Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboxane A2 (TXA2) is a key mediator of platelet aggregation and smooth muscle contraction. Its action is mediated by its G protein-coupled receptor of which two isoforms, termed TPalpha and TPbeta, occur in humans. TXA2 has been implicated in pathologies such as cardiovascular diseases, pulmonary embolism, atherosclerosis, and asthma. This study describes the pharmacological characterization of BM-613 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a new combined TXA2 receptor antagonist and TXA2 synthase inhibitor. It exhibits a strong affinity for human platelet TP receptors (IC50 = 1.4 nM), TPalpha and TPbeta expressed in COS-7 cells (IC(50) = 2.1 and 3.1 nM, respectively), and TPs expressed in human coronary artery smooth muscle cells (IC50 = 29 microM). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED50 = 1.52 microM) and guinea pig trachea (ED50 = 2.5 microM) induced by TXA2 agonist U-46619 (9.11-dideoxy-9.11-methanoepoxy-prostaglandin F2). Besides, BM-613 antagonizes TPalpha (IC50 = 0.11 microM) and TPbeta (IC50 = 0.17 microM) calcium mobilization induced by U-46619 and inhibits human platelet aggregation induced by U-46619 (ED50 = 0.278 microM), arachidonic acid (ED50 = 0.375 microM), and the second wave of ADP. BM-613 also dose dependently prevents TXA2 production by human platelets (IC50 = 0.15 microM). In a rat model of ferric chloride-induced thrombosis, BM-613 significantly reduces weight of formed thrombus by 79, 49, and 28% at 5, 2, and 1 mg/kg i.v., respectively. In conclusion, BM-613 is a dual and potent TP receptor antagonist and TXA2 synthase inhibitor characterized by a strong antiplatelet and antithrombotic potency. These results suggest that BM-613 could be a potential therapeutic drug for thrombotic disorders.
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PMID:In vitro and in vivo pharmacological characterization of BM-613 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a novel dual thromboxane synthase inhibitor and thromboxane receptor antagonist. 1562 21

Acute disorder of mesenteric circulation (ADMC) is an emergency pathology of the abdominal organs. It occurs in 0.2% of general surgery patients. A total of 346 patients with verified (before, during operation and/or on autopsy) diagnosis of ADMC were analyzed retrospectively. There were 217 (62.7%) women and 129 (37.3%) men. The mean age of the patients was 68.4+/-3.6 years. In 50.7% of patients, ADMC was induced by thrombosis of the unpaired visceral branches of the abdominal aorta, in 29.1% -- by embolism of the superior mesenteric artery (SMA), in 7.8% -- by thrombosis of the portomesenteric bed, in 7.5% -- by non-occlusion mesenteric ischemia (NOMI), and in 4.9% by diseases of the parietal vessels of the bowel. The most prevalent risk factors of ADMC were: atherosclerosis of the aorta and its branches, previous reconstructions for occlusion-stenotic arterial lesions, episodes of arterial embolism in the anamnesis, congenital and acquired hemostatic disorders, oral contraception, thromboses of the deep veins and/or pulmonary embolism in the anamnesis, operations on the abdominal organs, different types of acute end chronic heart failure. In SMA thrombosis, occlusion most frequently affects the orifice (93.5%) and initial segment of the great vessel, In embolism it occurs before or at the level of the middle colic artery (in 57.9%). Disseminated bowel necroses are more frequently encountered in occlusions of the arterial bed (87.7% in thromboses and 83.3% emdolism) than in the venous system (8.3%).
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PMID:Acute disorders of mesenteric circulations: the etiology, risk factors and incidence of lesions. 1562 45

Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.
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PMID:Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms. 1592 98

Cholesterol crystal embolization (CCE) is a severe systemic disorder caused by vascular migration of cholesterol crystals originating from ulcerative atherosclerotic plaques located in large arteries. We report 2 cases of CCE diagnosed on bladder transurethral resection in 2 men aged 94 and 72 years. Both patients had atherosclerosis disease. One patient had been treated by heparin 1 month before for pulmonary embolism and the other had had a coronary angiography and bypass graft surgery 5 months before for silent myocardial infarction. One patient presented with hematuria and the other with acute renal failure. Cystoscopy showed multiple papillary tumors of the bladder wall. Bladder transurethral resections showed transitional cell carcinoma with cholesterol crystals occluding the lumen of small arterioles in the submucosa. Eight cases of CCE in the bladder wall have been reported in the literature in 3 women and 5 men aged 56 to 79 years. Cholesterol crystal embolization is often discovered in the bladder wall on necropsy specimens. Only 2 cases have been fortuitously discovered on bladder transurethral resection performed for transitional cell carcinoma. Cholesterol crystal embolization in the bladder wall is often a marker of severe disease although the evolution is quite favorable in our patients, still alive 1 and 2 years after diagnosis.
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PMID:Cholesterol crystal embolization diagnosed on bladder transurethral resection. 1608 59

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.
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PMID:From the design to the clinical application of thromboxane modulators. 1653 59

Mortality has been reported to complicate gastric bypass, with common causes of death attributable to anastomotic leaks, sepsis, hemorrhage, and bowel obstruction. We evaluated autopsy reports from 10 patients having undergone gastric bypass. Medical records were reviewed to identify comorbidities. Data of interest included preoperative electrocardiogram (EKG) abnormalities, cause of death, body weight, anastamosis appearance, heart weight, extent of coronary artery disease, ventricular size, liver weight, and gall bladder status. A total of 7 men and 3 women were autopsied. Average age was 40 years (range, 30-49 years), and mean body mass index at autopsy was 60.3 kg/m(2) (range, 33.2-80.9 kg/m(2)). Evidence of anastomotic leaks was present in 7 cases, resulting in 4 deaths. Death was attributed to pulmonary embolism in one case. There were 5 cardiac-related deaths, all attributed to arrhythmias. Microscopic evidence of coronary artery disease was observed in 6. Cardiomegaly was seen in all patients, left ventricular hypertrophy in 8, right ventricular hypertrophy in 3, and hepatomegaly in all 10. Nine patients were status post cholecystectomy. Of the 8 preoperative EKG available, abnormalities were identified in 5. After gastric bypass, death was attributed to cardiac-related causes, pulmonary embolism, and operative complications. A significant proportion of cardiac-related deaths occured in the absence of atherosclerosis. Most patients had preoperative EKG abnormalities. As a high incidence of cardiomegaly was observed, operative stress associated with the procedure may increase the risk of arrhythmia in morbid obesity. Consequently, in morbidly obese patients, a detailed preoperative cardiovascular evaluation is warranted to reduce postoperative mortality.
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PMID:Postmortem findings in morbidly obese individuals dying after gastric bypass procedures. 1723 34

Pulmonary ischemia-reperfusion (IR) injury may result from trauma, atherosclerosis, pulmonary embolism, pulmonary thrombosis and surgical procedures such as cardiopulmonary bypass and lung transplantation. IR injury induces oxidative stress characterized by formation of reactive oxygen (ROS) and reactive nitrogen species (RNS). Nitric oxide (NO) overproduction via inducible nitric oxide synthase (iNOS) is an important component in the pathogenesis of IR. Reaction of NO with ROS forms RNS as secondary reactive products, which cause platelet activation and upregulation of adhesion molecules. This mechanism of injury is particularly important during pulmonary IR with increased iNOS activity in the presence of oxidative stress. Platelet-endothelial interactions may play an important role in causing pulmonary arteriolar vasoconstriction and post-ischemic alveolar hypoperfusion. This review discusses the relationship between ROS, RNS, P-selectin, and platelet-arteriolar wall interactions and proposes a hypothesis for their role in microvascular responses during pulmonary IR.
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PMID:Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions. 1752 80

Recent data have implicated a haplotype of the purinergic receptor P2Y, G-protein coupled, 12 gene (P2RY12), as potential risk determinant for atherothrombosis. However, to date, no prospective, genetic-epidemiological data are available. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the possible association of P2RY12 genetic variants, in particular a haplotype H2 (constituted by dbSNP rs10935838, rs2046934, rs5853517, and rs6809699) amongst 708 white males who subsequently developed a thromboembolic event (incident myocardial infarction (MI), ischemic stroke, or deep venous thromboembolism/pulmonary embolism (DVT/PE)) and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). The P2RY12 gene variants tested were in linkage disequilibrium. The haplotype H2 distribution was significantly different between the DVT/PE cases (12%) and their matched controls (21%), p-permuted=0.02. In an adjusted conditional logistic regression analysis, the haplotype H2 was significantly associated with a lower risk of incident DVT/PE as compared to the reference haplotype H1 (odds ratio=0.50, 95% CI=0.27-0.93, p=0.028). However, we found no evidence for an association of the P2RY12 variants or the haplotype H2 with incident MI or ischemic stroke. The present investigation provides evidence for an association of the P2RY12 haplotype H2 with lower risk of DVT/PE; however these findings require replication in other well-designed studies.
Atherosclerosis 2008 Apr
PMID:Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. 1770 82

Recent advances in computed tomography (CT) technology have made high resolution noninvasive coronary angiograms possible. Multiple studies involving over 2,000 patients have established that coronary CT angiography (CCTA) is highly accurate for delineation of the presence and severity of coronary atherosclerosis. The high negative predictive value (>95%) found in these studies suggests that CCTA is an attractive option for exclusion of coronary artery disease in properly selected emergency department patients with acute chest pain. CT is also a well established and accurate tool for the diagnosis of acute aortic dissection and pulmonary embolism. Recent technical developments now permit acquisition of well-opacified images of the coronary arteries, thoracic aorta and pulmonary arteries from a single CT scan. While this so called "triple-rule out" scan protocol can potentially exclude fatal causes of chest pain in all three vascular beds, the attendant higher radiation dose of this method precludes its routine use except when there is sufficient support for the diagnosis of either aortic dissection or pulmonary embolism. This article provides an overview of CCTA, and reviews the clinical evidence supporting the use of this technique for triage of patients with acute chest pain.
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PMID:Use of multislice CT for the evaluation of emergency room patients with chest pain: the so-called "triple rule-out". 1809 8

Postoperative venous thromboembolism (VTE) is a common cause of preventable patient morbidity and mortality. Hospitalized patients have multiple risk factors for VTE, which can exert a cumulative effect on the individual patient. Although effective thromboprophylactic measures are currently available, they are not commonly used for a number of reasons, in addition to heightened concern about increasing bleeding risk. Limited data are available characterizing the incidence of symptomatic VTE following major vascular surgery in the absence of thromboprophylactic therapy. Reported rates vary according to the type of surgery, type of prophylaxis used, and diagnostic modalities used for deep venous thrombosis (DVT) and pulmonary embolism (PE). Hospital-acquired DVT in the absence of thromboprophylaxis can occur in up to 40% of patients, occurring primarily in the proximal deep veins, which elevates the risk of PE. Risk factors for VTE in vascular surgery include limb ischemia, prolonged surgery duration, localized intraoperative trauma, and atherosclerosis. Advanced patient age is also a risk factor for VTE; however, the relationship between age and risk of VTE after surgery is complex and dependent on both the type of surgery and the underlying disease process. Evidence-based guidelines for venous thrombo-prophylaxis are now available; however, adoption of and compliance with these guidelines have lagged. Effective thrombo-prophylactic strategies exist and include both pharmacologic and nonpharmacologic approaches. For those surgical patients who develop a VTE, antithrombotic therapy remains the treatment of choice.
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PMID:Prevention and treatment of deep venous thrombosis. 1854 9


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