9,11-Iminoepoxyprosta-5,13-dienoic acid is a selective thromboxane A2 synthetase inhibitor.

9,11-Iminoepoxyprosta-5,13-dienoic acid inhibits the thromboxane A2 synthetase in platelet and lung microsomal enzyme preparations and in intact platelets. It does not inhibit the protaglandin I2 synthetase in aorta or lung microsomes and intact Balb 3T3 fibroblasts. In lung microsomes, which contain both enzymes, 9,11-iminoepoxyprosta-5,13-dienoic acid inhibits only thromboxane A2 formation and augments prostaglandin I2 formation. This inhibitor is more selective than other reported prostaglandin endoperoxide analogs which inhibit the platelet thromboxane synthetase.

A thiazole compound with potential antithrombotic activity.

A thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administrative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

Long term bile collection in the rat.

Bile was collected from the rat continuously, over an extended period, using an externalized cannula brought through an intrascapular incision. The cannula was protected by a 30-cm, 16-gauge stainless steel tube attached to the skin through the incision. The rat was housed in a 10.2 x 10.2 x 12.7 cm cage at a lever higher than the collection vial to aid in drainage of bile. A hole in the vial cap permitted the cannula to turn freely as the rat moved about the cage. This method allowed bile to be collected conveniently over long periods of time with minimal restraint of the animal.

Duration of activity of the acid, methyl ester and amide of an orally active platelet aggregation inhibitory prostanoid in the rat.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene PGE1 (OI-PGE1) has been shown to be a more potent inhibitor of ADP-induced human platelet aggregation than PGE1. OI-PGE1 inhibits ex vivo ADP-induced platelet aggregation for 60 minutes after an oral dose of 20 mg/kg to rats. Present studies compare duration of ex vivo inhibition of ADP-induced platelet aggregation in the rat by OI-PGE1, its methyl ester and amide after administration by various routes. All oral (p.o.) and intraduodenal (i.d.) doses were 20 mg/kg and all intravenous (i.v.) doses were 1 mg/kg. OI-PGE1 and its methyl ester had the same duration of activity after i.v. (60 min.) and p.o. (60 min.) administration, however, the methyl ester, when administered i.d., had a longer duration of activity than the free acid i.d. (greater than 90 min. vs. 60 min.). OI-PGE1-amide had significantly longer duration than the acid or methyl ester after i.v. (greater than 120 min.), p.o. (greater than 240 min.) or i.d. (greater than 240 min.) administration. Present data suggest that in the rat (1) intestinal absorption of OI-PGE1-methyl ester is more efficient than it is for the free acid and (2) due to metabolic and/or distributional differences between OI-PGE1 and its amide, the amide has a much greater duration of activity.

Intestinal absorption of polymeric derivatives of the food dyes sunset yellow and tartrazine in rats.

1. Absorption and metabolism of 14C-labelled sunset yellow (FD & C Yellow No. 6), tartrazine (FD & C Yellow No. 5) and high molecular weight polymeric derivatives of the two azo dyes were compared in rats. 2. A trace to 1.5 percent of unchanged monomeric dyes was excreted in urine and bile during the first 24 h after dosing. No unchanged dye was absorbed after administration of the polymeric derivatives. 3. In animals dosed with sunset yellow and its polymer derivative, absorption of the azo-bound cleavage product 1-amino-2-naphthol-6-sulphonic acid was 8.5 and 6.9 percent, respectively, while absorption of the cleavage product sulphanilic acid was 37.4 and 0 percent, respectively. 4. In animals dosed with tartrazine and its polymer derivative, absorption of the cleavage product aminopyrazolone and its metabolites was 4.0 and 4.6 percent, respectively. 5. Azo bond cleavage did not appear to be decreased in the polymer derivatives. However, the sulphanilic acid moiety of both dyes remained attached to the polymer backbone, resulting in a 95 percent decrease in sulphanilic acid absorption with polymeric tartrazine. 6. Decreased absorption of unchanged dyes and certain metabolites with the stable, non-absorbed polymeric derivatives may be significant in developing non-sensitizing substitutes for these two commonly used food colourants.

Hydrolysis of an orally active platelet inhibitory prostanoid amide in the plasma of several species.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGE1-amide (OI-PGE1-amide) has a prolonged duration of oral platelet aggregation inhibitory activity when compared to the parent free acid (OI-PGE1) in the rat. When incubated in rat plasma at 1 microgram/ml for 30 seconds prior to addition of ADP, OI-PGE1-amide inhibits in vitro rat platelet aggregation approximately 50%. OI-PGE1 inhibits at 1 ng/ml. Inhibition of platelet aggregation by plasma incubated with OI-PGE1-amide (1 microgram/ml) increases with time and the rate of this increase differs with species. Incubation of OI-PGE1 in plasma does not result in an increase of platelet inhibitory activity with time. The increase of platelet inhibitory activity was assumed to indicate hydrolysis of OI-PGE1-amide to the more active OI-PGE1. A compound, different from OI-PGE1-amide, was isolated by an ion exchange/silica gel separation sequence from an incubation of OI-PGE1-amide in rat plasma. It had potent platelet aggregation inhibitory activity. This material was shown to be OI-PGE1 by thin-layer chromatography, gas chromatography and mass spectral analysis. Studies with [3H]-OI-PGE1-amide confirmed the formation of OI-PGE1 in plasma incubations. Amide hydrolytic activity was significantly different between species, the rank order being: rat greater than guine pig greater than monkey = human greater than dog. This relationship corresponded with that determined by measuring the increase in platelet inhibitory activity with time in plasma incubations of OI-PGE1-amide reported above. Present data indicate that (a) OI-PGE1-amide is hydrolyzed to the parent acid by plasma enzymes of several species and (b) hydrolytic activity of plasma varies widely between species.

Guidelines for quality assurance in multicenter trials: a position paper.

In the wake of reports of falsified data in one of the trials of the National Surgical Adjuvant Project for Breast and Bowel Cancer supported by the National Cancer Institute, clinical trials came under close scrutiny by the public, the press, and Congress. Questions were asked about the quality and integrity of the collected data and the analyses and conclusions of trials. In 1995, the leaders of the Society for Clinical Trials (the Chair of the Policy Committee, Dr. David DeMets, and the President of the Society, Dr. Sylvan Green) asked two members of the Society (Dr. Genell Knatterud and Dr. Frank Rockhold) to act as co-chairs of a newly formed subcommittee to discuss the issues of data integrity and auditing. In consultation with Drs. DeMets and Green, the co-chairs selected other members (Ms. Franca Barton, Dr. C.E. Davis, Dr. Bill Fairweather, Dr. Stephen George, Mr. Tom Honohan, Dr. Richard Mowery, and Dr. Robert O'Neill) to serve on the subcommittee. The subcommittee considered "how clean clinical trial data should be, to what extent auditing procedures are required, and who should conduct audits and how often." During the initial discussions, the subcommittee concluded that data auditing was insufficient to achieve data integrity. Accordingly, the subcommittee prepared this set of guidelines for standards of quality assurance for multicenter clinical trials. We include recommendations for appropriate action if problems are detected.