Comparative study on the effect of aspirin, TP receptor antagonist and TxA2 synthase inhibitor on the vascular tone of human saphenous vein and internal mammary artery.

AIMS: Thromboxane (TxA2) is synthesized from arachidonic acid (AA) via thromboxane synthase (TxS) enzyme and induces vasoconstriction via TP receptor. Our aim is to compare the effects of aspirin, TxS inhibitor and TP receptor antagonist on vascular reactivity of bypass grafts (saphenous vein and internal mammary artery). MAIN METHODS: Using isolated organ bath, saphenous vein and internal mammary artery preparations were incubated with TP receptor antagonist, TxS inhibitor, aspirin, IP or EP4 receptor antagonist. Then prostaglandin (PG)E2, PGF2α, phenylephrine and AA were administered in concentration-dependent manner. The expression of prostanoid receptor and PGI2 synthase (PGIS) enzyme was determined by Western Blot. KEY FINDINGS: TP receptor antagonist inhibited the contraction induced by PGE2, PGF2α, and AA but not that induced by phenylephrine in both types of vessels. Aspirin increased phenylephrine-induced contraction only in internal mammary artery and decreased AA-induced contraction in saphenous vein. TxS inhibitor decreased both PGE2 and AA-induced contraction in both types of vessels. This decrease was reversed by co-incubation of TxS inhibitor and IP/EP4 receptor antagonists. The expressions of EP3 receptor and PGIS enzyme were greater in internal mammary artery compared to saphenous vein while IP and TP receptors expressed at similar levels. SIGNIFICANCE: TP receptor antagonist and TxS inhibitor are more effective to reduce contraction induced by different spasmogens in comparison to aspirin. Our results suggest that TP receptor antagonist and TxS inhibitor might have an advantage over aspirin due to their preventive effect on increased vascular reactivity observed in post-operative period of coronary artery bypass grafting.

Rutin present in Alibertia edulis extract acts on human platelet aggregation through inhibition of cyclooxygenase/thromboxane.

Alibertia edulis leaf extract is commonly used in folk medicine, with rutin caffeic and vanillic acids being its major compounds. The Alibertia edulis leaf extract was investigated for its pharmacological effects via platelet aggregation, calcium mobilization, cyclic nucleotides levels, vasodilator-stimulated phosphoprotein Ser157 and Ser239 and protein kinase Cß2 phosphorylation, thromboxane B2, cyclooxygenases 1 and 2, docking and molecular dynamics. Alibertia edulis leaf extract significantly inhibited (100-1000 µg mL-1) platelet aggregation induced by different agonists. Arachidonic acid increased levels of calcium and thromboxane B2, phosphorylation of vasodilator-stimulated phosphoprotein Ser157 and Ser239, and protein kinase Cß, which were significantly reduced by Alibertia edulis leaf extract, rutin, and caffeic acid as well mixtures of rutin/caffeic acid. Cyclooxygenase 1 activity was inhibited for Alibertia edulis leaf extract, rutin and caffeic acid. These inhibitions were firsrtly explored by specific stabilization of rutin and caffeic acid compared to diclofenac at the catalytic site from docking score and free-energy dissociation profiles. Then, simulations detailed the rutin interactions close to the heme group and Tyr385, responsible for catalyzing the conversion of arachidonic acid to its products. Our results reveal the antiplatelet aggregation properties of Alibertia edulis leaf extract, rutin and caffeic acid providing pharmacological information about its origin from cyclooxygenase 1 inhibition and its downstream pathway.

L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria.

Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.

A study of the pharmacokinetics and thromboxane inhibitory activity of a single intramuscular dose of carprofen as a means to establish its potential use as an analgesic drug in white rhinoceros.

The alleviation of pain and prevention of suffering are key aspects of animal welfare. Unfortunately, analgesic drugs are not available for all species. White rhinoceros (Ceratotherium simum), representing one of such species, which survive poaching attempts inflicted with severe facial injuries and gunshot wounds, nonetheless require analgesic support. To improve treatment conditions, this study explored the use of carprofen for the treatment of pain and inflammation in white rhinoceros. The pharmacokinetics of 1 mg/kg intramuscular carprofen was evaluated in six healthy white rhinoceros. The half-life of λz and mean residence time was 105.71 ± 15.67 and 155.01 ± 22.46 hr, respectively. The area under the curve and the maximum carprofen concentration were 904.61 ± 110.78 µg ml-1  hr-1 and 5.77 ± 0.63 µg/ml, respectively. Plasma TXB2 inhibition demonstrated anti-inflammatory properties and indicated that carprofen may be effective for a minimum of 48 hr in most animals. With its long half-life further indicating that a single dose could be effective for several days, we suggest that carprofen may be a useful drug for the treatment of white rhinoceros.

Thromboxane inhibition during concurrent therapy with low-dose aspirin and over-the-counter naproxen sodium.

Aspirin is the dominant antiplatelet therapy for cardiovascular disease. Naproxen is frequently used in aspirin-treated patients and may influence the antiplatelet effect of aspirin. We evaluated the pharmacodynamic interaction (lower bound of the one-sided 95% CI for serum TxB2 inhibition < 95%) between 220 mg immediate-release naproxen sodium (once or twice daily) and 81 mg daily immediate release aspirin at various dosing intervals. There was no interaction during the first day of concurrent treatment. After 10 days, irrespective of the timing and dose of naproxen in relation to aspirin dosing, a pharmacodynamic interaction occurred which persisted after discontinuing naproxen. In the control group (aspirin alone), the lower bound for serum TxB2 inhibition was > 98% at all time points. The clinical relevance of these observations remains unknown and merits further investigation since over-the-counter naproxen is widely used to relieve pain by individuals taking low dose aspirin for cardioprotection. CLINICAL TRIAL REGISTRATION: NCT02229461.

[Antiplatelet agents]. / Agents antiplaquettaires et athérothrombose.

Atherothrombosis is a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across multiple vascular beds but, when complicated by thrombosis, it can result in an acute coronary syndrome, stroke, transient ischemic attack, and critical limb ischemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous clinical trials have tested antiplatelet agents for primary and secondary prevention, and several new antiplatelet drugs are under development. There is evidence of clear benefit of single and, in some cases, dual antiplatelet therapy in the prevention of recurrent cardiovascular and cerebrovascular complications. Dual antiplatelet therapy has emerged as the standard of care for acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent ADP receptor antagonists (ticagrelor or prasugrel). Conversely, in chronic stable coronary disease, no benefit of dual antiplatelet therapy has yet been convincingly demonstrated Evidence supporting routine use of aspirin or any other antiplatelet agent for primary prevention is mixed, and this strategy should only be considered for individual high-risk patients in whom the thrombotic risk outweighs the risk of major bleeding complications.

Mecanismos de acción de los diferentes agentes antiplaquetarios / Mechanisms of action of antiplatelet agents

Las manifestaciones clínicas de la aterosclerosis, tales como los síndromes coronarios agudos, los eventos cerebrovasculares y la enfermedad arterial periférica, son las principales causas de morbimortalidad en el mundo. La activación y la agregación plaquetarias son, en última instancia, la causa de la progresión y las presentaciones clínicas de la enfermedad. Por ello, los antiagregantes plaquetarios son un pilar fundamental del tratamiento farmacológico de estos pacientes. Una amplia variedad de receptores de superficie tipo integrinas, familia rica en leucina, receptores acoplados a proteínas G y receptores de tirosincinasa, así como moléculas intraplaquetarias, desencadenan y regulan el proceso de activación/agregación plaquetaria. Todas estas moléculas son dianas potenciales de fármacos antiplaquetarios destinados a prevenir y tratar la trombosis arterial. A pesar del beneficio clínico obtenido con el ácido acetilsalicílico (inhibidor de la ciclooxigenasa), el clopidogrel (antagonista del receptor del ADP P2Y12) y los antagonistas de la glucoproteína IIb/IIIa (abciximab, eptifibatida, tirofibán, lamifibán) al disminuir significativamente el riesgo de episodios aterotrombóticos, la morbimortalidad residual sigue elevada. Por ello los esfuerzos se centran en la búsqueda de nuevos tratamientos antiplaquetarios a fin de mejorar su efectividad y su seguridad. De hecho, nuevos fármacos están en fase de desarrollo y varios han llegado ya a uso clínico. Entre ellos están los nuevos inhibidores de los receptores P2Y12 (prasugrel, ticagrelor, cangrelor y elinogrel), antagonistas del receptor PAR1 de la trombina (vorapaxar, atopaxar) y moléculas de señalización intraplaquetaria. Esta revisión profundiza en los mecanismos de acción del arsenal antiplaquetario actualmente en uso y las nuevas aproximaciones terapéuticas (AU)

The clinical manifestations of atherosclerotic diseases such as acute coronary syndromes, cerebrovascular events and peripheral arterial disease are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentation of the disease and, therefore, antiplatelet agents have become one of the mainstays of pharmacological treatment of these patients. A wide variety of surface receptors such as integrin family receptors, receptors rich in Leucine, protein G linked transmembrane receptor, tyrosine kinase receptors as well as intraplatelet molecules, trigger and regulate platelet activation/aggregation. All these molecules are potential targets for antiplatelet drugs to prevent and treat arterial thrombosis. Despite the overall clinical benefit obtained with aspirin (cyclooxygenase inhibitor), clopidogrel (ADP receptor antagonist P2Y12) and antagonists of the glycoprotein IIb/IIIa (abciximab, eptifibatide, tirofiban, lamifiban) to significantly reduce the risk of atherothrombotic events, residual morbidity and mortality remain high. Therefore efforts have focused on the search for new antiplatelet treatments to improve their effectiveness and safety. In fact, new drugs are in development and various drugs have already reached clinical use. Among them, new P2Y12 receptor blockers (prasugrel, ticagrelor, cangrelor and elinogrel), antagonists of the PAR1 thrombin receptor (vorapaxar and atopaxar) as well as intraplatelet signaling molecules. This review explores the mechanisms of action of the currently used antiplatelet armamentarium as well as new therapeutic approaches (AU)

Síndrome coronario agudo con y sin elevación del segmento ST: ¿cómo darles igualdad de oportunidades? / Acute coronary syndrome with or without st-segment elevation: how can we equalize patients’ prospects?

La activación y la agregación plaquetarias son clave en la progresión de la trombosis arterial y el principal objetivo terapéutico del manejo del síndrome coronario agudo. Actualmente, además de inhibir la formación de tromboxano A2 con ácido acetilsalicílico, se recomienda inhibir otra vía complementaria de la agregación plaquetaria para asegurar la eficacia del tratamiento y prevenir la trombosis coronaria. Los profármacos tienopiridínicos, como clopidogrel y prasugrel, y el derivado pirimidínico ticagrelor son las alternativas más extendidas. En esta revisión se discuten las indicaciones de estos fármacos antiagregantes y su evidencia científica en relación con el síndrome coronario agudo con y sin elevación del segmento ST (AU)

Platelet activation and aggregation play key roles in the development of arterial thrombosis. Accordingly, they provide the principle therapeutic targets in patients with acute coronary syndrome. At present, in addition to using aspirin to inhibit the formation of thromboxane A2 , it is also recommended that another complementary platelet aggregation pathway should be inhibited to ensure that treatment is effective and to prevent coronary thrombosis. Thienopyridine prodrugs, such as clopidogrel and prasugrel, and the pyrimidine derivative ticagrelor are the most widely used agents. This review includes a discussion of indications for these antiplatelet drugs and summarizes the scientific evidence for their use in patients with acute coronary syndrome, with or without ST-segment elevation (AU)

Designing multitarget anti-inflammatory agents: chemical modulation of the lumiracoxib structure toward dual thromboxane antagonists-COX-2 inhibitors.

A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX-2 inhibition and thromboxane A(2) prostanoid (TP) receptor antagonism. The compounds were synthesized through a copper-catalyzed coupling procedure and characterized for their pK(a) values. TP receptor antagonism was assessed on human platelets; COX-2 inhibition was determined on human isolated monocytes and human whole blood. TPα receptor binding of the most promising compounds was evaluated through radioligand binding assays. Some of the isosteric substitutions at the carboxylic acid group afforded compounds with improved TP receptor antagonism; of these, a tetrazole derivative retained good COX-2 inhibitory activity and selectivity. The identification of this tetrazole acting as a balanced dual-acting compound in human whole blood, along with SAR analysis of the synthesized lumiracoxib derivatives, might contribute to the rational design of a new class of cardioprotective anti-inflammatory agents.

A novel prostacyclin agonist protects against airway hyperresponsiveness and remodeling in mice.

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress.

It is now more than 15 years since the molecular structures of the major prostanoid receptors were elucidated. Since then, substantial progress has been achieved with respect to distribution and function, signal transduction mechanisms, and the design of agonists and antagonists (http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=58). This review systematically details these advances. More recent developments in prostanoid receptor research are included. The DP(2) receptor, also termed CRTH2, has little structural resemblance to DP(1) and other receptors described in the original prostanoid receptor classification. DP(2) receptors are more closely related to chemoattractant receptors. Prostanoid receptors have also been found to heterodimerize with other prostanoid receptor subtypes and nonprostanoids. This may extend signal transduction pathways and create new ligand recognition sites: prostacyclin/thromboxane A(2) heterodimeric receptors for 8-epi-prostaglandin E(2), wild-type/alternative (alt4) heterodimers for the prostaglandin FP receptor for bimatoprost and the prostamides. It is anticipated that the 15 years of research progress described herein will lead to novel therapeutic entities.

Prostanoid receptors as possible targets for anti-allergic drugs: recent advances in prostanoids on allergy and immunology.

Prostanoids, consisting of prostaglandins and thromboxane, are cyclooxygenase metabolites of arachidonic acid released in various pathophysiological conditions which exert a range of actions mediated through their respective receptors expressed on target cells. Although it has been difficult to analyze the physiological role of prostanoids, recent developments in both the disruption of the respective gene and receptor selective compounds have enabled us to investigate the physiological roles for each receptor. It has been demonstrated that each prostanoid receptor has multiple functions, and that their expression is regulated in a context-dependent manner that sometimes results in opposite, excitatory and inhibitory, outcomes. The balance of prostanoid production and receptor expression has been revealed to be important for homeostasis of the human body. Here, we review new findings on the roles of prostanoids in allergic and immune diseases, focusing on contact dermatitis, atopic dermatitis, asthma, rheumatoid arthritis, and encephalomyelitis, and also discuss the clinical potentials of receptor-selective drugs.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 µm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice.

BACKGROUND: ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation. METHODS: Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function. RESULTS: Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells. CONCLUSIONS: These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Nuevos antiagregantes en el síndrome coronario agudo. El futuro es hoy / New antiaggregants in acute coronary syndrome. The future is here

Las guías actuales de práctica clínica recomiendan la doble terapia antiagregante con aspirina y clopidogrel en los pacientes con síndrome coronario agudo. La eficacia del clopidogrel se ve limitada por la lenta y variable transformación del profármaco en metabolito activo, una modesta y variable inhibición plaquetaria, el incremento del riesgo de sangrado y el mayor riesgo de trombosis de stent e infarto agudo de miocardio en los pacientes con pobre respuesta. Tres nuevos inhibidores del receptor P2Y12 han mostrado una inhibición plaquetaria mayor y más rápida que la del clopidogrel. El prasugrel, una nueva tienopiridina, muestra beneficio clínico neto sobre el clopidogrel en pacientes con síndrome coronario agudo sometidos a intervencionismo coronario. El ticagrelor, inhibidor oral directo, produce una disminución en la mortalidad y el infarto de miocardio sin incremento del sangrado en un amplio espectro de pacientes con síndrome coronario agudo. Por el contrario, el cangrelor, potente inhibidor intravenoso, no ha mostrado el beneficio esperado. La incorporación de prasugrel y ticagrelor a la práctica clínica implica un cambio importante en el manejo de estos pacientes (AU)

Current clinical practice guidelines recommend dual antiplatelet therapy with aspirin and clopidogrel for patients with acute coronary syndrome. The effectiveness of clopidogrel is hampered by slow and variable conversion of the prodrug to the active metabolite, by modest and variable platelet inhibition, by an increased risk of bleeding, and by an increased risk of stent thrombosis and myocardial infarction in poor responders. Three new P2Y12-receptor inhibitors have been shown to produce faster and more substantial platelet inhibition than clopidogrel. Prasugrel, a novel thienopyridine, has demonstrated a net clinical benefit over clopidogrel in patients with acute coronary syndrome who are undergoing percutaneous coronary intervention. Ticagrelor, an oral direct-acting P2Y12-inhibitor, has been shown to produce clinically significant reductions in mortality and myocardial infarction in a broad spectrum of patients with acute coronary syndrome, without increasing the risk of bleeding. In contrast, the potent intravenous P2Y12-inhibitor cangrelor has not produced the expected clinical benefits. The rapid incorporation of prasugrel and ticagrelor into clinical practice has led to a significant change in the management of these patients (AU)

[Risk of gastrointestinal bleeding with aspirin and platelet antiaggregants]. / Riesgo de hemorragia digestiva con aspirina y antiagregantes plaquetarios.

Aspirin is widely used for the prevention of thrombotic cardiovascular disease. The effect of platelet antiaggregation is achieved with low doses of 75-325 mg/day. Due to COX-1 inhibition, associated gastrointestinal adverse effects can occur. Other drugs whose platelet antiaggregant effect is achieved through different mechanisms of action have been developed, such as clopidogrel and ticlopidine, which do not inhibit COX-1. The proportion of patients taking low-dose aspirin alone or in combination with other antiaggregants is high and consequently the use of these drugs should be optimized by reducing their gastrointestinal adverse effects to a minimum. Knowledge of the risk factors that increase the risk of gastrointestinal adverse effects with platelet antiaggregants, such as age, concomitant use of other drugs such as anticoagulants or non-steroidal anti-inflammatory drugs, a history of peptic ulcer -whether complicated or uncomplicated-, and Helicobacter pylori infection, would help to allow management to be individually tailored to each patient. The use of proton pump inhibitors and/or H. pylori eradication should allow a positive balance, even in patients with gastrointestinal risk factors.

Pharmacological profile of a novel H(2)S-releasing aspirin.

The pharmacological profile of a new, safe, and effective hydrogen sulfide (H(2)S)-releasing derivative of aspirin (ACS14) is described. We report the synthesis of ACS14, and of its deacetylated metabolite (ACS21), the preliminary pharmacokinetics, and its in vivo metabolism, with the H(2)S plasma levels after intravenous administration in the rat. ACS14 maintains the thromboxane-suppressing activity of the parent compound, but seems to spare the gastric mucosa, by affecting redox imbalance through increased H(2)S/glutathione formation, heme oxygenase-1 promoter activity, and isoprostane suppression.

Selective thromboxane inhibition after vascular protectant AGI-1067: results of assessment of lipoprotein profiles (ALPS) biomarkers in vitro and in vivo substudy.

BACKGROUND: Oxidative stress play an important role triggering platelet/endothelial activation. AGI-1067 is a novel, phenolic antioxidant, and vascular protectant which dose-dependently inhibits PEA biomarkers in vitro. Whether treatment with AGI-1067 alters platelets in vivo is not known. We serially assessed release of established PEA biomarkers in subjects treated with AGI-1067 versus placebo in the frame of Assessment of Lipoprotein Profiles Randomized Trial (ALPS). METHODS: Healthy subjects (18-65 years) with multiple risk factors for coronary artery disease were randomized 1:1 to receive 300 mg AGI-1067 (n = 112) or matching placebo (n = 117) daily for 12 weeks. Anticoagulants, aspirin, NSAIDS, and COX inhibitors were not permitted in this study. Plasma samples were collected at baseline, and at week 12 after randomization. Platelet factor 4 (PF4), beta-thromboglobulin (betaTG), P-selectin, thromboxane (TxB2), and prostacyclin (6-keto-PGF1a) were measured by ELISA. RESULTS: Treatment with AGI-1067 was associated with a highly significant reduction of TxB2 release (P < 0.0001) when compared to the placebo. There were no differences in PF4, betaTG, P-selectin, and 6-keto-PGF1a between and within groups. AGI-1067 also inhibits TxB2 release from calcium ionophore (A23187)-stimulated human platelets with the IC50 equals 1 microM; but does not interfere with 6-keto-PGF1alpha release in either A23187-, or TXA2-stimulated human aortic endothelial cells. CONCLUSION: AGI-1067 selectively reduces TxB(2 )production from stimulated platelets, and diminishes plasma TxB2 levels in ALPS participants. These data support earlier in vitro, and pilot ex vivo experiments suggesting antiplatelet properties of AGI-1067. Lack of 6-keto-PGF1a down regulation may represent an attractive advantage of AGI-1067 over currently available antiplatelet regimens.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk.

BACKGROUND: Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk. METHODS AND RESULTS: Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels. CONCLUSIONS: In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.