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Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha1-adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current gold standard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α1-adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A2 (TXA2), endothelins, or muscarinic receptor agonists. Here, we studied effects of the thromboxane A2 receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α1-adrenoceptor agonist phenylephrine, the thromboxane A2 analog U46619, and electric field stimulation (EFS) induced concentration- or frequency-dependent contractions of trigone tissues in an organ bath. Picotamide (300µM) inhibited carbachol-, phenylephrine-, U46619-, and EFS-induced contractions. Endothelins 1-3 induced concentration-dependent contractions of prostate tissues, which were inhibited by picotamide. Analyses using real time polymerase chain reaction and antibodies suggested expression of thromboxane A2 receptors and synthase in trigone smooth muscle cells. Thromboxane B2 (the stable metabolite of thromboxane A2) was detectable by enzyme immune assay in trigone samples, with most values ranging between 50 and 150pg/mg trigone protein. Picotamide inhibits contractions induced by different stimuli in the human lower urinary tract, including cholinergic, adrenergic, thromboxane A2- and endothelin-induced, and neurogenic contractions in different locations of the outflow region. This distinguishes picotamide from current medical treatments for LUTS, and suggests that picotamide may induce urodynamic effects in vivo.

Effects of picotamide and zileuton on tonic contractile activity of the rat portal vein preparations, induced by acetylcholine (2.10(-5) mol/1) and phenylephrine (5.10(-7) mol/1) were investigated. Conversion of arachidonic acid products (prostaglandins, leukotrienes) synthesized by endothelial cells, plays an important role in the local regulation of vascular tone. The compounds formed in a cascade of enzymatic transformations can modulate the effect of other vasoactive factors. Picotamide (6,5.10(-5) mol/1) - thromboxane receptor and thromboxane -synthase blocker - depress acetylcholine-induction tonic contraction of isolated segments of portal vein with intact endothelium by 29% and norepinephrine-induction reduction of 45% relative to the control values. The obtained results indicate a participation of thromboxane and/or endoperoxide H2 in this reaction. Partial inhibition of the contractions by 5-lipoxygenase blocker zileuton(4,2.10(-5) mol/1) at 23% relative to control values suggests, that products of lipoxigenase pathways of arachidonic acid conversion are involved in mechanisms of specified reactions. These data indicate complex mechanisms of regulation of vascular tone of the portal vein, which play an important role eicosanoids. Further study of these mechanisms is necessary for the formation of basic knowledge, as well as to elucidate the mechanisms of occurrence and development of pathological conditions of vessels and the development of methods of their correction.

Thromboxane A 2 (TXA 2 ) upregulates and activates NADPH oxidase (Nox) both of which are associated with cardiovascular disease. The aim of this study, therefore, was to investigate the relationship between thromboxane A 2 synthase (TXAS) status and Nox in human vascular smooth muscle cells (hVSMCs), in particular, whether superoxide (O 2 ▪− ) derived from Nox influences TXAS expression and activity. hVSMCs were incubated with TNFα: (10 ng/ml), TXA 2 mimetic U46619 (100 nM), 8-isoprostane F 2α (8-IP; 100 nM) and hypoxia. Expression of TXAS was assessed using western blotting and quantitative PCR. The role of Nox1 and Nox4 was studied using apocynin and mRNA silencing. The effect of the thromboxane receptor antagonist picotamide and of iloprost, a prostacyclin (PGI 2 ) analogue was also studied. TNF-α, U46619 and 8-IP and hypoxia all augmented TXAS expression as well as TXA 2 formation, effects inhibited by apocynin. Nox-1 (but not Nox4) gene silencing inhibited the increase in TXAS expression and activity. Both picotamide and iloprost inhibited the upregulation of TXAS as well as TXA 2 formation induced by TNF-α, U46619 and 8-isoprostane F 2α and hypoxia. It is concluded that upregulation of TXA 2 synthase expression and activity in human VSMCs is mediated by an a priori upregulation of Nox1 and represents a self amplifying cascade. The inhibition of this effect with iloprost consolidates that PGI 2 plays a protective anti-oxidative role in the vasculature and that picotamide and like drugs may be effective in reducing the incidence of cardiovascular disease associated with an oxidative aetiology.

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.

This review describes the current status of antiplatelet therapy in prevention of cardiovascular events of an atherothrombotic nature. The efficacy of aspirin clearly outweighs bleeding risk in secondary prevention, with the relevant exception of patients with peripheral arterial disease (PAD). In trials of primary prevention, aspirin has a limited advantage, which is challenged by the risk of major bleeding. A typical example is primary prevention in type 2 diabetes mellitus, in which a number of trials and a recent meta-analysis have confirmed these limitations. In various settings, clopidogrel has been shown to be marginally more effective than aspirin. Despite a non-negligible bleeding risk, the combination of aspirin-clopidogrel has provided satisfactory results in conditions at high thrombotic risk but rather disappointing results in the long-term treatment of chronic stable cardiovascular disease. The combination of aspirin-dipyridamole was shown to be superior to aspirin alone and equivalent to clopidogrel alone for secondary prevention in cerebrovascular patients. Limitations in the efficacy of antiplatelet agents are partly inherent in their mechanism of action and should not be considered simply as 'treatment failures'. Among other factors, individual variability of response to antiplatelet drugs also plays a meaningful role. Variability of response and 'resistance' may result from drug interactions, baseline and residual platelet hyperactivity, increased platelet turnover, pharmacogenetic factors and others. Poor biological response to aspirin and/or clopidogrel is also frequent in clinical settings such as diabetes, obesity and acute coronary syndromes. The correlation between biological resistance and impaired clinical efficacy of aspirin, and especially clopidogrel, is currently accepted, although with limitations due to the different methods used to assess platelet response. Indeed, the concept of individual 'tailoring' of antiplatelet regimens on the basis of previous laboratory or 'point of care' platelet function tests has been validated in a number of recent trials. The search for and validation of new antiplatelet agents with already known, or totally new, mechanisms of action have also been undertaken with increasing eagerness. Among new adenosine diphosphate receptor antagonists, prasugrel is already registered, and ticagrelor and cangrelor are being developed. New mechanisms being explored are blockade of thrombin-induced platelet aggregation (vorapaxar [SCH 530398]), and inhibition of collagen and ristocetin-mediated platelet functions (DZ-697b). Reappraisal of the neglected class of direct thromboxane A(2) antagonists was followed with less interest. Besides blocking the effects of thromboxane produced from platelets, drugs of this class (such as terutroban sodium and picotamide) may also protect cells from thromboxane produced by sources other than platelets, and some of them may preserve or enhance prostacyclin production. Terutroban is presently being tested in PAD and stroke prevention. Picotamide, marketed in Italy, was shown to reduce cardiovascular events and mortality in studies of PAD patients with diabetes. The results available with thromboxane inhibitors are particularly interesting because they are being obtained in conditions, such as type 2 diabetes and PAD, which are known to be refractory to aspirin.

Aims Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD). Methods and results A total of 1209 adults aged 40–75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31–0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance. Conclusion Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.

OBJECTIVE: Scavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling. APPROACH AND RESULTS: Male C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11-12, p

2-1(4-Cyanophenyl)aminol-3-chloro-1,4-naphthalenedione (NQ-Y15) is a dual action drug which acts as a thromboxane A2 (TXA2) synthase inhibitor and TXA2/PGH2 receptor antagonist. In the present study, we examined the effects of NQ-Y15 on Ca2+ mobilization, which is the common event in various types of platelet activation, in arachidonic acid (AA)-stimulated rat platelets. The elevation of cytosolic Ca2+ concentration ([Ca2+]i) induced by AA was inhibited by NQ-Y15 in a concentration-dependent manner. This inhibition-effect of NQ-Y15 was found to be based on the suppression of the rise in [Ca2+]i by the inhibition of both Ca2+ release from internal stores and Ca2+ influx from the extracellular space. Our successive trial was focused on the role of cyclic AMP (cAMP) in the action of NQ-Y15, because cAMP was reported to be increased by dual action drugs such as picotamide and to inhibit the increase in [Ca2+]i. NQ-Y15 was confirmed to increase cAMP in AA-stimulated rat platelets. These results suggested that NQ-Y15 might inhibit the rise in [Ca2+]i in AA-treated rat platelets by increasing cAMP, which is involved in the inhibition of platelet activation.

In a controlled, randomized, 6-year trial the safety and efficacy of picotamide, a dual-action antithromboxane agent, were assessed in 50 patients with type 2 diabetes mellitus at increased risk of thrombotic vascular events. The patients were randomized to two groups of equal size and received 900 mg picotamide daily or placebo. After phase I (double-blind; years 1–2), patients receiving placebo were treated, if necessary, with antiplatelet drugs (aspirin, ticlopidine) while members of the other group continued to receive 600 mg picotamide daily. In the course of the study 21 vascular events occurred: 16 in the group receiving placebo (fatal myocardial infarction, n = 7; non-fatal stroke, n = 3) and five in the group receiving drug (fatal myocardial infarction, n = 2) ( P < 0.005; Fisher's exact test). One patient (placebo group) died of malignant disease. During the initial double-blind phase a total of nine vascular events was observed (six and three in the groups receiving placebo and drug, respectively). Picotamide treatment was well tolerated and no major side-effects were observed during the study periods.

Picotamide is an antiplatelet drug with a peculiar dual mechanism of action: it inhibits thromboxane A2 synthase and antagonizes the pharmacological responses mediated by thromboxane A2 receptor. We investigated the in vitro effect of picotamide on smooth muscle cell migration and proliferation. Picotamide (1–500 μM) decreased human and rat smooth muscle cell proliferation, evaluated as cell number, in a concentration-dependent and reversible manner. Picotamide inhibited DNA synthesis induced by fetal calf serum (10%), platelet-derived growth factor (PDGF-BB (20 ng/ml)), epidermal growth factor (EGF (1 nM)) and (15S)-hydroxy-11,9-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619 (10 μM, thromboxane A2 receptor agonist)). Co-incubation of U46619 together with EGF or PDGF-BB resulted in a marked amplification of [ 3 H ]thymidine incorporation that was completely reversed by picotamide. The drug also inhibited smooth muscle cell migration induced by fibrinogen (600 μg/ml) or PDGF-BB (20 ng/ml) in a concentration-dependent manner. The ability of picotamide to interfere with myocyte migration and proliferation confers, at least in vitro, a pharmacological interest on the compound in atherogenesis.

Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.

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.

The effects of the antiaggregating drug picotamide on platelet and hemocoagulative parameters were evaluated in a group of 28 elderly atherosclerotic patients. After 1 month of treatment, consisting of one 300 mg tablet three times per day, a significant inhibition of platelet aggregability in response to ADP, adrenaline, arachidonic acid and collagen and a reduction of the mean platelet volume (-4.62+/-7.46%, P

Picotamide is a dual TxA2 receptor antagonist/Tx A2 synthetase inhibitor. As the picotamide effect is maximum only after 5–10 min of incubation, aim of the present work was to study whether the effect of picotamide could be observed even after wash out of the drug from the external buffer. Platelet aggregation, serotonin release and changes in intracellular calcium were analyzed in platelets treated with picotamide and then gel-filtered, in comparison with gel-filtered platelets treated with picotamide. To exclude the possibility that the inhibitory effect of picotamide is due to its intracytosolic storage, serotonin release in digitonin-permeabilized platelets was measured. Platelet aggregation and serotonin release in response either to U46619, a synthetic agonist of the thromboxane A2 receptor, or arachidonic acid or collagen, as well as the changes in intracellular calcium concentration after U46619 or arachidonic acid stimulation, were inhibited by picotamide even when it had been washed out by gel-filtration. Both inhibitions were very similar to that observed in experiments in which picotamide was present in the medium. As the serotonin release in digitonin permeabilized platelets presented the same inhibition it may be excluded that picotamide effect is consequent upon the cytosolic storage of the drug. Since our results clearly indicate that the action of picotamide persists even after washing out of the drug from the medium, the idea that this antagonistic effect may be dependent on its binding to platelet plasma membrane rather than on its cytosolic concentration, is strongly substantiated. Copyright © 1997 Elsevier Science Ltd

Inhibition of prostate smooth muscle contraction is an important strategy for medical treatment of lower urinary tract symptoms (LUTS). Besides α1-adrenoceptors, prostate smooth muscle contraction is induced by activation of thromboxane (TXA2) receptors (TXA2-R). Here, we examined the effects of the TXA2-R antagonist picotamide on contraction of human prostate tissue. Prostate tissues were obtained from radical prostatectomy. The effects of picotamide (300 μM), L-665,240 (3 μM), and seratrodast (3 μM) on U46619-, electric field stimulation- (EFS-), phenylephrine-, and norepinephrine-induced contractions were studied in organ baths. Expression of TXA2-R and TXA2 synthase (TXS) was examined by fluorescence stainings. Picotamide, seratrodast, and L-655,240 inhibited concentration-dependent contractions induced by the TXA2 analog U46619. Picotamide, but not seratrodast or L-655,240, inhibited frequency-dependent contractions induced by EFS. Picotamide inhibited concentration-dependent contractions induced by norepinephrine or by the selective α1-adrenoceptor agonist phenylephrine. In prostate strips, where only submaximal contraction by a low dose of phenylephrine was induced, application of U46619 raised tone to maximum phenylephrine-induced tension. Immunoreactivity for TXA2-R and TXS was observed in the stroma and in epithelial cells of glands. Colocalization of both immunoreactivites was observed with the smooth muscle markers calponin and α-smooth muscle actin, with the epithelial marker pan-cytokeratin, and with prostate-specific antigen in the stroma and glands. The receptor antagonist picotamide inhibits α1-adrenergic, TXA2-mediated, and EFS-induced contractions in the human prostate. To the best of our knowledge, this is the first antagonist able to inhibit two different contraction systems in the prostate.

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.

This editorial refers to "Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2 year mortality in diabetics with peripheral arterial disease: the DAVID study" " by GGN Serneri et al. on page 1845 . It is only in the last decade or so that peripheral arterial disease (PAD) has come to the general attention of clinicians as a condition that can greatly increase the risk of ischaemic cardiovascular events and mortality, and it is only lately that actions have been undertaken to increase the awareness of this clinical condition and to institute appropriate therapies aimed at reducing the incidence of adverse cardiovascular events. Thus, PAD has rapidly transformed from a largely overlooked condition, managed solely by a 5-word prescription (stop smoking and go walking), to a disease requiring multi-therapeutic interventions and extensive programmes of detection. The initial lack of attention to these patients is witnessed by the small number of PAD patients enrolled in the early studies of prevention of cardiovascular events by antiplatelet agents in patients at risk. Indeed, no direct evidence on the efficacy of aspirin in patients with PAD exists, and the indication to use aspirin in this clinical condition1 comes mainly from the meta-analysis of the antithrombotic trialists' collaboration2 or from extrapolation of trial results from similar high risk conditions.3 More recently, the concept of atherothrombosis as an underlying condition common to cerebrovascular, cardiac and peripheral arterial disease has emerged and many more patients with PAD have been included in secondary or primary prevention trials.2,4–6 The analysis of the subgroup of PAD patients in these trials has shown that those with intermittent claudication and a reduced ankle/brachial index (

G 619 is 3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide. The compound is structurally related to picotamide, a previously reported dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist, which displays inhibitory activity on tumor necrosis factor-alpha. The aim of the present work was to study the effect of G 619 on tumor necrosis factor-alpha synthesis both in vivo and in vitro. Salmonella enteritidis lipopolysaccharide was used to induce tumor necrosis factor-alpha production. Septic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg (LD90) of Salmonella enteritidis lipopolysaccharide. Rats were pretreated with G 619 (50 mg/kg, i.v.) or vehicle (1 ml/kg, i.v.) 1 h before endotoxin challenge. Salmonella enteritidis lipopolysaccharide administration dramatically reduced survival rate (0%, 72 h after endotoxin administration), reduced mean arterial blood pressure, increased plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha and enhanced serum levels of tumor necrosis factor. Furthermore, endotoxic shock produced characteristic gastric damage, consisting of haemorrhagic infiltrates. Pretreatment with G 619 in vivo significantly protected against Salmonella enteritidis lipopolysaccharide-induced lethality (80% survival rate and 60% survival rate 24 h and 72 h after Salmonella enteritidis lipopolysaccharide injection, respectively), reduced hypotension, decreased plasma thromboxane B2 and serum tumor necrosis factor-alpha levels and enhanced blood levels of 6-keto-prostaglandin F1 alpha. In rat peritoneal macrophages, G 619 in vitro (25, 50 and 100 microM) significantly blunted (P0.001) Salmonella enteritidis lipopolysaccharide-stimulated production of tumor necrosis factor-alpha, whereas it increased 6-keto-prostaglandin F1 alpha and cyclic AMP levels. The present data indicate that G 619 may be useful during disease states characterized by elevated tumor necrosis factor-alpha levels.

We compared the effects of two antiplatelet agents, picotamide, a dual antithromboxane inhibitor, and aspirin, a nonselective cyclooxygenase inhibitor, on microalbuminuria and cutaneous microcirculation in diabetic patients. Twenty patients with type II diabetes mellitus with micro- or macroalbuminuria (urinary albumin excretion rate ⩾ 30 mg/24 h) (8 men, 12 women; mean age, 62 ± 3 years) were enrolled in an open-label, 3-month pilot study and randomly assigned to receive picotamide 300 mg twice daily (10 patients), or aspirin 325 mg/day (10 patients). The 24-hour urinary albumin excretion rate was measured at baseline and after 3 months using a commercial radioimmunoassay kit. Cutaneous microcirculation was assessed at the same time by means of laser-Doppler flowmetry. Supine resting flow (RF) and standing flow (SF) (after 3 minutes in the upright position) were also measured. The arteriovenous response (AVR) was calculated as (RF — SF)/RF × 100. The microangiopathy index (MI) was expressed as the ratio AVR:RF. Urinary albumin excretion rate increased significantly ( P P = not significant). Urinary albumin excretion rate increased in 6 patients in the aspirin group and in 1 patient in the picotamide group ( P P P

Background and Purpose We assessed the effects of long-term treatment with picotamide, an antiplatelet agent with dual antithromboxane activity, on the evolution of early asymptomatic carotid atherosclerotic lesions in diabetic patients. Methods In a double-blind, placebo-controlled, 2-year study, 50 type II normotensive diabetic patients (35 men; mean age, 66±5 years) with asymptomatic mild or moderate nonstenotic ( Results At baseline, mean±SD numbers of carotid atherosclerotic lesions per patient were 2.7±1.8 and 2.2±1.2 in the picotamide and placebo groups, respectively. Mean±SD percent stenosis was 25.3±7% in the picotamide group and 27.3±6% in the placebo group. Forty-nine patients completed the study. At month 24, the placebo group (n=24) showed a significant progression in number of carotid atherosclerotic lesions (3.04±1.8; P P P P P =.07). Conclusions In diabetic patients compared with patients receiving placebo, long-term treatment with picotamide can slow the evolution of early carotid atherosclerotic lesions, inhibiting progression of plaque number and growth.

SummaryIt was the aim of the present study to investigate if antiplatelet treatment reduced cardiovascular events in patients with claudication and/ or an ankle/brachial index (ABI) ≤0.99 and to analyse if specific antiplatelet treatment had a different impact on clinical outcome. We performed a meta-analysis of 29 clinical randomized trials on antiplatelet therapy for prevention of vascular death, myocardial infarction, and stroke in 10,735 peripheral artery disease patients. The primary end-point utilizing in the meta-analysis construction was Cardiovascular Adverse Event. We found 1,900 (17.70%) patients in trials with aspirin, 5,326 (49.61%) in those with thienopyridines, 2,324 (21.65%) in those with picotamide and 1,185 (11.04 %) in those with others antiplatelet drugs. A statistically significant effect of antiplatelet treatment [odds ratio (OR) 0.839; 95% confidence interval (CI) 0.729–0.965; p=0.014] was observed. There was a statistically significant reduction of clinical outcome [OR 0.779; 95% CI 0.639–0.950; p=0.014] in the thienopyridine-treated group vs. control. Patients treated with picotamide [OR 0.785; 95% CI 0.495–1.243; p=0.302] or aspirin [OR 0.847; 95%CI 0.653–1.097; p=0.084] showed reduced cardiovascular outcomes, that, however, did not reach significance. The study confirms that anti-platelet treatment reduces vascular outcome in claudicants. Significant reduction was observed with thienopyridines while data regarding aspirin and picotamide were inconclusive.

ObjectivesThe aim of this study was to evaluate whether thromboxane inhibition can favorably affect renal perfusion and clinical conditions in patients affected by severe heart failure.BackgroundThe renal formation of the vasoconstrictor thromboxane A2(TxA2) is increased during cardiac failure.MethodsBy oral administration of picotamide (a renal TxA2synthase and TxA2/prostaglandin H2receptor inhibitor), we blocked renal TxA2. Fourteen patients in New York Heart Association functional class IV were studied according to a randomized, double-blinded, cross-over design. Each of the two eight-day periods of testing was preceded by a three-day period during which certain vasoactive medications were stopped.ResultsDaily 24-h total urinary thromboxane B2(TxB2), the stable metabolite of TxA2, dropped at the end of picotamide treatment (p < 0.01 vs. baseline). Compared with placebo, effective renal plasma flow and the glomerular filtration rate increased (p < 0.01 and p < 0.05, respectively), thus leading to a significant decrease in the filtration fraction (p < 0.01). Renal vascular resistance decreased consistently (p < 0.01). In all patients, picotamide treatment was associated with an increase in diuresis and natriuresis (p < 0.001 vs. baseline). Plasma creatinine decreased (p < 0.05 vs. baseline). Patients also showed improvement in several clinical parameters, including a significant decrease in both pulmonary and venous pressure (p < 0.01 vs. baseline).ConclusionsThese results indicate that renal thromboxane formation plays an important role in renal vascular resistance in patients with severe heart failure, such as those described in the present study. Inhibition of TxA2improves renal hemodynamics and kidney function and favorably affects indexes of cardiac performance.

Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.

Patients with chronic myeloproliferative disease are at increased risk of both thromboembolic and haemorrhagic complications. Cerebral thrombosis is a common cause of death in myeloproliferative disease patients. Picotamide is a new anti-platelet drug sharing a dual anti-thromboxane activity: inhibition of thromboxane A2 synthase and thromboxane A2 receptor antagonism. Picotamide inhibits in vitro and ex vivo platelet aggregation induced by different agonists. Interestingly, in vitro studies show that picotamide is able to increase prostacycline biosynthesis. In the clinical setting, picotamide treatment induces only a slight prolongation of bleeding time. The safety and efficacy of picotamide long-term treatment in 15 patients with essential thrombocytosis and a positive history of previous thromboembolic events was evaluated. After 12-month treatment with picotamide no patients suffered from thrombotic events and only one minor and transient bleeding episode was observed. This observational long-term trial shows that picotamide treatment in patients with thrombocytosis at high risk of thrombotic events is safe and well tolerated. Picotamide did not increase the risk of bleeding in these patients, while at the same time, no thrombotic events were observed during the 1-year treatment.

The effect of picotamide (G137 or N,N'-bis-3-picolyl-4-methoxyisophthalamide), a dual thromboxane A2 (TxA2) synthetase inhibitor/TxA2 endoperoxide receptor antagonist, on the phospholipase C (PLC) activation and calcium mobilization in human platelets stimulated by arachidonic acid (AA) and TxA2 receptor synthetic agonist U46619, has been studied. Preincubation with picotamide (10(-4) M) for 1 and 3 min significantly reduced (p0.03 and p0.005 respectively) the calcium concentration changes induced in gel-filtered platelets (GFPs) by U46619 125 nM and 250 nM. Picotamide also reduced the calcium concentration changes induced in GFPs by AA 75 and 150 microM and by ADP 5 and 10 microM. In thrombin degranulated platelets picotamide inhibited the effect of U46619 up to 500 nM. The PLC activation, as indicated by inositol-1,3,4 P3 (Ins 1,3,4 P3) formation in response to U46619 250 nM and AA 150 microM was also inhibited by picotamide. These results may suggest a dual effect of picotamide on the receptor/effector systems through which TxA2 mediates platelet activation.

1. Picotamide was shown to inhibit platelet binding of thromboxane A2 (TxA2)-mimetics and to cause a reduction of TxA2 platelet receptors after in vivo administration. The present study aimed to investigate directly [3H]-picotamide binding to human platelets and in particular the relationship between binding kinetics and antiaggregating properties. 2. [3H]-picotamide time-dependently bound to a single class of platelet TxA2 receptors with a KD of 325 nmol l-1 at equilibrium. The binding was displaceable by TxA2 analogues U46619 and ONO11120 (Ki 19 and 28 nmol l-1 respectively) but not by prostacyclin (PGI2), prostaglandin E2 (PGE2) and TxB2. Antiaggregating activity and TxA2 formation inhibition paralleled with binding kinetics. 3. By prolonging the incubation time from 30 to 120 min, picotamide showed a progressively increasing non-displaceable binding, whereas specific displaceable binding decreased in comparison to the values reached at 30 min. Non displaceable binding was specific, temperature-dependent saturable and followed a Michaelis-Menten kinetic (Vmaxapp = 130 fmol per 10(8) platelets h-1, KMapp = 330 nmol l-1). Picotamide progressively underwent a specific stable interaction with its platelet receptor. 4. In conclusion, after an initial reversible binding, a progressive stabilization of picotamide binding takes place resulting in a progressively more stable interaction with platelets.

Effects of picotamide on platelet activity and on some hemorheologic, coagu lative, and hemodynamic parameters were investigated in a randomized, dou ble-blind, placebo-controlled study for eighteen months. Twenty patients, average age 61.5±9.6 (SD) years, with peripheral arterial disease (PAD) at functional stage 2 of the Fontaine classification and with intermittent claudica tion for at least six months were studied. Ten patients received tablets of picotamide, 300 mg three times a day, and 10 subjects received three identical placebo tablets each day. Similar atheroscler otic disease risk factors were present in both groups. Picotamide induced a significant decrease of plasma viscosity, fibrinogen, and beta-thromboglobulin and an increase of amplitude of the photoplethysmo graphic wave.

BACKGROUND Patients with peripheral vascular disease (PVD) undergo a clinical course that can be complicated by cardiovascular events occurring in several areas of the circulation. METHODS AND RESULTS In the present study we investigated the ability of picotamide, a substance that inhibits platelet thromboxane A2 (TxA2) synthase and antagonizes TxA2 receptors, to reduce cardiovascular complications in PVD patients. The study was double blind and placebo controlled. After a 1-month run-in period, 2,304 patients were randomly allocated to either placebo or picotamide (300 mg t.i.d.) and followed for 18 months. Major and minor events were analyzed. Results of an "intention-to-treat analysis" were that patients on picotamide suffered 45 major events (3.9%) and 77 minor events (6.7%), whereas those taking placebo suffered 52 major (4.5%) and 99 minor events (8.6%). There was borderline statistical difference between the two groups with respect to the sum of the major and minor events (risk reduction, 18.9%; p = 0.056, log-rank test). Results of an "on-treatment" analysis were that patients on picotamide suffered 40 major (3.8%) and 66 minor events (6.3%), whereas those taking placebo suffered 45 major (4.2%) and 95 minor events (8.9%). The sum of both major and minor events was 106 (10.1%) in the picotamide group and 140 (13.1%) in the placebo group. This difference was significant (risk reduction, 23%; p = 0.029, log-rank test). CONCLUSIONS The results of this study indicate that picotamide reduces cardiovascular complications in PVD patients. The apparently low effect of this drug in reducing major events suggests that further studies be made with picotamide in PVD patients who are at high risk of cardiovascular complications so as to further assess its clinical efficacy.

We investigated the short-term effect of the TXB inhibitor picotamide on albuminuria induced by exercise in 15 microalbuminuric (i.e., with UAE at rest between 20 and 200 μg/min) type II diabetic patients (12 men and 3 women, age 56 ± 2, BMI 28 ± 1 kg/m2) and in six normal age-matched control subjects. The diabetic subjects performed five submaximal exercise tests (90% of theoretical heart rate) on a cycle ergometer: the first two under basal conditions; the third and fifth after subjects had received picotamide (900 mg/day) or placebo (3 tablets/day) for 10 days; the fourth exercise always was performed after 10 days of wash-out. Control subjects performed two exercises: the first in baseline conditions and the second after 10 days of picotamide administration (900 mg/day). When diabetic patients were untreated, a significant (P < 0.05) increase in UAE with respect to baseline levels was observed immediately after and 1 h after the exercise test. After picotamide administration, UAE significantly decreased (P < 0.05) immediately after and 1 h after exercise, as compared with diabetic patients given a placebo. In normal subjects, exercise was followed by a slight increase in UAE, which was not significantly affected by picotamide administration. Our results show that short-term administration of picotamide is associated with a reduction in UAE after exercise in type II diabetes patients with microalbuminuria while at rest. Picotamide, a TXB synthetase and receptor inhibitor, may decrease exercise-induced albuminuria in diabetic patients through a reduction in circulating TXB levels andinhibition of TXB action, which in turn may act by lowering glomerular capillary hydraulic pressure.

1. Picotamide has been shown to interfere competitively with the thromboxane A2 (TxA2) platelet receptor. In the present study the effect of in vivo administration of picotamide on TxA2 human platelet receptors was investigated in 10 healthy subjects. 2. Picotamide (300 mg x 3 daily) or placebo were administered in a double-blind, cross-over, placebo controlled study, each treatment lasting 1 week with a 2 week interval period. TxA2 receptors were investigated by a direct radioligand binding assay method employing [125I]-PTA-OH as labelled ligand. Platelet studies were performed on the first day of treatment immediately before and 2, 4 and 8 h after the ingestion of the drug. The effects of chronic administration were assessed on the seventh day. 3. Two and 4 h after the administration of picotamide 300 mg orally platelet TxA2 receptors were significantly reduced from 1366 +/- 237 to 957 +/- 221 (P less than 0.05) and 753 +/- 119 receptors/platelet (mean +/- s.d.) (P less than 0.03). After 8 h platelet receptor population was restored (1362 +/- 324, NS). The same pattern was observed after 7 days of treatment. Thus picotamide seems to induce a short lasting down regulation of platelet TxA2 receptors.

SummaryEffects of picotamide (900 mg in 3 oral administrations for 7 days) on ex vivo and in vivo platelet T×A2 production and on platelet aggregation wpre evaluated in 8 patients with peripheral arteriopathy and in 8 normal subjects. Picotamide significantly reduced ADP-induced platelet aggregation, but had no effect on that induced by arachidonic acid or the thromboxane analogue U46619. Though ex vivo platelet T×A2 production (T×B2 concentration after arachidonic-acid-induced aggregation) was reduced from 946 ± 141 (mean ± SD) to 285 ± 91 ng/ml in controls and from 1515 ± 673 to 732 ± 420 ng/ml in patients with arteriopathy, there was no effect on urinary excretion of 2,3-dinor-T×B2 (in vivo indicator of platelet T×A2 production), or on in vivo PGI2 production (urinary excretion of 6-keto-PGF1α and 2,3-dinor-6-keto-PGF1α). In the same subjects, single-dose aspirin reduced ex vivo T×B2 production by at least 98% and 2,3-dinor-T×B2 excretion from 116.7 ± 61.4 to 32.6 ± 17.0 nglg creatinine in control subjects, and from 156.3 ± 66.1 to 59.1 ± 19.2 ng/g creatinine in patients with peripheral arteriopathy. Our data suggest that inhibition of platelet T×A2 production in vivo may not be picotamide’s main mechanism of action.

SummaryWe have previously characterized the new antiplatelet agent picotamide as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. We have now studied the antithrombotic activity of this drug in a simple animal model of lung platelet thromboembolism in the mouse. Picotamide, given i. p. 1 hr before the thrombotic challenge, protected mice from death caused by the i. v. injection of collagen plus epinephrine in a dose-dependent way; the dose reducing mortality by 50% was 277 mg/kg while for aspirin it was 300 mg/ kg. Picotamide was also able to reduce the mortality provoked by the i. v. injection of the stable TxA2 mimetic U46619; BM 13.505, a pure TxA2-receptor blocker, was also effective while aspirin was totally inactive. Picotamide, finally, reduced the lethal consequences of the i. v. injection of a 12.5% suspension of hardened rat red blood cells, a model in which platelets are not involved; aspirin was totally ineffective in this model while nicardipine, a calcium channel blocker, was active. Picotamide did not inhibit the formation of TxB2 in serum at any of the doses tested (100 to 750 mg/kg i.p.) while it did enhance significantly PGI2-synthesis from mice aortae and, even more, from mice lungs. The i.v. administration of picotamide (250 mg/kg 2 min before the thrombotic challenge) lead to a strong inhibition of serum TxB2 (−84.6%) and was associated with a higher antithrombotic effectPicotamide (375 mg/kg) reduced also significantly the drop in the number of circulating platelets and the number of histologi-cally-detected lung thromboemboli provoked by i. v. collagen plus epinephrine; however, aspirin (300 mg/kg), although less effective against mortality, was more active than picotamide in this respect. Finally, the addition of aspirin (100 and 300 mg/kg) to picotamide (250 and 375 mg/kg) led to a better antithrombotic effect despite a strong inhibition of PGI2 synthesis. Our data show that picotamide prevents sudden death provoked in mice by platelet lung thromboembolism through a mechanism largely independent from eicosanoid synthesis and only partially dependent on platelet inhibition. This drug reduces also the lethal consequences of mechanical (platelet-independent) lung embolism. A direct vasodilatory action on pulmonary vessels might explain the protective effects of picotamide in this model.

Source Citation Neri Serneri GG, Coccheri S, Marubini E, Violi F. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral art...

Picotamide was administered in a daily dose of 1500 mg per os for 30 days to 30 aged, arteriosclerotic subjects and as single doses of 500 mg and 1000 mg to another group of 16 subjects. A reduction of platelet aggregation (methods of Born and Breddin) was observed within 24 hours of commencement of treatment and became more evident in the subsequent days. The reduction was both consistent and significant. A marked increase in fibrinolytic activity (fibrin plate method) was observed during the first 24 hours, particularly for euglobulins with activator. The reaction and clot formation times (r and k) were prolonged and the maximal amplitude (ma) in thrombelastogram was reduced by a definite, though small amount. After the administration of a single dose the maximal effect was observed after eight hours and was still evident after 48 and, to a lesser degree, after 72 hours. The drug was in all cases well tolerated, without any significant side-effects nor untoward reactions.

SummaryAn open study was carried out in 14 patients with peripheral arterial disease to investigate the effects of prolonged therapy with picotamide on platelet activity. Patients received daily oral doses of 900 mg picotamide for 1 month, 600 mg per day during the second month and 300 mg per day from the third to the sixth month of the study. Measurements were made before and during therapy of blood coagulation parameters and factors influencing platelet function, i.e. plasma β-thromboglobulin and serum thromboxane B2. The results showed that there were no significant variations in platelet count, prothrombin time, partially activated thromboplastin time, presence and amount of fibrinogen in blood, and antithrombin III. Examination for fibrinogen degradation products was constantly negative and unaltered during therapy. Although plasma β-thromboglobulin values did not vary significantly, there was a significant and progressive reduction throughout treatment in serum levels of thromboxane B2.

The efficacy of N,N'-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P less than 0.05) inhibited basal and LPS-stimulated synthesis of TxA2 measured by its stable immunoreactive (i) metabolite TxB2 in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF1 alpha, the stable metabolite of PGI2, and produced significant shunting to i6-keto-PGF1 alpha. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P less than 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA2 synthesis.

To assess the effects of picotamide, an antithromboxane receptor and antithromboxane synthase drug, on vascular function and endothelin-1 release, 20 patients with peripheral arterial disease, without hypertension or diabetes mellitus, receiving placebo and pico tamide (900 mg/day) were studied. The modifications of vascular parameters were evaluated by arterial distensibility index and postischemic hyperemia test (postischemic perfusion index and recovery time). Endothelin-1, prostacycline, and thromboxane B2 were determined under resting conditions and after treadmill test. Picotamide treatment caused a decrease of resting thromboxane B2 and endothelin-1 concentrations, produced an improvement of the vascular function as seen by the increase of vascular parameters reported, and attenuated the ischemic treadmill-induced increase of thromboxane B 2, but not of endothelin-1. These data confirm that the picotamide improved vascular flow by the reduction of thromboxane-mediated effects, reduced resting endothelin-1 levels, but did not attenuate endothelin-1 concentrations induced by the treadmill stress.

Picotamide is a thromboxane A2 (TXA2 ) receptor antagonist and TXA2 synthase inhibitor. In clinical studies, it has been considered as a platelet aggregation inhibitor and improved renal function. In vitro studies suggested inhibition of smooth muscle contraction by picotamide, which is poorly understood. Here, we examined effects of picotamide on contractions of renal interlobar and coronary porcine arteries, induced by different vasoconstrictors. Contractions were induced in an organ bath by agonists or electric field stimulation (EFS). Picotamide inhibited EFS-induced contractions of interlobar arteries around 50% using concentrations of 100 and 300 µM. In interlobar arteries, concentration response curves for contractions induced by three different α1 -adrenoceptor agonists were shifted to the right by picotamide (2-10-fold increases in EC50 ). In coronary arteries, α1 -adrenergic contractions were inhibited without right shift (approx. 50%). Contractions induced by two different cholinergic agonists in coronary arteries were inhibited by picotamide (≥50%) withouth right shift. Inhibition of serotonin-induced contractions by picotamide showed features of a right shift, whereas contractions induced by the TXA2 analog U46619, angiotensin-II, and endothelin-1 were inhibited by picotamide in interlobar and coronary arteries without right shifts and to different degree. Picotamide inhibits a wide spectrum of vasoconstrictor-induced contractions in porcine interlobar and coronary arteries. Inhibition of vasocontraction may contribute to beneficial effects of picotamide in the cardiovascular system and kidney.

BACKGROUND The role of thromboxane A2 (TxA2) in unstable angina has not yet been defined. TxA2 receptor antagonists may be of value in studying this role. METHODS To investigate whether TxA2 has a pathogenetic effect on the occurrence of myocardial ischemia and from what source TxA2 originates, we studied TxA2 formation by unstimulated monocytes from patients with unstable angina (n = 40), stable effort angina (n = 20), and controls (n = 20). We also compared the effects of picotamide (1200 mg/day), a TxA2-synthase inhibitor and TxA2-receptor antagonist, with those of aspirin (325 mg/day) on myocardial ischemia and TxA2 formation by monocytes and platelets. The double-blind randomized study was performed on patients with unstable angina on continuous Holter monitoring. RESULTS In the presence of autologous lymphocytes, unstimulated monocytes from patients with unstable angina formed significantly (P < 0.001) more TxA2 than those from controls or from patients with effort angina. Although TxA2 formation by circulating monocytes and platelets was inhibited to a greater degree by aspirin than by picotamide (88 +/- 6 and 98 +/- 2%, respectively, versus 65 +/- 2 and 74 +/- 1%, P < 0.001), aspirin failed to affect the occurrence of myocardial ischemia whereas picotamide significantly (P < 0.001) reduced the number of anginal attacks (84.8%), silent ischemic episodes (64.2%), and overall duration of ischemia (69.8%), in comparison to the run-in period. CONCLUSIONS These results indicate that TxA2 formed by monocytes contributes to the pathogenesis of myocardial ischemia in unstable angina. TxA2 formation occurs mainly in extravascular spaces, probably within the coronary vascular wall. Picotamide appears to control myocardial ischemia effectively in patients with unstable angina.

Summary Background The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved. Methods Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B 2 and 6-keto-PGF 1α were measured to assess any changes in endoperoxide metabolism during the study periods. Findings 11-dehydro-thromboxane-B 2 (TXB 2 ) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB 2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF 1α , and their ratio of 11-dehydroTXB 2 to 6-keto-PGF 1α was twice that of the controls (1·40 [95% Cl 0·86–1·95] vs 0·61 [0·37–0·84]). Interpretation A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Picotamide is an antiplatelet drug which inhibits thromboxane A2 (TxA2) synthase and antagonizes TxA2 receptors. In the ADEP (Atherosclerotic Disease Evolution by Picotamide) trial, 2304 patients with peripheral obstructive arterial disease (POAD) were studied in a double-blind, placebo-controlled, 18-month, multicentre trial. In this study, 151 events (13.1%) occurred on placebo and 122 (10.6%) on picotamide (900 mg day-1). The relative risk reduction was 19%, (P = 0.056). This paper reports a post-hoc analysis in a subgroup of 438 diabetic patients (picotamide = 230; placebo = 208). There were 32 vascular events on placebo (15%) and 18 on picotamide (8%) (relative risk reduction: 48%; 95% CI = 26, 76; P = 0.022). The results of this retrospective analysis suggest that a prospective study to investigate events in claudicant patients with diabetes mellitus is warranted.

SummaryPicotamide is a dual thromboxane (Tx) A2 receptor antagonist/Tx synthase inhibitor although some observations suggest an anti-vasoconstrictor effect independent of TxA2 inhibition/antagonism. The aim of our study was to assess whether picotamide antagonises vascular contractions induced by different vasoactive substances in vitro. Picotamide inhibited competitively the contraction of rabbit aortic rings induced by the TxA2 mimetic U46619 (pA2 = 3.59) but also the contractions induced by phenylephrine (pA2 = 3.93) and serotonin (5-HT) (pA2 = 5.81) although in a not competitive way. Picotamide did not inhibit potassium-induced contractions, thus excluding aspecific effects on vascular smooth muscle. Picotamide inhibited 5-HT-induced platelet aggregation in vitro with an IC50 (212 μM) similar to that found when other aggregating stimuli are used, but it did not affect shape change (IC50> 1 mM) suggesting that the effects of picotamide can not be ascribed to 5-HT2-receptor antagonism; in the same experimental conditions neither a Tx-receptor antagonist (BM13.177) nor a dual Tx-receptor antagonist/synthase inhibitor (ridogrel) affected 5-HT-induced platelet responses.Our studies demonstrate that picotamide exerts antivasoconstrictor and platelet inhibitory effects unrelated to TxA2 antagonism. This activity may contribute to the anti-thrombotic/anti-ischaemic effects of the drug in vivo.