Diclofenac epolamine topical patch for the treatment of pain.

Topical nonsteroidal anti-inflammatory drugs produce local pain relief while avoiding systemic adverse events, thanks to minimal systemic absorption. This review evaluates the effectiveness and safety of a topical diclofenac preparation, diclofenac epolamine (DHEP) patch 1.3% or diclofenac epolamine patch with heparin as excipient (DHEP+H) in treating mild-to-moderate pain. DHEP patch was associated with significant pain relief and improved function in numerous pain conditions, from minor soft tissue injuries to osteoarthritis and myofascial pain syndromes. Tolerability was good-to-excellent in all studies, with no serious adverse events. DHEP+H further improved efficacy without affecting tolerability. This patch is effective and safe for localized mild-to-moderate somatic pain.

Short- and long-term risk of cardiovascular events in white-coat hypertension.

The prognostic impact of white-coat hypertension is not yet completely clear. In this study, we investigated cardiovascular outcome in sustained hypertension, white-coat hypertension and normotension in the short and long term. The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1732 subjects with clinical hypertension (1333 with sustained and 399 with white-coat hypertension) and 305 with normotension. White-coat hypertension was defined as clinical hypertension and daytime blood pressure <135/85 mm Hg. During the period of observation (mean 6.4 years, range 0.7-13.1), 152 cardiovascular events occurred. The event rate per 100 patient-years in subjects with normotension, white-coat and sustained hypertension was 0.38, 0.44 and 1.58, respectively. Event-free survival was significantly different among the groups (P<0.0001). After adjustment for several covariates, Cox regression analysis showed that cardiovascular risk was significantly higher in patients with sustained than in those with white-coat hypertension (relative risk (RR) 3.32, 95% confidence interval (CI) 1.81-6.12, P=0.0001), whereas there was no significant difference between normotension and white-coat hypertension. When events were analysed separately, cardiac and cerebrovascular risk were significantly higher in sustained than in white-coat hypertension (RR 4.16, 95% CI 1.48-11.6, P=0.007, and RR 4.12, 95% CI 1.62-10.5, P=0.003, respectively) and not significantly different between white-coat hypertension and normotension. Event-free survival had the same trend for the whole period of observation both when cardiovascular events were examined together and when cardiac and cerebrovascular events were analysed separately. In this study, cardiovascular risk in white-coat hypertension was significantly lower than that in sustained hypertension and not significantly different from normotension both in the short and long term.

Effect of ischemia and reperfusion on antioxidant enzymes and mitochondrial inner membrane proteins in perfused rat heart.

Experiments were performed to investigate the effects of 60 min severe global ischemia followed by 30 min reperfusion on the antioxidant enzymatic system in the isolated perfused rat heart. Ischemia induced a significant increase of cytoplasmic and mitochondrial selenium-dependent glutathione peroxidase (EC 1.11.1.9) activity. In reperfused hearts, only the mitochondrial form showed a further significant increase. Glutathione reductase (EC 1.6.4.2) was increased in ischemic hearts, whilst the reperfused hearts showed a decrease towards the level found in aerobic hearts. Mitochondrial superoxide dismutase (EC 1.15.1.1) activity was depressed in ischemic as well as in reperfused hearts, though the cytoplasmic form was unmodified. Catalase (EC 1.11.1.6), glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and glutathione transferase (EC 2.5.1.18) activities were unchanged throughout the experiment. Ischemia and reperfusion induced a significant fall in tissue-reduced glutathione content concomitant with an increase of its oxidized form. We have also studied the mitochondrial inner membrane proteins for both molecular weight, with Coomassie blue, and thiol status, with monobromobimane stain, using a sodium dodecyl sulfate polyacrylamide gel electrophoresis technique. Neither ischemia nor reperfusion effected any relevant modification of the molecular weight of the mitochondrial inner-membrane proteins either in the presence or absence of a reducing agent. However, two of these proteins with an apparent molecular weight of 52,0000 and 12,000 showed a decrease in the monobromobimane stain, probably due to the oxidation of their thiol groups.

Limitations in the use of [2-14C]acetate for measuring gluconeogenesis in vivo.

This study was undertaken to test two assumptions critical for use of [2-14C]acetate to measure gluconeogenesis in vivo. For the assumption that incorporation into glucose of products of [14C]acetate metabolism does not affect the distribution of label within the glucose molecule, we infused [2-14C]acetate in 17 healthy subjects and [3-14C]lactate in 10 healthy subjects and compared the ratio of the resultant specific activities of plasma glucose carbons 1, 2, 5, 6, and 3, 4 obtained with each tracer. The ratio obtained with [2-14C]acetate (2.99 +/- 0.07) was significantly different from the ratio obtained with [3-14C]lactate, (3.82 +/- 0.2, P < 0.01). Because the model predicts that these ratios should be identical, these results indicate that either the model is incorrect or that metabolism of [14C]acetate to other compounds affects the distribution of the label within the glucose molecule. To test the assumption that plasma 3-OH-butyrate specific activity approximates the specific activity of hepatic intramitochondrial acetyl CoA, we compared the ratio of specific activities of plasma glucose and 3-OH-butyrate obtained in 7 healthy subjects infused with [2-14C]acetate and [2-14C]octanoate. The ratio obtained with [2-14C]acetate (0.18 +/- 0.03) was significantly different from that obtained with [2-14C]octanoate, (0.10 +/- 0.02), P < 0.001. These results suggest compartmentalization of acetyl CoA within liver mitochondria and indicate that plasma 3-OH-butyrate specific activity may not necessarily approximate intramitochondrial acetyl CoA specific activity during [2-14C]acetate infusion. We conclude that assumptions critical for use of [2-14C]acetate to measure gluconeogenesis in vivo are not valid.

Circadian blood pressure changes and myocardial ischemia in hypertensive patients with coronary artery disease.

OBJECTIVES: We sought to evaluate whether different circadian blood pressure (BP) changes could influence the occurrence of ischemic episodes in untreated and treated hypertensive patients with stable coronary artery disease (CAD). BACKGROUND: In hypertensive patients with CAD the occurrence of myocardial ischemia could be influenced by either high or low BP values. Ambulatory monitoring has shown that circadian BP profile is not uniform in hypertensive patients. METHODS: Twenty-one patients with a nighttime BP fall < 10% ("nondippers"), 35 with a nighttime BP fall between > 10% and < 20% ("dippers") and 14 with a nighttime BP fall > 20% ("overdippers") with CAD underwent simultaneous ambulatory BP and electrocardiographic monitoring before and during drug therapy with nitrates and atenolol or verapamil in a prospective, randomized, open, blinded end point design. RESULTS: Daytime BP was not significantly different among the groups both before and during therapy. Nighttime BP was different by definition. Treatment significantly reduced BP values in each group (p < 0.05). Daytime ischemic episodes did not differ among the groups either before or during therapy. Drug therapy significantly reduced daytime ischemia (p < 0.05). In untreated patients, nighttime ischemia was more frequent in nondippers than in dippers and overdippers (p < 0.05). Drug therapy significantly reduced nocturnal ischemia in nondippers (p < 0.05), had no significant effect in dippers and significantly increased nighttime ischemia in overdippers (p < 0.05). During treatment, nighttime ischemia was more frequent in overdippers than in dippers and nondippers (p < 0.05). The same results were achieved when ischemic episodes were defined with more restrictive criteria (ST segment depression > or = 2 mm). CONCLUSIONS: Circadian BP changes can influence the occurrence of myocardial ischemia in untreated and treated hypertensive patients with CAD. Nocturnal ischemia was found to be more frequent in nondippers among untreated patients and in overdippers among treated patients, potentially suggesting different therapeutic approaches based on circadian BP profile.

Target organ status and serum lipids in patients with white coat hypertension.

Target organ status and serum lipids were investigated in white coat hypertension in comparison with sustained hypertension and normotension. We selected three groups balanced for sex, age, body mass index, and smoking habit: 50 sustained hypertensives (clinical hypertension and 24-hour ambulatory blood pressure > 135/85 mm Hg, a cutoff limit obtained from a normotensive population), 25 white coat hypertensives (clinical hypertension and 24-hour ambulatory blood pressure < 135/85 mm Hg), and normotensives. Subjects underwent echocardiographic examinations to assess left ventricular mass index, carotid ultrasonography to evaluate intima-media thickness and atherosclerotic plaques, venous occlusion plethysmography to record minimum forearm vascular resistance, and determinations of serum lipid profile and 24-hour urinary albumin excretion. Compared with sustained hypertensives, the white coat hypertensives had significantly lower values of left ventricular mass index (125.9 +/- 20 versus 97.6 +/- 11.5 g/m2, P < .05, intima-media thickness (0.85 +/- 0.18 versus 0.71 +/- 0.15 mm, P < .05), minimum forearm vascular resistance (2.33 +/- 0.11 versus 2.04 +/- 0.08 resistance units, P < .05), urinary albumin excretion values (15.1 +/- 13.8 versus 4.45 +/- 1.48 mg per 24 hours, P < .0001), prevalence of left ventricular hypertrophy (versus 4%, P < .002), intima-media thickening 28% versus 4%, P < .015), and microalbuminuria (22% versus 0%, P < .015). No significant difference, however, was observed between the white coat hypertensives and the normotensives. Serum lipid profile was similar in the white coat hypertensives and in the normotensives.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidant activity of allopurinol on copper-catalysed human lipoprotein oxidation.

We found that allopurinol, at therapeutically relevant concentrations (9-58 microM), significantly counteracted copper-catalysed human non-HDL lipoprotein oxidation, as assessed by thiobarbituric acid reactant content and kinetics of conjugated diene formation. Oxypurinol was ineffectual. Both drugs had no activity on metal-independent, peroxyl radical-induced lipoprotein oxidation. Specific fluorescence-quenching experiments revealed that only allopurinol could interact with copper antagonizing metal binding to lipoproteins. Thus, therapeutic allopurinol concentrations can inhibit copper-catalysed lipoprotein oxidation through metal complexation, suggesting some antioxidant-antiatherogenic activity of the drug in vivo.

Antioxidant properties of omeprazole.

Potential antioxidant properties of therapeutically achievable concentrations of the protonated, active form of omeprazole (OM) were investigated in vitro at specific acidic pH values to mimic intragastric conditions in the clinical setting. We found that OM is a powerful scavenger of hypochlorous acid (HOCl) even at a drug concentration of 10 microM at pH 5.3 or 3.5. This effect is also evident in the presence of the physiological HOCl scavenger ascorbate. Moreover, 10 and 50 microM OM inhibit significantly both iron- and copper-driven oxidant damage at pH 5.3 and 3.5, respectively. Since oxidative stress is involved the gastric injury of peptic ulcer and gastritis, it may be hypothesized that some therapeutical effects of OM could also be related to its antioxidant properties.

Plasma copper and lipid peroxidation in cigarette smokers.

Plasma levels of copper and lipid peroxidation were evaluated in 14 smokers as compared to 14 nonsmokers. Plasma copper concentrations were higher in smokers than in nonsmokers (122.5 +/- 19.15 vs. 101.5 +/- 16.2 micrograms/dl, P < .01). Plasma lipoperoxidation, evaluated as fluorescent damage products of lipid peroxidation (FDPL), also was higher in smokers than in nonsmokers (20.35 +/- 2.6 vs. 17.1 +/- 2.95 units of relative fluorescence/ml, P < .01). A significant and positive correlation between the number of cigarettes smoked, expressed as pack years, and the levels of either FDPL (r = .61, P < .025) or copper (r = .55, P < .05) was found. Moreover, a significant and positive relationship between copper and FDPL values was observed in smokers (r = .64; P < .025), but not in nonsmokers. These data indicate that cigarette smoke-related plasma oxidant load may be partly due to enhanced levels of the prooxidant metal cooper, potentially suggesting the supplementation of specific antioxidants (e.g., zinc) to counteract cigarette smoke-induced oxidative stress in smokers.

Antioxidant properties of ticlopidine on human low density lipoprotein oxidation.

We found that ticlopidine, at therapeutically relevant concentrations (2.5-10 microM), but not aspirin nor salicylate, significantly counteracted copper-driven human LDL oxidation. Ticlopidine, at 5 and 10 microM, was also antioxidant on peroxyl radical-induced LDL oxidation; yet it was ineffectual on thiol and ascorbate oxidation mediated by peroxyl radicals themselves, suggesting that drug antioxidant capacity is somehow related to the lipoprotein nature of the oxidizable substrate, but not to radical scavenging. The drug could not indeed react with the stable free radical 1,1-diphenyl-2-pycrylhydrazyl, nor had apparent metal complexing-inactivating activity. Thus, ticlopidine has antioxidant effects on LDL oxidation, which, together with its anti-platelet activity, could confer peculiar antiatherogenic properties to the drug in vivo.

Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma.

The thiobarbituric acid (TBA) reactivity of human plasma was studied to evaluate its adequacy in quantifying lipid peroxidation as an index of systemic oxidative stress. Two spectrophotometric TBA tests based on the use of either phosphoric acid (pH 2.0, method A) or trichloroacetic plus hydrochloric acid (pH 0.9, method B) were employed with and without sodium sulfate (SS) to inhibit sialic acid (SA) reactivity with TBA. To correct for background absorption, the absorbance values at 572 nm were subtracted from those at 532 nm, which represent the absorption maximum of the TBA:MDA adduct. Method B gave values of TBA-reactive substances (TBARS) 2-fold higher than those detected with method A. SS lowered TBARS by about 50% with both methods, indicating a significant involvement of SA in plasma TBA reactivity. Standard SA, at a physiologically relevant concentration of 1.5 mM, reacted with TBA, creating interference problems, which were substantially eliminated by SS plus correction for background absorbance. When method B was carried out in the lipid and protein fraction of plasma, SS inhibited by 65% TBARS formation only in the latter. Protein TBARS may be largely ascribed to SA-containing glycoproteins and, to a minor extent, protein-bound MDA. Indeed, EDTA did not affect protein TBARS assessed in the presence of SS. TBA reactivity of whole plasma and of its lipid fraction was instead inhibited by EDTA, suggesting that lipoperoxides (and possibly monofunctional lipoperoxidation aldehydes) are involved as MDA precursors in the TBA test. Pretreatment of plasma with KI, a specific reductant of hydroperoxides, decreased TBARS by about 27%. Moreover, aspirin administration to humans to inhibit prostaglandin endoperoxide generation reduced plasma TBARS by 40%. In conclusion, reaction conditions affect the relationship between TBA reactivity and lipid peroxidation in human plasma. After correction for the interfering effects of SA in the TBA test, 40% of plasma TBARS appears related to in vivo generated prostaglandin endoperoxides and only about 60% to lipoperoxidation products. Thus, the TBA test is not totally specific to oxidant-driven lipid peroxidation in human plasma.

Impaired glutathione biosynthesis in the ischemic-reperfused rabbit myocardium.

Non-protein thiols (NP-SH) and the activities of the glutathione status-regulating enzymes gamma-glutamylcysteine synthetase (G-GCS), gamma-glutamyl transpeptidase (G-GT) and glutathione reductase (GR) were assessed in perfused rabbit hearts subjected to severe (60 min) or mild (7 min) total ischemia and 30 min reperfusion. Severe ischemia significantly decreased NP-SH, which were further depressed on reperfusion together with a significant decline in G-GCS activity; G-GT and GR activities were unchanged. Specific analytes were unaffected by mild ischemia-reperfusion. Thus, impaired enzymatic biosynthesis of GSH is operative in the reperfused rabbit myocardium after 60 min ischemia. This phenomenon may favour myocardial GSH depression and oxidative reperfusion injury after severe ischemia.

Increased type II transforming growth factor-beta receptor expression in liver cells during cholesterol challenge.

A large body of evidences implicates transforming growth factor-beta (TGF-beta) in the pathogenesis of atherosclerosis. In this context, TGF-beta receptor dysfunction has been suggested to be relevant. We tested the effect of hypercholesterolemia, a well-known risk factor for atherosclerosis, on liver type II TGF-beta receptor (TbetaR-II) expression in atherosclerosis-susceptible C57BL/6 mouse strain fed atherogenic diet. In addition, the relationship between cholesterol and TbetaR-II expression was verified by cholesterol challenge on human hepatoma cell (HepG2) cultures. The susceptible C57BL/6 mice fed atherogenic diet exhibited significant mRNA and immunohistochemical TbetaR-II liver expression at 2, 5, 9 and 15 weeks as compared to animals fed a regular diet. The TbetaR-II profile on HepG2 resulted in a time-dependent increased expression when the cells were incubated with soluble free cholesterol, associated with an increased TGF-beta-dependent biological activity as detected by luciferase assay of reporter gene. These data provide evidence for a cholesterol-dependent TbetaR-II induction that may play a potentially relevant role in the development of hypercholesterolemia and atherogenesis.

Vitamins E, C and lipid peroxidation in plasma and arterial tissue of smokers and non-smokers.

An imbalance between pro-oxidants and antioxidants is operative in atherosclerosis. Cigarette smoke is a major risk factor of atherosclerosis and has been reported to contain large amounts of oxidants. We assessed arterial (internal mammary artery) and plasma levels of vitamins E and C and lipid peroxides in 48 male patients, 24 smokers and 24 non-smokers, undergoing coronary bypass surgery. Lipid peroxidation was studied using fluorescent products of lipid peroxidation (FPLs). Tissue vitamins E and C levels were significantly lower and FPLs significantly higher in smokers than in non-smokers (P < 0.0006, 0.0005 and 0.0005, respectively). This pattern was associated with lower vitamin C and higher lipid peroxide plasma levels in smokers than in non-smokers (P < 0.0002 and 0.0005, respectively). Vitamins E and C plasma levels were strongly related to their tissue content both in smokers (r = 0.60, P < 0.005 and r = 0.57, P < 0.01) and in non-smokers (r = 0.42, P < 0.05 and r = 0.46, P < 0.05). Moreover, vitamin E content was significantly related to that of vitamin C only in the arterial tissue of both groups, pointing to the existence of a functional interaction between these antioxidants. In both groups, FPLs were significantly and inversely related to vitamin C in plasma and to vitamin E in tissue, suggesting the antioxidant primary of vitamin C and vitamin E in the plasma and arterial tissue compartments, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic antioxidant defence mechanisms: time-related changes in cholesterol-fed rabbits.

In 24 rabbits fed a hyperlipidic diet (0.5% cholesterol, 5% lard and 5% peanut oil) for 10 (group A1), 30 group B1) and 60 days, (Group C1), compared to 24 control rabbits fed a standard diet for the same periods, antioxidant defence system (total superoxide dismutase, catalase, total thiol compounds selenium-dependent and selenium-independent glutathione peroxidase, glutathione reductase, glutathione transferase) and lipid peroxidation (thiobarbituric acid-reactive substances) in the aortic wall were tested. The percent of intima with grossly apparent atherosclerosis, is assessed by staining with the lipophilic dye Sudan IV, was negligible in group A1, but increased progressively in groups B1 (22.7-6.7%) and C1 (56.8-8.8%). Compared to the controls, a significant rise in superoxide dismutase activity was observed after 30 days of hyperlipidic diet, with a further marked increase at 60 days. Total thiol compounds and selenium-dependent glutathione peroxidase activity rose progressively from 10 to 30 and 60 days in cholesterol-fed rabbits. On the contrary, catalase, glutathione reductase and glutathione transferase activities significantly decreased in all experimental groups. Selenium-independent glutathione peroxidase activity was not detectable. Thiobarbituric acid-reactive substances increased about 3 times in hyperlipidemic rabbits. In conclusion, the changes in aortic antioxidant defence mechanisms and lipid peroxidation precede the massive vascular lipid infiltration in cholesterol-fed rabbits; some antioxidant mechanisms are stressed (superoxide, dismutase, glutathione peroxidase, total thiol compounds), whereas others are depressed (catalase, glutathione reductase, and glutathione transferase), thus potentially reducing or increasing vascular susceptibility to oxidative injury.

Twenty-four-hour autonomic nervous function in sustained and "white coat" hypertension.

BACKGROUND: It is unknown whether "white coat" hypertension, also known as isolated clinic hypertension, shares similarities in pathophysiologic background with sustained hypertension. Therefore we evaluated 24-hour autonomic nervous function in sustained and white coat hypertension. METHODS: We selected 12 patients with sustained hypertension (clinic blood pressure >/=140/90 mm Hg and daytime blood pressure >135/85 mm Hg) and 12 patients with white coat hypertension (clinic blood pressure >/=140/90 mm Hg and daytime blood pressure <135/85 mm Hg) from patients undergoing ambulatory blood pressure monitoring and 12 normotensives for study inclusion. Groups were matched for age, sex, and body mass index and had similar dietary pattern and occupational status (civil servants with sedentary jobs). Subjects underwent noninvasive 24-hour monitoring of blood pressure, R-R interval of the electrocardiogram, body position, activity rate, and ambient temperature. Power spectral analysis of R-R intervals was performed with an autoregressive model to obtain the low-frequency component, the high-frequency component, and their ratio. Subjects also collected 24-hour urine samples for examination of norepinephrine and epinephrine excretion by high-performance liquid chromatography. RESULTS: Work and sleep time, body position, ambient temperature, and activity were not different among the groups. Daytime, nighttime, and 24-hour low-frequency/high-frequency ratios were significantly higher in patients with sustained hypertension than in patients with white coat hypertension (3.4 +/- 0.45 vs 2.65 +/- 0.45, 2.35 +/- 0.60 vs 1. 82 +/- 0.45, and 3.04 +/- 0.45 vs 2.4 +/- 0.35, respectively, P <. 05). Urinary norepinephrine excretion (53 +/- 12 microg vs 29.5 +/- 6 microg; P <.05) and vanillylmandelic acid excretion (4.45 +/- 0.6 mg vs 3.1 +/- 0.55 mg; P <.05) during the 24 hours were significantly higher in patients with sustained hypertension than in those with white coat hypertension. There was no difference between those with white coat hypertension and normotensives concerning the aforementioned parameters. CONCLUSIONS: Our findings indicate whole-day sympathetic overactivity in sustained hypertension but not in white coat hypertension, suggesting that these conditions show some differences in pathophysiologic background.

Vascular changes in hypertensive patients with different left ventricular geometry.

OBJECTIVE: To evaluate vascular structural changes in hypertensive patients with different patterns of left ventricular geometry. DESIGN AND METHODS: From 250 untreated hypertensive patients who underwent ambulatory blood pressure monitoring and echocardiographic study, we selected four groups matched for sex, age, body mass index, smoking habits and serum lipid values: 25 hypertensive subjects with normal left ventricular geometry, 16 with concentric left ventricular remodeling, 26 with concentric left ventricular hypertrophy and 18 with eccentric non-dilated left ventricular hypertrophy. These patients underwent carotid ultrasonography to evaluate the intimal-medial thickness and lumen diameter, and venous occlusion plethysmography to record minimum forearm vascular resistance (an index of arteriolar structural changes). RESULTS: The intimal-medial thickness and minimum forearm vascular resistance were significantly higher (both P<0.05) in hypertensive subjects with concentric left ventricular remodeling (0.95 mm, 2.68 RU) and concentric left ventricular hypertrophy (0.96 mm, 2.71 RU) than in those with eccentric non-dilated left ventricular hypertrophy (0.81 mm, 2.36 RU) and normal left ventricular geometry (0.71 mm, 2.15 RU). There was no difference between hypertensive patients with concentric left ventricular remodeling and concentric left ventricular hypertrophy. The intimal-medial thickness and minimum forearm vascular resistance tended to be higher in hypertensive subjects with eccentric non-dilated left ventricular hypertrophy than in those with normal left ventricular geometry, but this difference did not attain statistical significance. CONCLUSIONS: This study shows that the spectrum of cardiac adaptation to hypertension is associated with a spectrum of vascular adaptation which might be related both to hemodynamic stimuli and differences in the expression or activity of vascular growth factors.

Mechanism of isoproterenol-induced angina pectoris in patients with obstructive hypertrophic cardiomyopathy and normal coronary arteries.

In 14 patients with obstructive hypertrophic cardiomyopathy and angiographically normal coronary arteries, 8 with angina (group B) and 6 without (group A), the effects of intravenous isoproterenol, 2 to 4 micrograms/min, followed by intravenous propranolol, 0.2 mg/kg, were studied. An intraventricular systolic gradient less than 50 mm Hg, high-quality echocardiograms and cineangiograms and high-fidelity pressure tracings were selection criteria. Hemodynamic and metabolic variables were assessed during basal conditions, after 5 minutes of isoproterenol infusion or at angina and ST-segment depression, and 5 and 10 minutes after intravenous propranolol infusion. Isoproterenol increased the intraventricular systolic gradient more significantly in group B than in group A (102.4 +/- 8.3 vs 52.2 +/- 8.2, p less than 0.0001). Group B also had higher left ventricular end-diastolic pressure (32.5 +/- 3.9 vs 20.2 +/- 5.7), lower mean arterial pressure (69.7 +/- 3.5 vs 84.7 +/- 4.8) and a smaller increase in coronary sinus flow (176.1 +/- 9.2 vs 261.5 +/- 33.9, all p less than 0.0001), concomitant with lactate release and ST-segment depression. Propranolol promptly reversed hemodynamic and metabolic changes caused by isoproterenol, except for a further coronary sinus flow increase (from 176.1 +/- 9.2 to 219 +/- 14.2 ml/min, p less than 0.001), and heart rate decrease below basal values (57.8 +/- 7.5 vs 79.9 +/- 9.8 beats/min, p less than 0.001) in group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidant activity of amiodarone on human lipoprotein oxidation.

Lipoprotein oxidation is crucial in atherogenic processes. Amiodarone is a lipophilic antiarrhythmic/antianginal drug which is able to influence the physicochemical status of biological lipid components. Since oxidation of lipids is affected by their physicochemical state and amiodarone binds to lipoproteins, we hypothesized that the drug may exert an antioxidant activity on human lipoprotein oxidation. Dose-dependent effects of therapeutically achievable amiodarone concentrations (1.5, 3, 5, 7 and 10 microM) were studied on copper-catalysed oxidation of the non-HDL fraction in vitro. Amiodarone inhibited oxidation as judged by generation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and fluorescent products of lipoperoxidation (FPL) as well as from the kinetics of conjugated diene formation. This antioxidant activity was significant at 1.5 microM with total inhibition at 10 microM and an IC(50) of 4 microM. The primary in vivo metabolite of amiodarone, namely desethylamiodarone, also exhibited specific antioxidant properties although it was less effective than amiodarone with an IC(50) of 7 microM. In further in vivo experiments, susceptibility to copper-mediated oxidation of the non-HDL fraction was investigated before and 4 weeks after oral amiodarone administration to humans. Following treatment, significant inhibition of TBARS, LOOH and FPL generation was observed in comparison with baseline levels and a placebo-treated control group, highlighting an effective antioxidant capacity of amiodarone in vivo. Amiodarone did not change lipoprotein vitamin E and phospholipid content in vivo and did not show scavenging effects on oxidizing species involved in lipoprotein oxidation, such as peroxyl radicals, nor metal-binding/inactivating properties, suggesting that physicochemical modifications of lipoprotein lipids induced by the lipophilic drug may be involved in its antioxidant activity. In conclusion, amiodarone, and its primary metabolite desethylamiodarone, show previously unrecognized antioxidant activity on human lipoprotein oxidation. This effect is also evident in vivo and at therapeutically achievable drug concentrations. Thus, amiodarone may act as an antioxidant/antiatherosclerotic agent in humans, although this issue warrants further clinical study.