thromboxane-a2 and Peripheral-Vascular-Diseases

Eicosanoids may have many potential uses in paediatric practice. Since E-type prostaglandins were first applied to treat ductus-dependent congenital heart diseases in paediatric practice, many eicosanoid-related drugs have been examined for the treatment of pathophysiological conditions in children. Prostaglandins (PG), thromboxane (TX) and leukotrienes (LT), produced from arachidonic acid in the phospholipids of cell membranes, are considered to be biologically active eicosanoids. Corticosteroids reduce eicosanoid production by impairing phospholipase A2 activation, while cyclo-oxygenase inhibiting drugs such as the nonsteroidal anti-inflammatory drugs (NSAID) suppress PG and TX production. PGE1 (alprostadil) and PGE2 (dinoprostone) therapy has been shown to improve oxygenation in neonates whose pulmonary and systemic blood flow are dependent on a patent ductus arteriosus, while epoprostenol (prostacyclin, PGI2) and beraprost (beraprost sodium), another PGI2 analogue, are often effective as acute vasodilators in paediatric pulmonary hypertension. Synthetic PGE analogues such as misoprostol have gastric antisecretory and cytoprotective effects, and are effective in both prophylaxis and treatment of NSAID-induced gastroduodenal mucosal lesions. Both alprostadil and epoprostenol have been shown to be effective in treating peripheral vascular and skin diseases. Since TX, a platelet aggregator and vasoconstrictor, has been implicated as a potential mediator of asthma, its inhibition by agents such as seratrodast (AA-2414) and ozagrel (OKY-046) has proven effective in the treatment of adult patients with asthma; studies of these agents in paediatric patients is awaited with interest. Developing the clinical use of eicosanoid-related drugs and assessing the potential use of these drugs requires a 3-phase approach: reducing the complications in the treatment of neonates with ductus-dependent congenital heart diseases and primary pulmonary hypertension requiring PGE1, PGE2 and PGI2 therapy; conducting clinical trials of the synthesis inhibitors and receptor antagonists of TXA2 and LT that have already been used in the treatment of adult patients with bronchial asthma; and evaluating the efficacy of new modulators of eicosanoid biosynthesis, such as eicosapentaenoic acid and antiallergy drugs, in the treatment of eicosanoid-related diseases in children.

Topics: Child; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Eicosanoids; Eicosapentaenoic Acid; Humans; Hypertension, Pulmonary; Leukotriene Antagonists; Peripheral Vascular Diseases; Skin Diseases; Thromboxane A2

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).. 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.. Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.

Topics: Adult; Aged; Aspirin; Diabetic Angiopathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Phthalic Acids; Platelet Aggregation Inhibitors; Risk Factors; Survival Analysis; Thromboxane A2

Topics: Animals; Atorvastatin; Biomarkers; Disease Models, Animal; Epoprostenol; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metabolic Syndrome; Microcirculation; Microvessels; Models, Cardiovascular; Muscle, Skeletal; Nitric Oxide; Oxygen Consumption; Peripheral Vascular Diseases; Physical Conditioning, Animal; Physical Exertion; Rats, Zucker; Regional Blood Flow; Running; Thromboxane A2; Time Factors

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.

Topics: Animals; Arterioles; Fructose; Hypertension, Renal; Microcirculation; Muscle, Skeletal; Nitric Oxide; Oxygen Consumption; Perfusion; Peripheral Vascular Diseases; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Zucker; Risk Assessment; Sodium, Dietary; Thromboxane A2