salicylates and Vascular-Diseases

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Arthritis, Rheumatoid; Atrophy; Betamethasone; Drug Interactions; Glucocorticoids; History, 20th Century; Humans; Hydrocortisone; Infections; Injections, Intra-Articular; Joint Diseases; Methylprednisolone; Necrosis; Osteoporosis; Peptic Ulcer; Prednisolone; Prednisone; Rheumatic Diseases; Salicylates; Skin Diseases; Substance Withdrawal Syndrome; Synovitis; Triamcinolone; Vascular Diseases

The mean follow-up in the clinical trials of antiplatelet drugs in the secondary prevention of ischemic atherothrombotic stroke ranges from 1 to 5.5 years. Thus, the safety and efficacy of these drugs in the very long term is not totally documented. We have assessed the safety and effectiveness of triflusal and aspirin for a very long-term period in the secondary prevention of patients with ischemic atherothrombotic stroke.. Patients with atherothrombotic ischemic stroke, including TIA, who participated in randomized clinical trials of triflusal versus aspirin were included in the study. The period of recruitment was between 1983 and 1999. After finishing their participation in the clinical trials, patients were followed up in the Neurology Department of our hospital. All patients were treated with aspirin or triflusal during a mean period of 17.2 years. Groups were comparable with respect to sex, age, risk factor and etiology of the stroke. Adverse events and vascular events (including stroke recurrence, ischemic heart disease and vascular death) that appeared throughout the study were registered. Statistical analysis was performed using the statistical package SPSS 15.0 for Windows. Kaplan-Meier curves and the log-rank test were used to compare treatments.. A total of 441 patients (305 men) with a mean age (±SD) of 51.1±12.4 years were included in the study; 288 patients (65.3%) were treated with triflusal and 153 with aspirin. There were no statistically significant differences between aspirin and triflusal concerning new vascular events (72.5 vs. 60.4%; p=0.28), stroke recurrence (49.7 vs. 46.5%; p=0.53), ischemic heart events (54.9 vs. 55.6%; p=0.90), vascular death (25.5 vs. 24%; p=0.73) and global mortality (42.5 vs. 42%; p=0.92). The incidence of serious bleeding (upper digestive tract hemorrhage and cerebral hemorrhage) was 18.3% in aspirin-treated patients and 5.5% in triflusal-treated patients (p<0.001). In reference to other adverse events, no significant differences were found between aspirin and triflusal.. In the secondary prevention of ischemic stroke, very long-term treatment with triflusal or aspirin seems to have a similar efficacy, but triflusal is safer with a lower hemorrhagic risk. Triflusal may be an alternative therapy, particularly in patients who present aspirin resistance.

Topics: Aged; Aspirin; Brain Ischemia; Dyspepsia; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Intracranial Arteriosclerosis; Ischemic Attack, Transient; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Secondary Prevention; Vascular Diseases

We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower (P<0.01) in vitamin D-insufficient (3.7 ± 0.2%; serum 25-hydroxyvitamin D [25(OH)D]: 20 to 29 ng/mL; 62 ± 1 years of age; n = 31; mean± SE) and vitamin D-deficient (3.2 ± 0.3%; 25(OH)D: <20 ng/mL; 63 ± 2 years of age; n = 22) versus vitamin D-sufficient (4.6 ± 0.4%; 25(OH)D: >29 ng/mL; 61 ± 1 years of age; n = 22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ (P = 0.45). Among all subjects, brachial flow-mediated dilation was positively related to serum 25(OH)D (%Δ: r = 0.35; P<0.01) but not 1,25-dihydroxyvitamin D (r = -0.06; P = 0.61), the active form of vitamin D. Vascular endothelial cell expression of the proinflammatory transcription factor nuclear factor κB was greater in deficient versus sufficient subjects (0.59 ± 0.07 versus 0.44 ± 0.05; P<0.05), and inhibition of nuclear factor κB (4 days oral salsalate) improved flow-mediated dilation to a greater extent in subjects with lower versus higher 25(OH)D (+3.7 ± 0.6 versus +2.0 ± 0.2%; P<0.05). Endothelial cell expression of the downstream proinflammatory cytokine interleukin-6 also was higher in deficient versus sufficient subjects (0.67 ± 0.08 versus 0.47 ± 0.05; P<0.01) and inversely related to serum 25(OH)D level (r = -0.62; P<0.01), whereas vitamin D receptor and 1-α hydroxylase, the 25(OH)D to 1,25-dihydroxyvitamin D converting enzyme, were lower (P<0.05). Inadequate serum 25(OH)D is associated with vascular endothelial dysfunction among healthy middle-aged/older adults, and this is mediated in part by nuclear factor κB-related inflammation. Reduced vitamin D receptor and 1-α hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Aged; Brachial Artery; Endothelium, Vascular; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; NF-kappa B; Nitroglycerin; Receptors, Calcitriol; Salicylates; Vascular Diseases; Vasodilation; Vitamin D; Vitamin D Deficiency

In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia-reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. I kappaB kinase-beta (IKK beta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKK beta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKK beta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3-4.5 g daily); indeed, this is likely to be the mechanism responsible for salicylate's utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.

Topics: Dose-Response Relationship, Drug; Humans; I-kappa B Kinase; Metabolic Syndrome; NF-kappa B; Oxidative Stress; Salicylates; Vascular Diseases

Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.. Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor alpha (TNFalpha) production, and real-time polymerase chain reaction to examine TNFalpha-mediated expression of matrix metalloproteinase 9 (MMP-9).. At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNFalpha expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNFalpha production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNFalpha. TNFalpha activity was a prerequisite for local expression of MMP-9 at the coronary artery.. Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNFalpha and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Immunoglobulins, Intravenous; Immunologic Factors; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucocutaneous Lymph Node Syndrome; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Salicylates; T-Lymphocytes; Tumor Necrosis Factor-alpha; Vascular Diseases

Topics: Aged; Aged, 80 and over; Aspirin; Delayed-Action Preparations; Female; Humans; Male; Salicylates; Salicylic Acid; Vascular Diseases

Topics: Humans; Platelet Aggregation; Salicylates; Thromboembolism; Vascular Diseases

Topics: Antidepressive Agents; Barbiturates; Blood Circulation; Carbamates; Carbon Monoxide Poisoning; France; Humans; Hypoxia; Lung Diseases; Morphinans; Phenothiazines; Poisoning; Respiration; Salicylates; Seizures; Trichloroethylene; Vascular Diseases

Topics: Angioedema; Animals; Blood Coagulation Factors; Bradykinin; Carboxypeptidases; Carcinoid Tumor; Catecholamines; Chemical Phenomena; Chemistry; Colchicine; Complement System Proteins; Female; Glucocorticoids; Guinea Pigs; Haplorhini; Humans; Inflammation; Kallidin; Kallikreins; Kidney; Kinins; Muscle Contraction; Phenothiazines; Rats; Salicylates; Sheep; Shock, Septic; Stimulation, Chemical; Uterus; Vascular Diseases; Vascular Resistance; Vasodilator Agents

Topics: Blood Circulation; Humans; Ointments; Salicylates; Vascular Diseases

Topics: Colonic Diseases; Histamine; Humans; Nicotinic Acids; Salicylates; Vascular Diseases; Vitamin E

Topics: Angiography; Arteriosclerosis Obliterans; Atherosclerosis; Barbiturates; Diagnosis, Differential; Drug Therapy; Humans; Ischemia; Leg; Salicylates; Thiamine; Thrombophlebitis; Vascular Diseases; Vascular Surgical Procedures; Vasodilator Agents; Vitamin B 12; Vitamin B Complex

Topics: Anticoagulants; Cardiovascular Diseases; Peripheral Vascular Diseases; Salicylates; Vascular Diseases

Topics: Aesculus; Balneology; Fagaceae; Peripheral Vascular Diseases; Salicylates; Vascular Diseases

Topics: Aspirin; Capillaries; Capillary Fragility; Hemorrhage; Hemorrhagic Disorders; Humans; Salicylates; Vascular Diseases