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In order to discover novel compounds with anti-platelet aggregation activities, a series of novel 2-methoxy-5-arylamido-N-(pyridin-3-ylmethyl)benzamides (1a-n) were synthesized and their anti-platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP) (5 mM/L), arachidonic acid (AA) (20 µM/L), and collagen (1 mg/mL). Those synthesized compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit-8 (CCK-8) assay. The biological evaluation revealed that compound 1a (IC50 : 0.21 µM/L) exhibited the highest anti-platelet aggregation activities when ADP was selected as an inducer, and compound 1b (IC50 : 0.23 µM/L) showed the best activities when AA was selected as inducer, and compound 1m (inhibition rate: 55.06%) had significant anti-platelet aggregation activities when collagen was selected as inducer among all target compounds. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L929 cells. Therefore, 2-methoxy-5-arylamido-N-(pyridin-3-ylmethyl)benzamides have the potential to become a novel kind of anti-platelet drugs and deserve further study.

OBJECTIVES To explore the possible role of of 8-isoprostane F2α (8-IPF2α) in the aetiology of erectile dysfunction (ED), as the over-production of superoxide (O2-) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in the formation of 8-IPF2α in vascular tissue, which has similar properties to thromboxane A2 (TXA2). TXA2 is vasoconstrictor and up-regulates the expression of NADPH oxidase and phosphodiesterase type 5 (PDE5). MATERIALS AND METHODS Cavernosal vascular smooth muscle cells (CVSMCs) were incubated with 8-IPF2α or the TXA2 analogue, U46619, ±sildenafil, iloprost (a stable prostacyclin [PGI2] analogue) or the nitric oxide (NO) donor NONOate for 16 h. The formation of O2- was then measured, PDE5 expression assessed using Western blotting and PGI2 and 8-IPF2α formation measured using enzyme-linked immunoassays. RESULTS 8-IPF2α promoted the formation of O2-, an effect inhibited by apocynin (an NADPH oxidase inhibitor) and up-regulated the expression of PDE5. Under identical incubation conditions, 8-IPF2α induced an increase in the formation of 8-IPF2α but reduced the formation of PGI2. All, these effects were reversed by sildenafil, iloprost, NONOate and picotamide. CONCLUSIONS These data show that O2- derived from NADPH oxidase influences the relative balance of PGI2 and 8-IPF2α in CVSMCs, which in turn alters the degree of PDE5 expression. This is a novel pathogenic mechanism underlying ED and a novel mechanism of action of sildenafil.

Pancera P, Sansone S, Secchi S, Covi G, Lechi A (University of Verona, Verona, Italy). The effects of thromboxane A2 inhibition (Picotamide) and angiotensin II receptor blockade (Losartan) in primary Raynaud's phenomenon. J Intern Med 1997; 242: 373–6. Objectives To assess the role of thromboxane A2 and of angiotensin II in patients with primary Raynaud's phenomenon. Design After an eight-day run-in period, the patients were enrolled in a single-blind, cross-over, study. Setting Patients were examined at the Ambulatory for Microcirculatory Diseases of the Clinic of Internal Medicine, University Hospital, Verona. Subjects Fifteen subjects affected by primary Raynaud's phenomenon were included. Main outcome measures A piezoelectric plethysmography to evaluate the distensibility of the digital arteries as the ratio between peak time (PT) and total time (TT), and an oscillometric blood pressure recorder were used after the run-in period, and after a two-week course of picotamide (300 mg b.i.d., i.e. two times daily) or losartan (12.5 mg once daily) with an interval of a week of placebo between the active treatments. The tests were performed after every treatment in basal condition and during mental stress. The patients reported in a diary the number and the severity (from 0 to 4 +) of the vasospastic crises. Results The change in TP/TT ratio appeared statistically significant only after losartan treatment, both in basal condition and during mathematical stress. Both pharmacological treatments, with respect to placebo, showed an improvement of the scores, derived from the number and severity of vasospastic attacks, but only the therapy with losartan determined a statistically significant improvement. Conclusions The inhibition of the type 1 receptor for angiotensin II seems highly effective in the reduction of the vasospastic crises in the subjects with primary Raynaud's phenomenon. According to our experience, losartan could be used more extensively in the treatment of these patients besides arterial hypertension.

Background : Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A 2 has been proposed as a possible inflammatory mediator ; its suppression may be a useful therapeutic option. Methods : Using a tissue incubation technique, we compared release of immunoreactive thromboxane B 2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. Results : Increased amounts of thromboxane B 2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147-325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61-140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64-206), 8). Incubation with picotamide at concentrations between 100 μM and 1 mM reduced thromboxane B 2 release (IC 50 890 μM). Conclusion : Since increased thromboxane A 2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.