Effects of atorvastatin on heart mitochondrial function and coenzyme Q content in the experiment.

We focused on determination of whether atorvastatin: 1) reduces CoQ content, 2) impairs mitochondrial function and 3) induces dose-dependent changes. Although the high dose of atorvastatin exerted a beneficial effect on the lipid peroxidation in plasma, coenzyme Q content was reduced and heart mitochondrial function was impaired. Physicians should be aware when prescribing statins mainly in higher doses to the patients with co-existing proved or supposed CoQ10 deficiency resulting from age-related decline, and metabolic or mitochondrial diseases (Ref. 3).

Does rooibos tea (Aspalathus linearis) support regeneration of rat liver after intoxication by carbon tetrachloride?

This study evaluates the effect of rooibos tea (RT, Aspalathus linearis) on biochemical and histological parameters during rat liver regeneration after intoxication by carbon tetrachloride (CCl4). From the 10th week, when the administration of CCl4 was terminated, the liver tissue began to regenerate. Seven days later in the regeneration phase, the animals treated by RT during whole period of the experiment, and those which drunk RT only during the regeneration period, exhibited a trend for decrease in the activity of alanine aminotransferase and significant decrease in the activity of aspartate aminotransferase and in total bilirubin content when compared with the water-drinking group. At the same time, the concentration of plasma albumin was elevated and that of tissue malondialdehyde decreased in the both groups drinking RT. After 42 days of regeneration, all biochemical parameters in all three groups reached the level of control healthy animals. In both groups treated with RT, the extent of fibrotic tissue was lower than in the group which received water. We conclude that RT can be recommended not only for the prevention but also as a co-adjuvant for the therapy of liver diseases.

Rooibos tea (Aspalathus linearis) partially prevents oxidative stress in streptozotocin-induced diabetic rats.

The aim of this study was to investigate the effects of rooibos tea as a natural source of a wide scale of antioxidants on the prevention and treatment of oxidative stress in streptozotocin-induced diabetic rats. Expected significant changes of biochemical parameters characteristic for experimental diabetic state were found in plasma and tissues eight weeks after single dose streptozotocin application. Administration of aqueous and alkaline extracts of rooibos tea (or N-acetyl-L-cysteine for comparison) to diabetic rats did not affect markers of the diabetic status (glucose, glycated hemoglobin and fructosamine). Besides the parameters characterizing hepatotoxic effect of streptozotocin, rooibos tea significantly lowered advanced glycation end-products (AGEs) and malondialdehyde (MDA) in the plasma and in different tissues of diabetic rats, particularly MDA concentration in the lens. From these results we can conclude that antioxidant compounds in rooibos tea partially prevent oxidative stress and they are effective in both hydrophobic and hydrophilic biological systems. Therefore, rooibos tea as a commonly used beverage can be recommended as an excellent adjuvant support for the prevention and therapy of diabetic vascular complications, particularly for protecting ocular membrane systems against their peroxidation by reactive oxygen species.

Smoke cardiomyopathy: disturbance of oxidative processes in myocardial mitochondria.

The effect of inhalation of cigarette smoke (passive smoking) on the oxidative and phosphorylating processes of rabbit myocardial mitochondria was studied in three experimental models after a single smoke lasting 30 min, after 2 weeks smoking twice daily and after 8 weeks smoking twice daily. A significant decrease in respiration as well as in the phosphorylation rate of mitochondria was found; whereas the respiratory control index and coefficient of oxidative phosphorylation did not change. Both factors of cigarette smoke (carbon monoxide and nicotine) participate in the metabolic injury of mitochondria. Long term cigarette smoking causes considerable metabolic and morphological alterations to the heart muscle which can be characterised as smoke cardiomyopathy.

Determination of apigenin in rat plasma by high-performance liquid chromatography.

Apigenin (4',5,7-trihydroxyflavone, AP) belongs to a less-toxic and non-mutagenic flavone subclass of flavonoids, the biotransformation and metabolism of which have been little studied until now. Therefore, this study is focussed on the determination of AP in free form. AP was administered to rats via the i.p. route (25 mg kg(-1)) and then the blood was collected at 10, 15, 30 and 45 min after injection. Methanol was used for rat plasma deproteinization. The HPLC assay (mobile phase, 2% formic acid-acetonitrile-methanol, 40:35:25, v/v; flow-rate, 1 ml min(-1); UV detection at 349 nm) for AP determination was validated and used for the quantification of AP in rat plasma. The unknown concentration was calculated from the equation obtained by the least-squares regression analysis (y = 0.521x + 1.130, r2 = 0.998). The highest concentration of AP in plasma was found to be 30 min after injection. The concentration profile of AP obtained here may contribute to until known results about AP metabolism. They could be applied to other studies of AP or related flavonoids because of favourable effects on human health.

Effect of pharmacist interventions on medication use and cost in hospitalized patients with or without HIV infection.

Pharmacotherapeutic interventions and drug acquisition costs in HIV-positive and HIV-negative patients on a hospital medical service were studied. In November and December 1995, HIV-positive and HIV-negative patients were randomly selected and matched on the basis of admission date. Pharmacotherapeutic interventions were recorded by a pharmacist until the time of discharge. Drug acquisition costs were obtained through records of medications ordered. The two patient groups were compared with respect to length of stay (LOS), number and cost of medications, and number of interventions. HIV-positive patients had significantly more medication orders and required more interventions than HIV-negative patients. Mean LOS was not significantly different. HIV status and number of medications were significantly associated with requiring five or more interventions. Drug acquisition costs were significantly higher in the HIV-positive group. The mean pharmacist-attributed cost saving per patient was $134 for HIV-positive patients and $27 for HIV-negative patients. HIV-positive patients required more interventions and consumed more medication resources than HIV-negative patients. Pharmacist interventions produced drug acquisition cost savings for both groups, with more savings being realized for positive patients.

Rapid HPLC analysis of melphalan applied to hyperthermic isolation limb perfusion.

Hyperthermic isolated limb perfusion (HILP) with melphalan (MH) as a standard cytotoxic drug has been performed in 28 patients suffering from malignant melanoma. MH has been administered by HILP via extracorporeal circulation system. The drug given locoregionally reduces subsequent toxicity of organs. For all that residues can leak into the systemic circulation during HILP. Because of known carcinogenic potential and secondary cancer formation, the main interest of this work is to determine MH concentration profile in the patient plasma during and after HILP and evaluation of its potential toxicity in patients. Reversed-phase HPLC assay, which uses isocratic elution and fluorimetric detection has been shown to be sensitive, reliable and suitable for routine analyses. The assay was validated for the concentration range of 50-2500 ng.ml-1 with the limit of detection (LOD) 6.881 ng.ml-1. The samples were treated by methanol precipitation with the recovery more than 80%. The stability of standard solutions and methanolic extracts of MH were also followed. The concentration profile of MH in patient samples has been pursued in three time points during and after chemoperfusion (45 min after application of MH in extracorporeal circulation, 10 min after the joining the extremity to systemic circulation and one hour after the great vessels reconstruction). The concentrations of MH ranged 100-1500 ng.ml-1 and varied from patient-to-patient. Some complications were observed after HILP in 11 patients and are correlated with the higher con- centrations of MH (over 150 ng x ml-1) found in plasma.

Regeneration of coenzyme Q9 redox state and inhibition of oxidative stress by Rooibos tea (Aspalathus linearis) administration in carbon tetrachloride liver damage.

The effect of rooibos tea (Aspalathus linearis) on liver antioxidant status and oxidative stress was investigated in rat model of carbon tetrachloride-induced liver damage. Synthetic antioxidant N-acetyl-L-cysteine (NAC) was used for comparison. Administration of carbon tetrachloride (CCl4) for 10 weeks decreased liver concentrations of reduced and oxidized forms of coenzyme Q9 (CoQ9H2 and CoQ9), reduced -tocopherol content and simultaneously increased the formation of malondialdehyde (MDA) as indicator of lipid peroxidation. Rooibos tea and NAC administered to CCl4-damaged rats restored liver concentrations of CoQ9H2 and alpha-tocopherol and inhibited the formation of MDA, all to the values comparable with healthy animals. Rooibos tea did not counteract the decrease in CoQ9, whereas NAC was able to do it. Improved regeneration of coenzyme Q9 redox state and inhibition of oxidative stress in CCl4-damaged livers may explain the beneficial effect of antioxidant therapy. Therefore, the consumption of rooibos tea as a rich source of natural antioxidants could be recommended as a market available, safe and effective hepatoprotector in patients with liver diseases.

Influence of beta-resorcylidene aminoguanidine on selected metabolic parameters and antioxidant status of rats with diabetes mellitus.

We studied the effects of administration of beta-resorcylidene aminoguanidine (RAG) to Wistar strain rats with experimental diabetes mellitus (DM) induced by streptozotocin. The effects studied included antioxidant levels in plasma and the liver, oxidative damage of lipids represented by the formation of substances reacting with thiobarbituric acid (TBARP) and selected biochemical indicators. The administration of RAG did not significantly affect antioxidant status of diabetic rats or hemoglobin glycation and plasma concentration of fructosamine. In diabetic rats, application of RAG decreased formation of TBARP in plasma but not in the liver. Moderate steatosis of liver and increased plasma levels of triacylglycerols in diabetic rats were significantly improved by application of RAG.

Hepatoprotective effect of rooibos tea (Aspalathus linearis) on CCl4-induced liver damage in rats.

Hepatoprotective properties of rooibos tea (Aspalathus linearis) were investigated in a rat model of liver injury induced by carbon tetrachloride (CCl(4)). Rooibos tea, like N-acetyl-L-cysteine which was used for the comparison, showed histological regression of steatosis and cirrhosis in the liver tissue with a significant inhibition of the increase of liver tissue concentrations of malondialdehyde, triacylglycerols and cholesterol. Simultaneously, rooibos tea significantly suppressed mainly the increase in plasma activities of aminotransferases (ALT, AST), alkaline phosphatase and billirubin concentrations, which are considered as markers of liver functional state. The antifibrotic effect in the experimental model of hepatic cirrhosis of rats suggests the use of rooibos tea as a plant hepatoprotector in the diet of patients with hepatopathies.

Influence of 2,5-dihydroxybenzylidene aminoguanidine on lipid oxidative damage and on antioxidant levels in model diabetes mellitus.

2,5-Dihydroxybenzylidene aminoguanidine (BAG) is a structural analogue of the antidiabetic compound aminoguanidine, and is an example of a substance protecting diabetic rats from lipoprotein oxidation arising in oxidative stress conditions characteristic of diabetes mellitus. We found that administration of BAG to diabetic rats decreases their susceptibility to lipoprotein oxidation, decreases formation of conjugated dienes and 4-hydroxy-2-nonenal, and increases antioxidant potential of plasma. On the other hand, our results show that BAG has a negative influence on lipoprotein oxidation in control rats. Increased formation of 4-hydroxy-2-nonenal and conjugated dienes and a decrease in plasma antioxidant potential was observed when BAG was administered to control rats. It is therefore necessary to search for other structural modifications of this substance that would combine higher antidiabetic activity with less toxicity in healthy individuals.

Serum and ultradiafiltrate middle molecules in hemodialysed patients.

The gel filtration technique was used for the fractionation of middle molecular substances (MMS) in plasma from conservatively treated patients, from dialysed patients with renal failure and in the ultradiafiltrate from dialysed ones. The following observations were made: 1. MMS accumulate in the plasma of conservatively treated patients in chronic renal failure. 2. The accumulation of MMS in dialysed patients is even higher. 3. The elimination of the most important MMS in the ultradiafiltrate is excellent. 4. It is concluded that hemofiltration and ultradiafiltration are indicated also for the removal of MMS, namely in the case of clinical complications which cause a further accumulation of MMS.

[Alcoholic mitochondrial cardiomyopathy]. / Alkoholová mitochondriálna kardiomyopatia.

The effect of alcohol on oxidative phosphorylation, activity of cytochrome oxidase and the content of cytochromes in mitochondria of the heart muscle was studied in rabbits after 14- and 21-day subcutaneous administration of 20% alcohol solution. Alcohol was found to exert an inhibitory effect on oxygen consumption and on the rate of energy production in mitochondria of the heart muscle, to decrease the specific activity of cytochrome oxidase and to increase the cytochrome content in the mitochondria. The authors classify these metabolic derangements under the concept of alcoholic mitochondrial cardiomyopathy and discuss broader aspects of mitochondrial diseases in medicine.

[Increased levels of circulating advanced glycation end products in a model of acute renal insufficiency in rats]. / Zvýsenie koncentrácií cirkulujúcich koncových produktov pokrocilej glykácie v modeli akútnej renálnej insuficiencie u potkana.

BACKGROUND: Advanced glycation end products (AGEs) are formed from proteins and peptides by non-enzymatic glycation or glycooxidation. AGEs are formed slowly during aging, and they accumulate in circulation and tissues in diabetes and chronic renal failure. Kidney plays a key role in the disposal of AGEs. Aim of this study was to verify the hypothesis that, acute loss of renal function with enhanced oxidative and carbonyl stress should result in a rise of circulating AGEs levels. METHOD AND RESULTS: Acute renal failure (ARI) was induced in rats by bilateral nephrectomy (24-72 hours). The data on AGEs levels, oxidative status and antioxidative defense was compared to those of sham operated animals. 48 hours after the induction of ARI concentrations of AGEs, determined fluorimetrically or as carboxymethyllysine, rose 2-fold, and they correlated with concentrations of creatinine (r = 0.938, p < 0.001 and r = 0.815, p < 0.001, respectively). Malondialdehyde (MDA) and lipofuscine (LF) concentrations rose in a time dependent manner, suggesting an enhanced oxidative and carbonyl stress. Enhanced lipid peroxidation did not result from the suppressed antioxidant defense: activity of superoxide dismutase rose by 50%, while that of glutathione peroxidase was not compromised. Total antioxidant status increased, probably due to the accumulation of uremic toxins with scavenging capacity, such as hyppurate. CONCLUSIONS: According to our knowledge our data was first to show a rapid increase in circulating AGEs concentrations in the model of acute renal failure in rats. If AGEs accumulate in acute renal failure in humans, their contribution to acute toxicity, and/or to the development of later complications, might be of a great importance.

[Effect of losartan on antioxidant status in rats with diabetes mellitus]. / Vplyv losartanu na antioxidacný stav potkanov s diabetes mellitus.

The aim of this study was to monitor the effect of the administration of antihypertensive drug losartan on: (1) the antioxidant status of rats with experimental insulin-dependent diabetes mellitus; (2) oxidative damage which is represented by the production of compounds which can react with thiobarbituric acid (TBARP), and (3) some metabolic parameters. Losartan administration did not significantly influence the concentration of glucose, cholesterol, triacylglycerol, and uric acid in the plasma of control and diabetic animals. In the liver tissue, the concentration of triacylglycerols decreased after losartan administration, but the concentration of cholesterol did not change. The present authors have found that losartan administration increased the levels of water solubile antioxidants in the plasma of diabetic rats, which can result in a decrease of the TBARP levels in the plasma of diabetic rats.

[The effect of alcohol on the mitochondrial respiratory chain in the cardiac muscle]. / Vplyv alkoholu na dýchací retazec mitochondrií srdcového svalu.

The authors investigated the action of prolonged 2- and 3-week action of ethanol on the main parameters of oxidative processes and on the cytochrome content of mitochondria in the heart muscle in 3-month-old rats. They found a statistically significant reduction of the oxidative phosphorylation coefficient, the rate of energy formation and a transient increase of the cytochrome oxidase activity in mitochondria. Under these experimental conditions an increase of cytochromes (cyt aa3, b, c, c1, bc1, c + c1) in mitochondria of the heart muscle occurred.

Liver mitochondrial respiratory function and coenzyme Q content in rats on a hypercholesterolemic diet treated with atorvastatin.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are effective drugs in the treatment of hypercholesterolemia, however, their undesirable actions are not fully known. We investigated the effects of atorvastatin on the oxidative phosphorylation and membrane fluidity in liver mitochondria, and also on the coenzyme Q (CoQ) content in the mitochondria, liver tissue, and plasma of rats on a standard (C) and hypercholesterolemic (HCh) diet. Atorvastatin was administered at either low (10 mg kg(-1)) or high dose (80 mg kg(-1)) for four weeks. The high dose of the drug decreased the concentrations of total cholesterol and triacylglycerols in the plasma and liver of rats on a HCh diet. Administration of atorvastatin was associated with decreased oxygen uptake (state 3), and oxidative phosphorylation rate in the mitochondria of both C and HCh rats. Further, the drug influenced mitochondrial membrane fluidity and dose-dependently reduced concentrations of oxidized and reduced forms of CoQ in the mitochondria. Our findings point to an association between in vivo administration of atorvastatin and impaired bioenergetics in the liver mitochondria of rats, regardless of diet, in conjunction with simultaneous depletion of oxidized and reduced CoQ forms from the mitochondria. This fact may play a significant role in the development of statin-induced hepatopathy.