Thromboxane released from activated platelets and prostacyclin of the vessel wall may act as potent antagonistic modulators of platelet aggregability and coronary vascular tone. Therefore, urinary excretion of their major metabolites, 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1 alpha, was studied in 16 patients presenting with prolonged angina at rest. The 10 patients whose condition did not improve under vigorous antianginal treatment within 48 hours exhibited higher thromboxane metabolite excretion than did the 6 patients who responded to therapy (2,208 +/- 1,542 versus 609 +/- 312 ng/g creatinine; p less than 0.001). Elevated values were also found in four of eight patients with sustained postinfarction angina. Enhanced thromboxane metabolite excretion was frequently associated with angiographic evidence of thrombus formation. When nine patients were restudied in a stable phase after 11 +/- 5 months, thromboxane metabolite excretion was consistently normal or high normal. Excretion of prostacyclin metabolites was not depressed in any patient but correlated weakly with thromboxane (r = 0.41). Thus, enhanced thromboxane production as an index of platelet activation may identify patients with active thrombus formation who could benefit most from platelet inhibitory treatment.

The so-called simple proteins isolated from the endotoxin of Serratia marcescens 08 and whole cells Escherichia coli 0 141 :K85(B) by aqueous phenol treatment were characterized by the determination of hydrodynamic properties, electrophoretic behavior, immunochemical specificity and chemical analysis. The chemical composition of both proteins revealed the presence of small amount of lipid A constituents such as glucosamine, phosphorus and fatty acids ; the p-hydroxymyristic acid regarded as the characteristic marker for lipid A was present in all protein preparations. Since the treatment of intact endotoxin or bacterial cells with aqueous phenol results in the formation of two fragments (a lipopolysaccharide and a lipid A-protein), both of which are characterized by the presence of lipid A constituents, this dissociation seems to be caused by cleavage of a phenolsensitive linkage within the molecule of lipid A rather than at its point of attachment to the protein moiety. Thus, the %imple'' protein preparations consist of the protein moiety and a small segment of lipid A. Contrary to previous views, such protein preparations are not simple proteins if this designation implies absence of constituents other than amino acids. However, for a historical reason we suggest that the term simple protein be retained for protein fragments isolated by aqueous phenol treatment of intact endotoxins.The simple protein from Serratia marcescens 0s was treated successively with trypsin and pronase. The resulting trypsin and pronase cores contained increasing amounts of lipid A constituents firmly bound to the residual protein moiety. Since lipid A was separated as an entity from the protein moiety only after acid hydrolysis of the pronase core, it is proposed that in intact endotoxin lipid A is covalently linked to the protein moiety. The absence of any detectable glucosamine and fatty acids in the mixture of peptides and amino acids released by trypsin and pronase, indicated a single point attachment between the lipid A and protein moieties.The protein moieties from Serratia marcemens and Escherichia coli were immunogenic and possessed a common antigenic determinant. Both trypsin and pronase cores retained the immunogenicity and revealed the presence ofa common antigen with the parent simple protein. This second set of antigenic determinant(s) different from the specific 0-antigens seems to be located in the protein moiety close to lipid A.It is generally accepted that the endotoxin or somatic 0-antigen complexes occurring in the cell walls of gram-negative bacteria represent macromolecular entities composed of lipid, polysaccharide and protein moieties [1,2]. Evidence for this structural complexity was presented in early studies by Morgan and Partridge [3-51 who showed that endotoxins isolated from Shigella dysenteria and Salmonella typhosa could be resolved by successive treatments with formamide and 900/, phenol into a

Adverse events, particularly gastrointestinal, partially offset the therapeutic value of NSAIDs. The abilities of nimesulide to inhibit COX-2 preferentially and to exert other novel anti-inflammatory actions are consistent with good efficacy and safety. This is borne out by a double-blind multicentre comparison of nimesulide and diclofenac in 122 patients with acute shoulder, and by a meta-analysis of various nimesulide trials. At the end of the 14 day double-blind study, nimesulide was at least as effective as diclofenac (investigator ratings: good/very good in 79.0% of patients given nimesulide, and 78.0% with diclofenac; patient ratings: good/very good in 82.3 and 78.0% respectively). Four patients (6.5%) dropped out in the nimesulide group (two early recovery, one lack of effect, one adverse event), compared with 13 (21.7%) in the diclofenac group, due mainly to adverse events (P=0.003). Global tolerability was judged by the investigators to be good/very good in 96.8% of the nimesulide group compared with 72.9% of those given diclofenac. Judgements by the patients were 96.8 and 78.0% respectively. Both differences are highly significant statistically. The meta-analysis demonstrates that nimesulide given for 2 weeks is far more efficacious than placebo in treating osteoarthritis, and is at least comparable to other NSAIDs The benefit-risk ratio for nimesulide was better in all individual studies since 100 mg nimesulide twice daily was about equal to placebo in safety and tolerability, especially regarding gastrointestinal adverse events.

UK-38,485, a novel imidazole derivative, was used in two clinical trials with healthy male subjects to study the influence of thromboxane synthetase inhibition on prostanoid formation. In an open pharmacokinetic study, UK-38,485 administered orally in doses of 10,20, 40, 60, and 100 mg significantly reduced serum thromboxane (TXB2) concentrations. With lower doses (10 and 20 mg) peak inhibition of serum thromboxane occurred 2 hr after dosing, with a mean percentage inhibition of 78% and 91%, respectively. For the higher doses (40, 60, and 100 mg) peak inhibition exceeded 99% 1 hr after dosing. After 8 hr the inhibition was dose related, ranging between 59% and 75%, and after 24 hr between 0 and 35%. In a second multiple-dose, double-blind, placebo-controlled, cross-over study, 50 mg UK-38,485 given twice daily for 1 week selectively inhibited thromboxane synthetase. The excretion of 2,3-dinor-TXB2, the major urinary metabolite of endogenously formed thromboxane, was significantly reduced, whereas the urinary excretion of 2,3-dinor-6-keto-PGF,a, the main metabolite of endogenous prostacyclin, and the plasma concentrations of 6-keto-PGF,a showed no significant increases compared with levels in the placebo period. In platelet suspensions stimulated ex vivo with arachidonic acid and in serum of incubated whole blood, TXB2 concentrations were reduced and a significant redirection of endoperoxide metabolism to antiaggregatory and vasodilatory prostaglandins '2, E2, and D2 was demonstrated after the influence of UK-38,485. Platelet lipoxygenase metabolites were not measurably altered. The drug was well tolerated. In both studies, no clinically relevant changes in laboratory safety and hemodynamic parameters, bleeding, or clotting time were observed. From the time course of the plasma drug concentrations, the inhibition of thromboxane synthesis, and the redirection of endoperoxide metabolism it can be concluded that UK-38,485 is rapidly absorbed and has a long-lasting effect on prostanoid formation. Circulation 68, No. 4, 821-826, 1983. THROMBOXANE A2 (TXA2) and prostaglandin (PG) 12 exert opposite effects on platelet aggregation and vascular resistance, and the balance between these compounds has been proposed to be one of the factors that determine platelet reactivity, endothelial thromboresistance, and vascular tone. 485,'5 in healthy male subjects.The potency and specificity of action of this drug were examined by

The aim of the present investigation was to compare the efficacy and tolerability of azelastine (CAS 58581-89-8) (1.12 mg/day) and levocabastine (CAS 79547-78-7) (0.4 mg/day) nasal spray administered twice daily to patients with seasonal allergic rhinitis. A total of 180 patients participated in a 4-week, double-blind, parallel group (n = 90 each) study. Symptom severity of nasal, ocular and other symptoms were recorded, out of which a total symptom score (TSS) was calculated. Physicians assessed symptoms at baseline and at days 7, 14, and 28, patients and physicians evaluated the efficacy and tolerability. After 4 weeks of treatment with azelastine the mean overall TSS was reduced from a baseline score of 18.7 to 4.2, after levocabastine from 17.8 to 5.9. Patients morning scores for treatment days 1 to 28 gave a mean total score of 212.4 for the azelastine group and 230.6 for the levocabastine group; the equivalent evening scores yielded a mean total score of 115.5 and 175.6 respectively. Global efficacy was judged by physicians as either 'very good' or 'good' for 90% of azelastine patients and for 74% of the levocabastine group; 92% of azelastine patients and 76% of levocabastine patients judged treatment to be either 'very good' or 'good'. No serious adverse events were reported, all adverse events were related to nasal symptoms. Both azelastine and levocabastine administered twice daily as a nasal spray provide effective and well tolerated symptomatic treatment of seasonal allergic rhinitis. Azelastine, however, was statistically superior in efficacy as well as in safety (PWei-Lachin < 0.0001, combined results).