Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo-controlled study

Abstract:  Acute mental stress is a potent trigger of acute coronary syndromes. Catecholamine-induced hypercoagulability with acute stress contributes to thrombus growth after coronary plaque rupture. Melatonin may diminish catecholamine activity. We hypothesized that melatonin mitigates the acute procoagulant stress response and that this effect is accompanied by a decrease in the stress-induced catecholamine surge. Forty-five healthy young men received a single oral dose of either 3 mg melatonin (n = 24) or placebo medication (n = 21). One hour thereafter, they underwent a standardized short-term psychosocial stressor. Plasma levels of clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, and catecholamines were measured at rest, immediately after stress, and 20 min and 60 min post-stress. The integrated change in D-dimer levels from rest to 60 min post-stress differed between medication groups controlling for demographic and metabolic factors ( P  = 0.047,      = 0.195). Compared with the melatonin group, the placebo group showed a greater increase in absolute D-dimer levels from rest to immediately post-stress ( P  = 0.13;      = 0.060) and significant recovery of D-dimer levels from immediately post-stress to 60 min thereafter ( P  = 0.007;      = 0.174). Stress-induced changes in FVII:C, FVIII:C, fibrinogen, and catecholamines did not significantly differ between groups. Oral melatonin attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer without affecting catecholamine activity. The finding provides preliminary support for a protective effect of melatonin in reducing the atherothrombotic risk with acute mental stress.     

Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia

Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia.     

Effects of sulfinpyrazone, aspirin and propranolol on the isoproterenol-induced myocardial necrosis

Prophylactic effects of sulfinpyrazone (100 mg/Kg), aspirin (5 mg/Kg, 50 mg/Kg), and propranolol (2 mg/Kg, 10 mg/Kg) on myocardial necrosis and hypertrophy induced by isoproterenol were examined. Drugs were administered to rats daily by gavage for a period of 2 weeks and after that isoproterenol (40 mg/Kg) was injected subcutaneously. The control group received gavage of water and isoproterenol injection. The "no infarct" group received gavage of water and saline injection. Premedication of sulfinpyrazone and propranolol significantly preserved myocardial CK activity and decreased cardiac hypertrophy compared with control group (24 hours after isoproterenol injection) while aspirin did not have such effects. Myocardial cyclic AMP concentration significantly increased 30 min after isoproterenol injection in control and all the premedicated rats compared with the "no infarct" rats. The increment of cyclic AMP was not suppressed by sulfinpyrazone and propranolol during this period. Plasma levels of prostaglandins were significantly suppressed by the administration of sulfinpyrazone and 50 mg/Kg of aspirin, and were not suppressed by 5 mg/Kg of aspirin. It was concluded that premedication of sulfinpyrazone and propranolol reduce cardiac necrosis and hypertrophy induced by isoproterenol, but aspirin did not have such cardioprotective effects.     

Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial

The value of the addition of beta-blockers to coronary vasodilator therapy in the treatment of patients with unstable angina at rest is controversial. We conducted a double-blind, randomized, placebo-controlled 4 week trial of propranolol in 81 patients with unstable angina, 39 of whom were assigned to placebo and 42 of whom received propranolol in a dose of at least 160 mg daily. All patients were also treated with coronary vasodilators, including 80 mg nifedipine daily and long-acting nitrates. The incidences of cardiac death, myocardial infarction, and requirement for bypass surgery or coronary angioplasty did not differ between the two groups (propranolol = 16; placebo = 18). The propranolol group had a lower cumulative probability of experiencing recurrent resting angina than the placebo group (p = .013), and over the first 4 days of the trial the mean number of clinical episodes of angina (propranolol 0.9 +/- 0.2, placebo 1.8 +/- 0.3, p = .036), duration of angina (propranolol 15.1 +/- 4.3 min, placebo 38.1 +/- 8.4, p = .014), and nitroglycerin requirement (propranolol 1.1 +/- 0.3 tablets, placebo 3.5 +/- 0.8, p = .003) were also fewer. Continuous electrocardiographic recording for ischemic ST segment changes revealed fewer daily ischemic episodes in the propranolol group (2.0 +/- 0.5) than in the placebo group (3.8 +/- 0.7, p = .03), and a shorter duration of ischemia (propranolol 43 +/- 10 min, placebo 104 +/- 28 min, p = .039). Thus propranolol, in patients with unstable angina, in the presence of nitrates and nifedipine is not detrimental and reduces the frequency and duration of symptomatic and silent ischemic episodes.     

Effects of early intervention with low-dose aspirin (100 mg) on infarct size, reinfarction and mortality in anterior wall acute myocardial infarction

Recently, it was shown that aspirin given early in acute myocardial infarction (AMI) improves hospital survival, but the mechanisms involved are unclear. In a prospective, randomized placebo-controlled trial, the influence of early intervention with low-dose aspirin (100 mg/day) on infarct size and clinical outcome was studied in 100 consecutive patients with first anterior wall AMI. Infarct size was calculated by cumulative lactate dehydrogenase release in the first 72 hours after admission and was found to be (mean +/- standard deviation) 1,431 +/- 782 U/liter in the aspirin group (n = 50) and 1,592 +/- 1,082 U/liter in the placebo group (n = 50, p = 0.35). The study medication was given for 3 months, during which mortality was 10 (20%) in the aspirin patients and 12 (24%) in the placebo patients (p = 0.65). However, reinfarction occurred in 2 patients (4%) in the aspirin group and in 9 (18%) in the placebo group (p less than 0.03). Early intervention with low-dose aspirin showed, in comparison to placebo, a 10% decrease of infarct size, but this difference was not statistically significant. However, early low-dose aspirin effectively decreased the risk of reinfarction. Therefore, the favor able results of early aspirin on mortality in acute myocardial infarction are probably due more to prevention of reinfarction than to decrease of infarct size.     

Bedside measurement of factor VIII:C activity in individuals with hemophilia A

Factor VIII replacement therapy for patients with hemophilia A is conventionally monitored using a plasma-based factor VIII:C assay (a modified activated partial thromboplastin time [APTT] test). The plasma factor VIII assay requires the preparation of plasma from citrated whole blood and measurement of the clotting times of mixtures of patient plasma, factor VIII-deficient substrate, and APTT reagent. Results are not routinely available in less than 1.5 hr, reducing the clinical value of the laboratory data regarding the ability to immediately adjust patient therapy. Results from the whole blood factor VIII assay, performed on a portable coagulation analyzer and using test tubes prefilled with the necessary APTT and factor VIII-deficient reagents, are available within 5–7 min. This immediate determination of the factor VIII:C level from citrated whole blood provides the opportunity to greatly reduce turnaround time and improve the efficacy of factor VIII replacement therapy. Based on clotting time, factor VIII:C activity is read from a standard curve. A clinical evaluation of this whole blood test was performed in two hemophilia centers. A high degree of correlation was seen (r = 0.813, n = 220) between the whole blood values obtained and conventional laboratory results. This level of correlation was superior to that obtained when comparing two different plasma-based systems (r = 0.753, n = 23). Factor VIII:C activity levels measured using the whole blood assay system were similar, irrespective of the test operator (laboratory technologist, nurse clinician, or patient). This study indicates that the whole blood factor VIII assay provides results comparable to those of conventional plasma-based assays, but in a more rapid and efficient manner. It provides an opportunity to reduce unnecessary patient consumption of replacement preparations, hence reducing the cost of hemophilia A maintenance and prophylaxis regimens, and to reduce overall patient exposure to human blood products. © 1996 Wiley-Liss, Inc.     

Prolonged application of clopidogrel reduces inflammation after percutaneous coronary intervention in the porcine model

OBJECTIVE: We determined the effect of prolonged treatment with clopidogrel on C-reactive protein (CRP) concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty followed by intracoronary brachytherapy in the porcine model. ANIMAL MODEL: All 48 pigs received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose) 1 day before PCI, followed by a daily dose of clopidogrel (75 mg/day) in addition to aspirin. During PCI, one of two balloon-injured arteries was randomly assigned to receive immediate radiation treatment. Animals were sacrificed after 24 h, 1 month, and 3 months post-PCI. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups. The first group received clopidogrel in addition to aspirin for 3 months, and the second group received clopidogrel in addition to aspirin for only 1 month after PCI and then aspirin alone. METHODS: Blood was taken from all pigs before intervention, immediately after intervention, and before sacrifice. Serum CRP was measured by enzyme-linked immunosorbent assay. To analyze the procoagulant effects of PCI on blood thrombogenicity, a one-stage clotting assay was performed. RESULTS: Clopidogrel treatment for 3 months reduced CRP levels more than did clopidogrel therapy for 1 month only at 3 months post-PCI (27.9+/-3.9 vs. 56.6+/-11.3 microg/ml; P=.019). Baseline CRP levels were found to be 50.4+/-4.8 microg/ml. Plasma clotting was not affected by prolonged clopidogrel therapy (322.8+/-59.3 s vs. 295.2+/-52.5 s; P=ns). CONCLUSIONS: Prolonged treatment with clopidogrel reduced CRP levels post-PCI.     

The O blood group protects against venous thromboembolism in individuals with the factor V Leiden but not the prothrombin (factor II G20210A) mutation.

We investigated the influence of the ABO blood group in the observed prevalences of the recently described factor V R506Q and factor II G20210A mutations in a thrombotic population. We determined the ABO blood group in a sample of 178 unselected patients (aged 17-83 years), diagnosed at our center with deep vein thrombosis or pulmonary embolism. The results of this study show a high prevalence of thrombosis in the non-O blood group. In the general population, the prevalence as a fraction of the O blood group was 2.69 (confidence interval 1.90-3.82). Of the factor V R506Q carriers (n = 28), only one had O group blood and 27 of 28 were non-O (24 A, one B and two AB). However, within the group of factor II G20210A carriers (n = 17), seven had O, nine A and one B type blood. The prevalence of the factor V R506Q mutation within the O blood group was 2.4% (one of 42), significantly lower than in the A group (23.3%, 24 of 103; P = 0.002), or in the overall non-O group (19.9%, 27 of 136; P = 0.006). This prevalence was similar to that observed previously in the non-thrombotic population in our area (3.5%; P = 0.9). We analyzed the clotting activity of factor VIII and we found higher levels in the non-O group (1.78+/-0.61 U/ml) than in the O blood group (1.30+/-0.51 U/ ml; P < 0.0001). We speculate that factor Va in individuals with the factor V Leiden mutation could interact with the high levels of factor VIII clotting activity as a necessary cofactor.     

Platelet activation and secretion associated with emotional stress

Platelets are believed to play a role in the pathogenesis of atherosclerosis and of the vascular obstruction that causes the acute complications of coronary artery disease. Since specific behavioral patterns appear to be related to the development of coronary artery disease and since emotional stress may predispose an individual to acute cardiovascular ischemia, it was hypothesized that platelet activation by catecholamines might be involved in these events. To study emotional stress, plasma samples were obtained from 61 senior medical residents immediately before they were to speak in public. There were significant increases in the plasma concentrations of the platelet-secreted proteins platelet factor 4 and beta-thromboglobulin and epinephrine and norepinephrine immediately before speaking, which demonstrates that platelet activation and secretion occur in association with this type of emotional stress. Four trials were carried out to study the mechanism for this observed platelet secretion: (1) phenoxybenzamine, (2) propranolol, (3) 650 mg aspirin, and (4) 80 mg aspirin were given several hours before the public speaking engagement. Neither phenoxybenzamine nor propranolol in doses that blocked the hemodynamic effects of alpha 1- and beta 1-adrenergic stimulation modified platelet secretion. Aspirin also did not block platelet secretion, which suggests that platelets were not being stimulated through a cyclooxygenase-dependent pathway. This study provides direct evidence of platelet secretion in vivo in association with emotional stress, and underscores the potential importance of platelet activation and secretion in the acute events that occur in patients with vascular disease.     

Effects of carvedilol on oxidative stress in polymorphonuclear and mononuclear cells in patients with essential hypertension

PURPOSE: To compare the effects of carvedilol and propranolol on oxidative stress in leukocytes and C-reactive protein levels in patients with hypertension. METHODS: Sixty hypertensive patients were randomly assigned to carvedilol (20 mg; n = 30) or propranolol (60 mg; n = 30) for 6 months. Thirty normotensive subjects who were given placebo served as controls. Oxidative stress in polymorphonuclear cells and mononuclear cells were measured by gated flow cytometry. C-reactive protein levels were measured by immunonephelometric assay. RESULTS: Oxidative stress in polymorphonuclear cells and mononuclear cells was increased significantly in hypertensive patients compared with in normotensive controls. After 6 months of treatment, carvedilol decreased oxidative stress significantly in polymorphonuclear cells by a mean of 45 arbitrary units (95% confidence interval [CI]: 32 to 59 arbitrary units; P <0.001) and propranolol decreased oxidative stress significantly by 20 arbitrary units (95% CI: 7 to 33 arbitrary units; P <0.003; P = 0.001 for difference between treatments). Carvedilol also decreased oxidative stress significantly in mononuclear cells by 23 arbitrary units (95% CI: 15 to 31 arbitrary units; P <0.001), whereas propranolol decreased oxidative stress by 2 arbitrary units (95% CI: 7 to 12 arbitrary units; P = 0.62; P = 0.002 for difference between treatments). Carvedilol decreased C-reactive protein levels significantly by a median of 0.073 mg/dL (interquartile range, 0.034 to 0.112 mg/dL; P <0.001), whereas propranolol decreased levels by 0.012 mg/dL (interquartile range, 0.009 to 0.032 mg/dL; P = 0.26; P = 0.003 for difference between treatments). CONCLUSION: These findings suggest that carvedilol inhibits oxidative stress in polymorphonuclear and mononuclear cells, as well as lowers C-reactive protein levels, to a greater extent than does propranolol in hypertensive patients.     

Pathophysiological processes underlying emotional triggering of acute cardiac events

Acute negative emotional states may act as triggers of acute coronary syndrome (ACS), but the biological mechanisms involved are not known. Heightened platelet activation and hemodynamic shear stress provoked by acute stress may contribute. Here we investigated whether patients whose ACS had been preceded by acute anger, stress, or depression would show heightened hemodynamic and platelet activation in response to psychophysiological stress testing. We studied 34 male patients an average of 15 months after they had survived a documented ACS. According to an interview conducted within 5 days of hospital admission, 14 men had experienced acute negative emotion in the 2 h before symptom onset, and 20 men had not experienced any negative emotion. Hemodynamic variables and platelet activation were monitored during performance of challenging color-word interference and public speaking tasks and over a 2-h poststress recovery period. The emotion trigger group showed significantly greater increases in monocyte-platelet, leukocyte-platelet, and neutrophil-platelet aggregate responses to stress than the nontrigger group, after adjusting for age, body mass, smoking status, and medication. Monocyte-platelet aggregates remained elevated for 30 min after stress in the emotion trigger group. The emotion trigger group also showed poststress delayed recovery of systolic pressure and cardiac output compared with the nontrigger group. These results suggest that some patients with coronary artery disease may be particularly susceptible to emotional triggering of ACS because of heightened platelet activation in response to psychological stress, coupled with impaired hemodynamic poststress recovery.     

Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism

OBJECTIVE: The aims of the study were to evaluate the disturbances in the coagulation system in patients with overt hypothyroidism (OH), to assess the effects of levothyroxine (LT4) on the coagulation parameters, and to determine whether subclinical hypothyroidism (SH) affects concentrations of coagulation markers and several biochemical parameters, thereby supporting early substitution. DESIGN: The study included 15 patients with SH (TSH levels 5-10 mU/l), 15 patients with OH and 15 euthyroid controls. METHODS: Blood urea nitrogen, creatinine, creatine phosphokinase, aspartate aminotransferase, lactate dehydrogenase, total-cholesterol, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol and triglyceride levels, and bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), factor VIII activity, von Willebrand factor activity (vWF), platelet count and clotting time were evaluated just before and three months after the maintenance of euthyroidism with LT4 treatment. RESULTS: Factor VIII and vWF activities were lower in patients with SH than in controls (P < 0.01). Increased bleeding time, PT, APTT and clotting time and decreased factor VIII activity and vWF activity were observed in patients with OH when compared with controls. Bleeding time, PT, APTT and clotting time decreased and factor VIII activity, vWF and platelet count increased after LT4 in patients with OH. Increases in factor VIII activity and vWF (P < 0.01) were detected also in the SH group with treatment. CONCLUSIONS: OH is associated with significant abnormalities in clotting parameters which are reversed by LT4. In contrast, SH is associated with minor changes in factor VIII activity and vWF which are reversible by LT4. Serum lipids and other measured parameters are not improved by LT4 in patients with TSH < 10 mU/l and these data fail to demonstrate a need to treat such patients.     

Exaggerated cardiovascular stress responses and impaired beta-adrenergic-mediated pressor recovery in obese Zucker rats

Clinical studies have demonstrated that the pressor response to acute stress is larger in obese versus lean individuals. We therefore tested the hypotheses that the pressor response to behavioral stress is greater in obese (OZRs) versus lean Zucker rats (LZRs) and that reduced beta-adrenergic-mediated vasodilation contributes to the enhanced pressor response. Animals were restrained and subjected to acute pulsatile air jet stress (3 minutes), followed by a poststress period of 20 minutes; beta-adrenergic blockade was achieved with propranolol (5 mg/kg, IV) given 15 minutes before the start of air jet stress. Mean arterial pressure (MAP) was continuously monitored by telemetry. Untreated OZRs responded with a greater integrated pressor response (area under the curve [AUC]) to acute stress (41.2+/-6.1 versus 21.2+/-3.3 mm Hgx3 minutes, OZR versus LZR; P<0.05) and significantly reduced poststress recovery of MAP. Beta-adrenergic blockade had no effect on stress AUC in either LZRs or OZRs but significantly attenuated the poststress recovery of MAP in LZRs only (poststress AUC: -100.1+/-48.1 versus 49.0+/-13.5 mm Hgx20 minutes, untreated versus propranolol; P<0.05). In anesthetized animals, significantly smaller increases in mesenteric vascular conductance contributed to blunted depressor responses to isoproterenol in OZRs versus LZRs, suggesting that beta-adrenergic stimulation causes a greater reduction in total peripheral resistance in lean versus obese animals. We conclude that beta-adrenergic-mediated vasodilation facilitates blood pressure recovery after stress and that this pathway is compromised in an animal model of morbid obesity, resulting in the impaired ability to regulate blood pressure during stress.     

Properties of factor VIII/von Willebrand factor in two highly-purified factor VIII concentrates, Hemofil M and Monoclate, using monoclonal antibodies

Properties of F. VIII/vWF in highly-purified factor VIII concentrates were examined using monoclonal antibodies. The F. VIII: C levels obtained with the chromogenic assay agreed with those obtained with the one-stage clotting method. The ratio between F. VIII: Ag and F. VII: C in Hemofil M and Monoclate was 1.09 and 1.34, respectively. The F. VIII: Ag levels assayed by monoclonal ELISAs were the same as those assayed by polyclonal ELISA, except that those assayed by C 5-ELISA tended to be higher. The ratio between F. VIII: Ag and vWF: Ag in Hemofil M and Monoclate was 105 and 45, respectively. Both concentrates lacked the large multimers of vWF and showed the intensification of the satellite bands. SDS-PAGE patterns showed almost no contamination. Immunoblot analysis revealed that F. VIII in both concentrates could react with 6 kinds of monoclonal antibodies to F. VIII. These results suggest that the fundamental structure of F. VIII molecule for coagulant activity in both concentrates are preserved.     

氯吡格雷与阿司匹林或单独阿司匹林预防动脉粥样硬化血栓事件观察

目的:观察氯吡格雷联合阿司匹林对心血管病人或有动脉粥样硬化高危因素病人血栓事件的疗效。方法:选择2007年1月～2010年12月在我院治疗的心血管疾病或有多种危险因素聚集的605例患者,随机分为:联合用药组(302例,给予氯吡格雷75mg/d加阿司匹林75mg/d),阿司匹林组(303例,单用阿司匹林75mg/d),观察两组3年内主要不良心血管事件(MACE,包括心肌梗死,心性死亡,缺血性脑卒中)及次要不良心血管事件(不稳定型心绞痛,一过性脑缺血等)发生情况。结果:MACE发生率:联合用药组为6.8%,阿司匹林组为7.3%,相对风险0.93,95%CI 0.83～1.05,P=0.22,无显著差异。次要不良心血管事件:联合用药组16.7%,阿司匹林组17.9%,相对风险0.92,95%CI 0.86～0.995,P=0.04联合用药组的次要事件显著少于阿司匹林组;严重出血事件率两组分别为1.7%和1.3%,P=0.08,无显著差异;少量出血事件率两组分别为2.5%和1.3%,P<0.01。结论:氯吡格雷联合阿司匹林与单用阿司匹林比较对于心血管病人或有动脉粥样硬化高危因素病人主要不良心血管事件效果相当,次要不良心血管事件显著减少,但少量出血事件显著增加。     

Effects of beta-adrenoceptor blocking drugs on human sigmoid colonic motility

Effects of propranolol and metoprolol on sigmoid colonic motility were studied in 12 healthy volunteers in a double-blind randomized fashion. Colonic pressure was recorded 15-18 cm from anus and contractile activity quantified for periods of 25 min. On separate days propranolol, metoprolol, and placebo, respectively, was administered intravenously preceded by a control period. After propranolol, 10 mg intravenously, pressure activity increased significantly from 3.8 +/- 1.1 (SEM) kPa X min (28 +/- 8 mm Hg X min) to 5.9 +/- 1.0 kPa X min (44 +/- 8 mm Hg X min) (P less than 0.001). Also, after propranolol, 5 mg intravenously, the pressure activity was increased (P less than 0.05). After metoprolol, 10 mg intravenously, contractile activity increased from 4.3 +/- 0.9 kPa X min (32 +/- 7 mm Hg X min) to 6.1 +/- 1.0 kPa X min (46 +/- 8 mm Hg X min) (P less than 0.01). The two drugs caused equipotent reduction of heart rate. After placebo, no effect on sigmoid pressure or heart rate was observed. The study shows that unselective (propranolol) and beta 1-selective (metoprolol) beta-blocking drugs enhance distal colonic pressure in man. Colonic motility seems to be under sympathetic beta-adrenergic influence even under fairly unstrained conditions.     

Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress,arterial oxidation-specific epitopes,and atherogenesis in hypercholesterolemic mice

The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 +/- 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (-5.1 +/- 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages-derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.     

Hemodynamic effects of metoprolol in acute myocardial infarction. A randomized, placebo-controlled multicenter study

The central hemodynamic effects of metoprolol in acute myocardial infarction have been studied in a multicenter, double-blind, randomized trial. One hundred and ninety patients with acute myocardial infarction not previously on beta blockers with heart rate greater than 65 beats/min and blood pressure greater than 105 mm Hg and without clinical signs of serious heart failure were included. After insertion of a pulmonary artery catheter, patients were randomized to metoprolol, 15 mg intravenously, and 50 mg 4 times a day orally (n = 95) or placebo (n = 95) with a mean delay of 7.2 hours. Hemodynamic measurements were made at baseline and repeatedly during 24 hours. Heart rate, systolic blood pressure and cardiac index were all immediately reduced by 10 to 20% in the metoprolol group and the difference compared with placebo was maintained throughout the 24 hours (p less than 0.001). Pulmonary capillary wedge pressure (PCWP) in the metoprolol group increased from 13.7 +/- 6.7 to a peak of 15.5 +/- 5.5 mm Hg 30 minutes after injection. The difference compared with placebo was maintained for 8 hours (p less than 0.01). This increase was seen only in the patient group with initial PCWP below the median of 13 mm Hg. In patients with initial PCWP above the median a continuous decrease was observed in both the placebo and metoprolol groups. Thus high initial PCWP was not associated with intolerance to metoprolol. Based on hemodynamic measurements tolerance to metoprolol was good.     

Rofecoxib, a COX-2 inhibitor, lowers C-reactive protein and interleukin-6 levels in patients with acute coronary syndromes

BACKGROUND: Patients with acute coronary syndromes (ACS) have high levels of inflammatory mediators such as C-reactive protein (CRP) and interleukin (IL)-6. AIM: To evaluate whether patients with ACS treated with rofecoxib, a COX-2 inhibitor, will have reduced CRP, IL-6, and soluble tumor necrotic factor receptor-1 (sTNF-R1) levels and improved endothelial function. METHODS AND RESULTS: Thirty-four patients hospitalized with ACS were randomized to receive rofecoxib, 25 mg/d plus aspirin 100 mg/d, or placebo plus aspirin, 100 mg/d, for a period of 3 months. Blood samples for CRP, IL-6, and sTNF-R1 levels were drawn prior to randomization, and after 1 month and 3 months. CRP levels in the rofecoxib group (n = 18) were significantly lower both at 1 month and 3 months compared to the baseline levels (p < 0.02). IL-6 levels were significantly lower at 1 month (p < 0.02) in the rofecoxib group, but not at 3 months. There was no change in endothelial function or sTNF-R1 levels. CONCLUSION: Patients recovering from ACS had lower levels of CRP and IL-6 at 1 month and lower CRP levels at 3 months when treated with rofecoxib plus aspirin. Suppression of inflammatory processes may lead to retardation of coronary atherosclerosis and coronary events.     

Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study

OBJECTIVES:  Angiotensin II receptor antagonists have been shown to moderately lower portal pressure in some patients with cirrhosis but may have adverse effects on kidney function. This study aimed at comparing the effects of a combined treatment using irbesartan plus propranolol with propranolol monotherapy on portal pressure and kidney function in patients with cirrhosis.
METHODS:  Thirty-two patients were included (Child A/B/C: 13/18/1, etiology: 16 alcohol, 13 viral, 3 other; bilirubin 1.4 ± 1.1 mg/dL, creatinine 0.86 ± 0.20 mg/dL, baseline hepatic venous pressure gradient 18.7 ± 5.3 mmHg). All patients received 20 mg propranolol b.i.d. Additionally, they randomly received either placebo (N = 15) or irbesartan (step-up dosage titration up to 300 mg/d, N = 17). Patients were followed at weekly intervals, re-evaluation of hepatic venous pressure gradient (HVPG) was performed after 8 wk.
RESULTS:  One patient in the propranolol/irbesartan group was excluded due to variceal bleeding. No other adverse events occurred. Portal pressure declined in both groups (propranolol/irbesartan group 19.6 ± 1.5 mmHg to 16.6 ± 1.2 mmHg, P = 0.037, propranolol/placebo group 17.8 ± 1.1 mmHg to 15.1 ± 1.2 mmHg, P = 0.019). Sodium excretion significantly increased in the propranolol/irbesartan group (from 122 ± 20 mmol/d to 230 ± 23 mmol/d, P = 0.045), but not in the propranolol/placebo group.
CONCLUSIONS:  Combination treatment of propranolol plus irbesartan is well tolerated in cirrhotic patients when titrating the angiotensin II antagonist in a step-up manner, and it increases sodium excretion in patients with compensated or moderately decompensated cirrhosis. Addition of irbesartan has no effect on portal pressure.