found significantly higher with aspirin therapy (P less than 0.001). No laboratory abnormalities of clinical significance were attributed to either drug administration. Results after ten days of treatment show that oxaprozin in therapeutic dose levels (1200 mg once a day) produces significantly fewer changes in the gastric mucosa than aspirin (975 mg administered four times a day, total daily dose 3.9 Gm) in the same subjects, who received both drugs in this double-blind, crossover experiment with a four-week washout period between treatments.

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Preliminary clinical studies showed that oxaprozin (4,5 Diphenyl-2-oxazolepropionic acid) has anti-inflammatory and analgesic properties with a plasma half-life of about 40 hours. Consequently, a multicentre, double-blind parallel trial was conducted for 12 weeks at thirteen investigator sites, utilizing 212 patients with classic rheumatoid arthritis and comparing oxaprozin 600 mg/day, oxaprozin 1200 mg/day and aspirin 3900 mg/day. Both the oxaprozin and aspirin-treated patients had statistically significant improvement from baseline periods, in most key categories evaluated. Oxaprozin administered twice a day (b.i.d.) was as effective as aspirin administered four times a day (q.i.d.) and caused significantly less tinnitus (p less than 0.001). Fewer patients receiving high dose oxaprozin (2%) dropped out of the study because of unsatisfactory response than did those receiving aspirin (10%). There were no clinically significant laboratory abnormalities in the gastro-intestinal, renal, hepatic or haematological parameters monitored. This study suggests that oxaprozin is effective and well tolerated in the treatment of rheumatoid arthritis.

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The effect of intravenous and intramuscular administration of ceruletide on gallbladder contraction was investigated in 67 normal volunteers and patients. Of the 45 normal volunteers, 33 received the drug intravenously and 12 intramuscularly in graded ascending doses. By either means of injection, ceruletide produced a substantial contraction of the gallbladder with a measurable reduction in gallbladder area. Based on findings in these groups, the 22 patients requiring oral cholecystography for clinical evaluation received 0.3 microgram/kg intramuscularly. The intramuscular administration of synthetic ceruletide after oral cholecystography, in a dose of 0.o microgram/kg, afforded a safe and effective means of gallbladder contraction, with resultant cystic and common bile duct visualization. Side effects occurred less frequently when the drug was administered intramuscularly and were minimal and self-limiting. Peak contraction (40% or greater reduction in size) occurred as early as 5-15 min after after intramuscular injection and in most instances within 30 min.

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The intravenous administration of sincalide, the C-terminal octapeptide fragment of cholecystokinin, affords safe and effective means for gallbladder contraction with resultant cystic and common bile duct visualization. Intravenous sincalide circumvents the problem of unpredictability of response of the gallbladder to a fatty meal and variability in the rate of release of endogenous cholecystokinin. Peak gallbladder contraction occurs earlier than with a fatty meal.

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