Effects of vitamin E administration on the hemorheological status and redox homeostasis of patients with porphyria cutanea tarda treated with phlebotomy.

BACKGROUND: Conflicting results were reported about the efficacy of vitamin E (E) treatment in porphyria cutanea tarda (PCT). We conducted a study in PCT patients to investigate whether E treatment has any additional beneficial effects compared with phlebotomy (P) treatment alone on rheological and oxidative stress parameters. METHODS: Twenty three patients with sporadic PCT in clinical remission and 10 healthy control patients were studied. All patients were treated with P prior to the study until clinical remission was achieved. Baseline routine laboratory [blood glucose, serum lipids, C-reactive protein (CRP), iron metabolism indices, liver function tests], oxidative stress [serum thiobarbituric acid reactive substances (TBARS), plasma H-donor activity, plasma free SH-groups, erythrocyte glutathion peroxidase activity] and rheological parameters (whole blood and plasma viscosity, cell transit time, clogging rate) were measured in both groups. Then all PCT patients received E (tocopherol acetate) 200 mg/day for 8 weeks and at the end of treatment measurements identical to those performed at baseline were repeated. RESULTS: Increased urine uroporphyrin, serum CRP, TBARS concentrations, whole blood and plasma viscosity and decreased plasma H-donor activity, free SH-group level, erythrocyte glutathione peroxidase activity were detected in PCT patients treated with P alone compared with control group consistent with residual oxidative stress in PCT patients. E treatment decreased urine uroporphyrin and serum TBARS concentrations; increased plasma H-donor activity and did not influence whole blood and plasma viscosity compared with P treatment alone. CONCLUSIONS: E treatment reduced the residual oxidative stress and did not influence increased plasma and whole blood viscosity present in PCT patients receiving P treatment prior to clinical remission.

Silymarin and vitamin E do not attenuate and vitamin E might even enhance the antiarrhythmic activity of amiodarone in a rat reperfusion arrhythmia model.

Oxidative stress and lysosomal phospholipoidosis, which also might be partly attributed to free radicals induced by amiodarone (AM), may be involved in AM toxicity, which can be prevented by antioxidants. Our aim was to study if vitamin E (E) or silymarin (S), a lipid and a water-soluble antioxidant, modified the antiarrhythmic efficacy of AM in a rat reperfusion arrhythmia test. The following groups of male Sprague-Dawley rats (15 rats/group) were treated by gavage once a day for 4 weeks: 1. methylcellulose (MC, 0.4%), 2. sunflower seed oil (SSO), 3. AM, suspended in MC (30 mg/kg), 4. E, dissolved in SSO (100 mg/kg), 5. AM + E, 6. S, suspended in MC (80 mg/kg), 7. AM + S. The mean duration of ventricular tachycardia + fibrillation (MDVT + VF) and sinus rhythm (MDSR) the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) and mortality were measured during a 10-min reperfusion after a 5-min coronary artery occlusion in anaesthetized rats. An arrhythmia score, representing the combined incidence and duration of different types of ventricular arrhythmia, was calculated. Compared with the MC group, MDSR was longer and MDVT + VF was shorter in all drug treated groups and in the SSO group. In the AM + E treated group MDSR was prolonged more and MDVT + VF was shortened more than in the AM, E or SSO groups. Compared with the MC group, the incidence of VF and mortality was similarly decreased in the SSO group and in most drug treated groups. No significant difference in the incidence of VT was found among all groups. The arrhythmia score was reduced by all drug treatments. Combined treatment with AM + E decreased arrhythmia score more than treatment with AM or SSO alone, but arrhythmia score was similar in the AM + E and E groups. In conclusion, both AM and antioxidant treatments alone or together resulted in a marked reduction of reperfusion arrhythmias in this model. SSO also exerted a moderate antiarrhythmic effect. Antioxidants administered together with AM did not attenuate and E might have even enhanced the antiarrhythmic effect of AM, therefore the combination of antioxidants with AM may be advantageous to reduce AM toxicity.

Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.

The electrophysiological effects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje fibres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch-clamp techniques. Chronic treatment with dronedarone (2x25 mg(-1) kg(-1) day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg(-1) kg(-1) day p.o. for 4 weeks), did not lengthen significantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but significant use-dependent V(max) block was noticed, while after chronic amiodarone administration a strong use-dependent V(max) depression was observed. Acute superfusion of dronedarone (10 microM), similar to that of amiodarone (10 microM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6+/-5.3 to 248.6+/-5.3 ms, n=13, P<0.05), but shortened it in Purkinje fibres (at 1 Hz from 309.6+/-11.8 to 287.1+/-10.8 ms, n=7, P<0.05). Both dronedarone (10 microM) and amiodarone (10 microM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 microM dofetilide and 0.2 microM strophantidine in Purkinje fibres. In patch-clamp experiments 10 microM dronedarone markedly reduced the L-type calcium current (76.5+/-0.7 %, n=6, P<0.05) and the rapid component of the delayed rectifier potassium current (97+/-1.2 %, n=5, P<0.05) in ventricular myocytes. It is concluded that after acute administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the 'amiodarone like' chronic electrophysiological characteristics.

Comparison of the effects on drug concentrations, electrophysiologic parameters, and termination of atrial fibrillation in dogs when procainamide and ibutilide are delivered into the right atrium versus intravenously.

INTRODUCTION: We tested the hypothesis that right intra-atrial (i.a.) administration of antiarrhythmic drugs resulted in higher peak serum drug concentrations, greater electrophysiologic effects, and greater efficacy for termination of atrial fibrillation (AF) than intravenous (i.v.) drug delivery. METHODS AND RESULTS: Eight dogs were treated with 9.7 mg/kg procainamide infusion and eight dogs with 0.02 mg/kg ibutilide infusion, injected over 5 minutes. Each dog had both an electrophysiologic (EP) and an AF termination study during i.a. and i.v. drug administration at > or = 2-day intervals (total four studies each). Right atrial pacing capture threshold, right atrial effective refractory period (ERP), right atrial and right ventricular monophasic action potential (MAP) durations at 70% and 90% of repolarization (MAPD70, MAPD90), AH, HV, and QT intervals, QRS width, intra-arterial systolic and diastolic blood pressures, and cardiac output were measured at different time-points. Blood samples were drawn from the coronary sinus and femoral vein for drug level determination. The right atrium was paced at 400-msec cycle length throughout the study. AF was induced by rapid right atrial pacing and maintained by methacholine infusion at 1.5 to 3 microg/kg/min. The sustained AF was allowed to persist for 10 minutes before starting the antiarrhythmic drug infusion. We found no significant difference between the procainamide concentrations in the coronary sinus and femoral vein during i.a. and i.v. drug delivery. The time course and extent of increase in right atrial ERP, MAPD70, MAPD90, and all the other measured EP parameters did not differ between the two routes of drug administration. No significant difference was found in termination of AF between i.v. (5/7 procainamide; 4/8 ibutilide) or i.a. (3/8 procainamide; 3/8 ibutilide) drug delivery or between drugs (8/15 procainamide; 7/16 ibutilide). CONCLUSION: Our data do not support any beneficial effect of i.a. versus i.v. procainamide or ibutilide delivery.

The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation.

Previous studies have shown that free radical reactions may play an important role in the pathogenesis of the adverse effects of the antiarrhythmic agent amiodarone. The aim of this study was to investigate the role of free radical reactions in amiodarone-induced changes in the cell-mediated immune response. Therefore, we investigated the effects of amiodarone alone and in combination with either vitamin E or silymarin on (a) spontaneous blast transformation of splenocytes, (b) concanavalin A (con A)-induced proliferation of splenocytes at three different lectin concentrations, and (c) the content of conjugated dienes in liver homogenate. Forty-eight male Fischer 344 rats were randomized to one of the following groups: 1, control; 2, amiodarone; 3, vitamin E; 4, amiodarone+vitamin E; 5, silymarin; 6, amiodarone+silymarin. The con A-induced splenocyte proliferation was significantly decreased in amiodarone-treated rats at all three lectin concentrations. In the amiodarone-treated group, the change of spontaneous blast transformation was not significantly different from the control. In groups treated with amiodarone plus either antioxidant, both the spontaneous and con A-induced splenocyte proliferation were significantly increased compared with the amiodarone-treated group, and were similar to those in the control group. Amiodarone treatment significantly increased, and both silymarin and vitamin E combined with amiodarone significantly decreased, the conjugated diene content of liver homogenate compared with amiodarone treatment alone. In conclusion, free radicals generated by amiodarone may be implicated in the adverse effects of amiodarone on cell-mediated immune response, and antioxidants applied together with amiodarone may protect against or reduce both the unfavorable immunological effects of amiodarone and amiodarone toxicity.

[Bilateral renal artery stenosis diagnosed during pregnancy]. / Terhesség folyamán felismert kétoldali arteria renalis stenosis.

Bilateral renal artery stenosis was diagnosed noninvasively in the 17th gestational week, in a chronically hypertensive pregnant woman, by renal artery duplex ultrasound examination, MRI and MR angiography. Continuous monitoring of the mother and the fetus was performed. Blood pressure was stabilized by complex antihypertensive therapy, but from the beginning of the third trimester superimposed preeclampsia developed gradually. In the 34th gestational week a 1600-g newborn was delivered by elective cesarean section. The case report draws attention to the significance of the thorough examination of hypertensive women before pregnancy.

The role of free radicals in the pathogenesis of amiodarone toxicity.

INTRODUCTION: In vitro and in vivo studies were performed to elucidate the pathogenesis of amiodarone toxicity. METHODS AND RESULTS: Rats were treated with amiodarone alone (500 mg/kg body weight per day) or together with antioxidants (silibinin or MTDQ-DA: 50 mg/kg body weight per day) or with either antioxidant alone. They received amiodarone for 30 days and antioxidant for 33 days (3 days pretreatment). In vitro, amiodarone induced a dose-dependent chemiluminescence signal, which was inhibited by the two dihydroquinolin-type antioxidants (MTDQ-DA, CH 402). Chemiluminometric results from liver homogenate demonstrated that simultaneous treatment with silibinin partially prevented the liver homogenate superoxide anion radical scavenger capacity decreasing effect of amiodarone. Amiodarone treatment caused a significant increase of NADPH and Fe3+ induced lipid peroxidation in the liver microsomal fraction, which antioxidants (silibinin, MTDQ-DA) were unable to prevent. Light microscopy of the lung tissue in amiodarone-treated rats showed accumulation of foamy macrophages with thickening of the interalveolar septa, pneumonitis, and variable interstitial fibrosis. Antioxidant treatment did not prevent these changes. Electron micrographs of lung from amiodarone-treated rats showed lysosomal phospholipoidosis, intralysosomal electron dense deposits, and increased lysosome number and size. In contrast to rats treated with amiodarone alone, those treated with both amiodarone and silibinin had significantly fewer lysosomes (P < 0.01); the lysosome size, shape, and internal characteristics remained the same. Simultaneous treatment with silibinin and amiodarone decreased lysosomal phospholipoidosis compared to amiodarone treatment alone. Simultaneous treatment with MTDQ-DA and amiodarone did not show any beneficial effect. Pulse radiolysis and cobalt 60-gamma (60Co-gamma) radiolysis studies showed that the main free radical product in a reducing environment was a very reactive aryl radical formed after the partial deiodination of the amiodarone molecule. The radiosensitizing effect of amiodarone was also verified in rat liver microsomal preparations using in vivo amiodarone with or without MTDQ-DA pretreatment and 60Co-gamma irradiation with or without the in vitro addition of antioxidants (CH 402, MTDQ-DA). In vivo, the MTDQ-DA treatment also had a radiosensitizing effect; however, the in vitro addition of both antioxidants resulted in a radioprotective effect. The aryl radical also may emerge in vivo during the metabolism of amiodarone. CONCLUSION: These observations suggest that amiodarone in vitro and in vivo generates free radicals that may play a role in the pathogenesis of amiodarone toxicity beside other well-established mechanisms, and antioxidants may have a partial protective effect against amiodarone toxicity.

Role of free-radical reactions in liver diseases.

Role of free-radical reactions is most significant in toxic liver injuries. Two traditional groups of liver injuries induced by drugs and chemicals are distinguished, 1. direct toxic type and 2. idiosyncratic type. Liver injury of direct toxic type is generally developed following toxin exposure, it is dose dependent, incubation period is short, and the injury often affects other organs (e.g. kidney). Direct toxins frequently cause typical zonal necrosis usually without concomitant signs of hypersensitivity. It is typical of idiosyncratic reaction that it appears only in a shorter period of exposure, it cannot be predicted, it is not dose-dependent, its incubation period varies and sometimes (in one-fourth of cases) it is accompanied by extrahepatic symptoms of hypersensitivity (fever, leukocytosis, eosinophilia, rashes), its morphologic picture shows great variety. A part of direct toxins is toxic itself, in the other part the basic compound is not toxic but it changes into toxic metabolites in the liver. Liver is well-protected against free-radicals developing in the organism: it is one of our best antioxidant supplied organs. It is probably due to the one of the important tasks of liver, namely detoxication of drugs, chemicals and toxic materials, with subsequent release of free-radicals. It is proved by the fact that in normal bile peroxidized lipids produced by free-radical chain reactions can also be detected. The pathologic free-radical reactions and one of their sequelae, peroxidation of lipids (LPO) do not necessarily cause cell and tissue damage. Antioxidant protection of cells and tissues is able to prevent free-radical injury and it enables, that the already developed damages become reversible. According to recent investigations, the lipid peroxidation, caused by free-radical reactions, or covalent binding of radical products to biomolecules does not lead directly to cellular destruction, only via further reactions. Such intermediary steps can be the phospholipase A2 activation, accumulation of lysophosphatides, poly-ADP-ribose polymerase repair enzyme activation, following oxidative damage of DNA, with subsequent NAD and ATP depletion. Its significance may be that the irreversible cellular and tissue damage can be prevented perhaps not only by administration of antioxidants, but also by compounds (e.g. phospholipase A2 inhibitors) affecting the above-mentioned biochemical mechanisms.

[Possibilities of antioxidant therapy in the prevention of side effects of amiodarone]. / Az antioxidáns therapia lehetöségei az amiodaron mellékhatások megelözésében, illetve kivédésében.

The authors demonstrated the generation of a very reactive phenyl radical from amiodarone in a reducing molecular environment by pulse radiolysis study. The various antioxidants are probably not capable of preventing the generation of phenyl radical, as well as to protect against its damaging effects on the neighboring molecules. Electron microscopic studies from lung tissue of in vivo treated rats showed that the simultaneous Silibinin (a flavonoid type antioxidant) treatment with amiodarone decreased significantly the lysosomal phospholipoidosis induced by amiodarone compared with the amiodarone treated group, but it didn't prevent entirely the accumulation of lysosomal phospholipids. The in vitro lysosomal beta-glucuronidase enzyme release measured from the liver tissue of in vivo treated rats increased significantly on amiodarone treatment, the antioxidants used (Silibinin, and the dihydroquinoline type MTDQ-DA) didn't exert any favorable effect. The authors discuss in details the possible relationships between free radical reactions and lysosomal phospholipoidosis.

[The role of oxidative stress, caused by amiodarone, in the side effects of the drug]. / Az amiodaron által elöidézett oxidativ stresszállapot szerepe a gyógyszer mellékhatásaiban.

It was supposed that free radicals are produced during the metabolism of amiodarone and involved in the mechanism of the drug's side effects. In vitro and in vivo experiments were performed in rats to check this hypothesis. We verified that amiodarone generated free radicals in vitro by chemiluminometric method. The light emission induced by amiodarone was inhibited by dihydroquinoline type antioxidants CH 402 and MTDQ--DA in a dose dependent manner. The malondialdehyde content, --one of the end products of lipid peroxidation--was increased by in vivo amiodarone administration in the serum and liver homogenate of rats. Amiodarone treatment increased significantly the NADPH and Fe3+ induced lipid peroxidation in rat liver microsomal fractions. The protective effect of antioxidants, MTDQ--DA and silibinin were ambiguous in these in vivo "short term" experiments.

Effect of free radicals in ischaemic renal failure in the dog.

After a 30-minute control period ischaemia was evoked in dogs under Nembutal (30 mg/kg, i.v.) anesthesia, by clamping the left renal artery for 45 minutes. This was followed by a 90-minute reperfusion period when diuresis, GFR, PAH clearance, sodium and potassium excretion, malondialdehyde level in the plasma of the renal vein and SOD enzyme activity of the erythrocytes in renal venous blood were determined. Besides the control group (n = 6), the following treated groups were investigated: 1. Allopurinol (n = 7) in a dose of 100 mg/kg, given orally for two days, 2. Silibinin (n = 6) in a dose of 4 mg/kg/hour, given into the renal artery, 3. MTDQ-DS (n = 6) in a dose of 150 mg/kg/hour, given intravenously. 4. SOD (n = 4) 4 mg infusion (initiated 1 minute prior reperfusion). In the first 15-minute period following reperfusion GFR was 21%, cPAH 29% and sodium and potassium excretion 67 and 42% of the values of the contralateral kidney, respectively. Renal function improved gradually during the 90 minutes of reperfusion, and the above-mentioned parameters reached 59, 57, 65 and 76% of the corresponding control data. Increase of malondialdehyde level in the venous blood of the kidney during reperfusion might have been indicative of the production of free radicals; the difference, however, was not significant statistically. The administrations did not lead to considerable change in any of the parameters investigated. No difference could be demonstrated by histological methods between the kidneys of the treated and untreated animals. The compounds studied are thought to be free radical scavengers; in the present work, however, no protective effect could be demonstrated.

The effect of CH 402 dihydroquinoline type antioxidant on the activity of Na+-K+-ATP-ase and Mg++-ATP-ase of rat brain subcellular fractions in the presence and absence of ascorbic acid.

Authors studied the activities of Na+-K+-ATP-ase and Mg++-ATP-ase as indicators of lipid peroxidation on rat brain plasmamembrane and microsomal fraction. The CH 402 (Sodium(2,2-dimethyl-1,2-dihydroquinoline-4-yl)methane sulfonate) a synthetic, water soluble, non toxic dihydroquinoline type antioxidant proved to be effective in decreasing the membrane damage caused by ascorbic acid induced lipid peroxidation. The CH 402 did not inhibit the Na+-K+-ATP-ase and Mg++-ATP-ase activities even at a concentration of 10(-3) mol/l.

The effect of (+) cyanidanol-3 on the Na+-K+-ATP-ase and Mg++-ATP-ase activities of the rat brain in the presence and absence of ascorbic acid.

The authors investigated the effects of (+) cyanidanol-3-(Catergen) in vitro on the activities of rat brain plasma membrane and microsomal Na+-K+-ATP-ase and Mg++-ATP-ase, in the presence and absence of ascorbic acid. Due to lipid peroxidation induced by low concentration of ascorbid acid, activity of both ATP-ase decreased. (+) cyanidanol-3 proved to be an effective antioxidant in this system. It inhibited the decrease of ATP-ase activity which occurred as a result of lipid peroxidation promoted by ascorbic acid.

Effect of (+)-cyanidanol-3 on rat brain lipid peroxidation.

Non-enzymic lipid peroxidation was stimulated in homogenates, plasma membrane fractions and microsomes of rat brain in vitro by incubation with ascorbic acid. Malondialdehyde formation was determined by the thiobarbituric acid test. It has been established that (+)-cyanidanol-3 inhibits the ascorbic acid-stimulated lipid peroxidation in various fractions of rat brain. On the basis of these results it is suggested that (+)-cyanidanol-3 treatment protects brain suspensions against lipid peroxidation by acting as a free radical scavenger in vitro.

Experimental models for the study of hepatoprotection.

In the therapy of chronic liver diseases several drugs are currently used. This review summarizes the results of the authors in the therapy of chronic liver diseases with cyanidanol-3, as well as the beneficial effects of the new dihydroquinoline-type antioxidants in acute carbon tetrachloride induced and galactosamine induced liver lesions. In addition, the immunostimulant effects of Aicaphosphate is demonstrated in chronic active hepatitis.

Inhibition of doxorubicin-induced liver toxicity by a new dihydroquinoline type antioxidant.

The influence of a new dihydroquinoline type antioxidant on doxorubicin-induced hepatic toxicity was studied in mice (CFLP, LATI). Four groups of mice were studied: control, doxorubicin-treated, 5,6-methylen-bis (2,2,4/-trimethyl-1,2-dihydroquinoline/-disulphate (MDS)-treated, as well as doxorubicin and MDS-treated groups. Doxorubicin (15 mg/kg) was administered intraperitoneally, the MDS solution was given by a gastric tube. Liver function was assessed by the serum glutaminic-oxaloacetic-transaminase (SGOT) reaction. The lipid peroxidation in liver tissue was determined by the rate of malondialdehyd (MDA) production, the permeability of the liver lysosomal membrane was established by measuring beta-glucuronidase activity and its release from the cells. The MDS treatment proved to be effective in significantly reducing SGOT elevation, MDA production and lysosomal membrane damage in hepatic tissue. Clinical trials seem to be justified in using antioxidative substances to control doxorubicin toxicity.