Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male...
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Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (ir) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (ip) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSg values. In conclusion, our results demonstrated that (a) ir administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) ip TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the ip compared to ir route, and (e) TMZ seems to show its antioxidant effect via preserving the tissue's GSH/GSSG ratios.
Background This study determined whether evidence of congestion after 4 to 6 weeks of heart failure management predicted outcome for patients hospitalized with chronic New York Heart Association class IV symptoms. Cro...
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Background This study determined whether evidence of congestion after 4 to 6 weeks of heart failure management predicted outcome for patients hospitalized with chronic New York Heart Association class IV symptoms. Cross IV symptoms predict high mortality rates, but outcome is not known for patients who improve to establish freedom from congestion. Revised estimates at 1 month could facilitate decisions regarding transplantation and other high-risk interventions. Methods At 4 to 6 weeks after hospital discharge, 146 patients were evaluated for congestion by 5 criteria (orthopnea, jugular venous distention, edema, weight gain, and new increase in baseline diuretics). Heart failure management included inpatient therapy tailored to relieve congestion, followed by adjustments to maintain Fluid balance during the next 4 weeks. Results Freedom from congestion was demonstrated at 4 to 6 weeks in 80 (54%) patients, who had 87% subsequent 2-year survival compared with 67% in 40 patients with 1 or 2 criteria of congestion and 41% in 26 patients with 3 to 5 criteria. The Cox proportional hazards model identified left ventricular dimension, pulmonary wedge pressure on therapy, and freedom from congestion as independent predictors of survival. Persistence of orthopnea itself predicted 38% 2-year survival (without urgent transplantation) versus 77% in 113 without orthopnea. Serum sodium was lower and blood urea nitrogen and heart rate higher when orthopnea persisted. Conclusions The ability to maintain freedom From congestion identifies a population with good survival despite previous class IV symptoms. At 4 to 6 weeks, patients with persistent congestion may be considered for high-risk intervention.
A discussion of primary care issues related to the management of angina in the office setting is warranted because of recent developments. These developments include new pharmacotherapies, recent insights into the pat...
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A discussion of primary care issues related to the management of angina in the office setting is warranted because of recent developments. These developments include new pharmacotherapies, recent insights into the pathophysiology of angina, and increased recognition of the role of the diseased endothelium in sequelae of coronary artery disease.
OBJECTIVES To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND Although noninva...
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OBJECTIVES To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or hi) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of. treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS
The vascular system exhibits altered growth, calcium responses and metabolism during hypertension. To relate such changes, we compared histological, tension and metabolic responses in the aorta from 32-week-old sponta...
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The vascular system exhibits altered growth, calcium responses and metabolism during hypertension. To relate such changes, we compared histological, tension and metabolic responses in the aorta from 32-week-old spontaneously hypertensive rats (SHRs), normotensive Wistar-Kyoto (WKY) rats, and SHRs treated with Verapamil (V) and ACE-inhibitor, Trandolapril (T) as well as a combination of the two treatments (C). Vascular hypertrophy was apparent in the SHRs. Contractile responses induced by 50 mmol/l KCl and 2.5 mmol/l Ca2+ were significantly lower in the SHR (64.4 mN/mm(2) vs. 49.2 mN/mm(2)), but an associated increase in Ca2+-sensitivity (EC50 of extracellular Ca2+ (mu mol/l): SHR, 456 vs. WKY, 616) normalised tension generating ability. All treatments led to significant decreases in blood pressure, although only T and C treated animals became normotensive with concomitant normalisation of vascular hypertrophy. An increase in oxygen consumption was apparent in the SHR aorta, which was associated with significant differences in the activities of key metabolic enzymes. Anti-hypertensive treatment normalised many of the metabolic parameters, with the C therapy being the most efficacious. We conclude that the treatment of hypertension by combined therapy leads to a better normalisation of structural, contractile, and metabolic parameters in the SHR, than either treatment alone and that metabolic changes with the pathology are resolved with appropriate therapy.
PURPOSE: We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. PATIENTS AND METHODS: We enrolled patients with mo...
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PURPOSE: We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. PATIENTS AND METHODS: We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking distance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Mean maximal walking distance of cilostazol-treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pentoxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improvement (a 30% mean percent increase) with pentoxifylline (P <0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpitations, and diarrhea) were more common in the cilostazol-treated patients, but withdrawal rates were similar in the cilostazol (16%) and pentoxifylline (19%) groups. CONCLUSION: Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and placebo had similar effects. Am J Med. 2000;109:523-530. (C) 2000 by Excerpta Medica, Inc.
Objective Flow-mediated, endothelium-dependent dilatation (FMD) of the coronary and peripheral circulation is impaired by increased oxidative stress in patients with coronary artery disease (CAD). Carvedilol is a nove...
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Objective Flow-mediated, endothelium-dependent dilatation (FMD) of the coronary and peripheral circulation is impaired by increased oxidative stress in patients with coronary artery disease (CAD). Carvedilol is a novel P-blocker that also shows an antioxidant effect in vitro. However, the effect of carvedilol on endothelial dysfunction associated with established coronary atherosclerosis has not been examined in the clinical setting. Methods We studied 29 patients with CAD, including 17 with recent myocardial infarction and 12 with stable effort angina pectoris. Nineteen patients received carvedilol (10 with infarction and 9 with angina), and 10 were treated with placebo (7 with infarction and 3 with angina). We also studied 13 age- and sex-matched control subjects. Brachial FMD during reactive hyperemia a nd nitroglycerin-induced, endothelium-independent dilatation were assessed by high-resolution ultrasound. Results FMD was smaller in patients with CAD com pa red with controls, although nitroglycerin-induced dilatation was similar. Carvedilol significantly improved FMD after long-term treatment (5.1% +/- 0.4% at baseline to 7.8% +/- 0.3% after 4 months;P <.01) but not after short-term treatment (5.1% +/- 0.4% at baseline to 5.0% +/- 0.7% after 2 hours). Placebo therapy had no effect on endothelial dysfunction. Neither carvedilol nor placebo had an effect on nitroglycerin-induced dilatation after short- and long-term treatment. Long-term carvedilol therapy also significantly decreased the plasma level of thiobarbituric acid-reactive substances compared with placebo (carvedilol, 5.8 +/- 0.4 nmol/ml to 4.6 +/- 0.3 nmol/ml, P <.01;placebo, 5.9 +/- 0.4 nmol/ml to 5.8 +/- 0.4 nmol/ml, P = not significant). Conclusion These findings suggest that the improvement of endothelial function by carvedilol may be caused by its antioxidant activity.
Background Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that l...
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Background Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure. Methods At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin Ii, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo). Results Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at base line to 1625 pmol/L at 1 month [P = .0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P = .2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P = .002]). These changes were riot observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms. Conclusions Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level pre diets death. Flosequinan increases plasma norepinephrine level and heart r
OBJECTIVES The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (...
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OBJECTIVES The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD). BACKGROUND Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress. METHODS In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level greater than or equal to 9 mu mol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. RESULTS Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment. Plasma folate, homocysteine and FIL LD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 +/- 3.6% to 5.2 +/- 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FR ID from 2.6 +/- 2.4% to 4.0 +/- 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group. CONCLUSIONS Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events. (C) 2000 by the American College of Cardiology.
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