The effects of simvastatin and fenofibrate on malondialdehyde and reduced glutathione concentrations in the plasma, liver, and brain of normolipidaemic and hyperlipidaemic rats.

The objective of study was to investigate the effects of different doses of simvastatin and fenofibrate on malondialdehyde (MDA) and reduced glutathione (GSH) in the plasma, liver, and brain tissue of male normolipidaemic and hyperlipidaemic rats. Normolipidaemic (Wistar) rats were receiving 10 or 50 mg/kg a day of simvastatin or 30 or 50 mg/kg a day of fenofibrate. Hyperlipidaemic (Zucker) rats were receiving 50 mg/kg/day of simvastatin or 30 mg/kg/day of fenofibrate. Control normolipidaemic and hyperlipidaemic rats were receiving saline. Simvastatin, fenofibrate, and saline were administered by gavage for three weeks. In normolipidaemic rats simvastatin and fenofibrate showed similar and dose-independent effects on plasma and brain MDA and GSH concentrations. Generally, plasma and brain MDA decreased, while brain GSH concentration increased. In hyperlipidaemic rats simvastatin did not affect plasma and brain MDA and GSH concentrations but significantly decreased liver GSH. Fenofibrate decreased plasma and liver MDA but increased brain MDA. In both rat strains fenofibrate significantly decreased liver GSH concentrations, most likely because fenofibrate metabolites bind to GSH. Our findings suggest that simvastatin acts as an antioxidant only in normolipidaemic rats, whereas fenofibrate acts as an antioxidant in both rat strains.

Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats.

The study objective was to test the hypothesis that simvastatin and fenofibrate should cause an increase in butyrylcholinesterase (BuChE) activity not only in the plasma and liver but also in the brain of normolipidemic and hyperlipidemic rats. Catalytic enzyme activity was measured using acetylthiocholine (ATCh) and butyrylthiocholine (BTCh) as substrates. Normolipidemic and hyperlipidemic rats were divided in four groups receiving 50 mg/kg of simvastatin a day or 30 mg/kg of fenofibrate a day for three weeks and three control groups receiving saline. Simvastatin and fenofibrate caused an increase in brain BuChE activity in both normo- and hyperlipidemic rats regardless of the substrate. The increase with BTCh as substrate was significant and practically the same in normolipidemic and hyperlipidemic rats after simvastatin treatment (14-17% vs controls). Simvastatin and fenofibrate also increased liver and plasma BuChE activity in both normolipidemic and hyperlipidemic rats regardless of the substrate. In most cases the increase was significant. Considering the important role of BuChE in cholinergic transmission as well as its pharmacological function, it is necessary to continue investigations of the effects of lipid-lowering drugs on BuChE activity.

Effects of simvastatin on malondialdehyde level and esterase activity in plasma and tissue of normolipidemic rats.

BACKGROUND: We investigated the possible non-lipid effects of simvastatin (SIMV) on paraoxonase 1 (PON1) and butyrylcholinesterase (BuChE) activity, as well as on malondialdehyde (MDA) levels in normolipidemic rats. METHODS: Two experimental groups of Wistar rats (10mg/kg/day of SIMV) and two control groups (saline) underwent a 21-day treatment period (TP). On the 22nd day one experimental and one control group of rats were sacrificed. Remaining groups of animals were sacrificied on the 32nd day of the study (10-day after-treatment period (AT)). Blood samples and slices of liver, heart, kidney, and brain tissue were obtained for the measurement of PON1 and BuChE activity and levels of MDA. Data were analyzed by means of t-test for independent samples. p values≤0.05 were considered as statistically significant. RESULTS: SIMV caused a significant decrease of serum and liver PON1 activity (18-24%, p≤0.05) and MDA concentrations in the plasma, heart, liver, kidney, and brain (9-40%, p≤0.05), while plasma and liver BuChE activity increased by 29% (p≤0.05) and 18%, respectively. All effects of SIMV were largely diminished following AT. The exception was MDA, which remained significantly decreased in plasma and all tissues analyzed. CONCLUSION: SIMV significantly decreased PON1 activity and MDA levels and increased BuChE activity. We suggest that the decrease of MDA levels is a beneficial therapeutic effect of SIMV, for example in cardiovascular disorders, while the increase of BuChE activity, especially in brain, may be a potential adverse effect in patients with Alzheimer disease.

[Ethics of scientific research using patients' archived biological material and their medical data]. / Eticki pristup znanstvenim istrazivanjima u kojima se koriste pohranjeni bioloski materijali pacijenata i njihovi medicinski podatci.

Informed consent represents the standard for adequate protection of all participants in biomedical research. This standard is affirmed in international legal documents concerning biomedical research, as well as in Croatian legislation. However, some questions regarding informed consent remain open. One of such questions that research ethics committees around the world and in the Republic of Croatia often deal with, is the question of whether to obtain informed consent for the research on archived material or previously collected research data taken from the patients during diagnostic or therapeutic procedures. This contribution provides an overview of both Croatian and international legal documents and guidelines that deal with this issue, together with an overview of the literature concerning this issue. Since in the Republic of Croatia there are no regulations regarding this type of research, the authors of this contribution are presenting conduct guidelines for researchers and ethics committees in such cases. The implementation of the proposed guidelines would facilitate scientific research and international cooperation for Croatian scientific institutions.

The influence of gemfibrozil on malondialdehyde level and paraoxonase 1 activity in wistar and fisher rats.

There are diverse experimental data about the influence of gemfibrozil (GEM) on the production of hydrogen peroxide (H(2)O(2)) and antioxidant enzymes. We investigated the influence of GEM treatment on the production of malondialdehyde (MDA) level in tissues of normolipidaemic Wistar and Fisher rats which is an index of lipid peroxidation. Because serum paraoxonase 1 (PON1) is an important enzyme with specific protective function on metabolism of lipid peroxides, we examined the influence of GEM on PON1 activity in liver and serum. MDA level and enzyme activities were also determined 10 days after withdrawal of GEM treatment. The significantly increased levels of MDA in liver, kidney and heart of both rat strains were obtained after 3 weeks of GEM treatment. We propose two possibilities for the increase of MDA levels caused by GEM, induction of peroxisome proliferation and activities of enzymes that participated in occurrence of H(2)O(2) and possible reduction of enzyme activities including in H(2)O(2) metabolism. Ten days after withdrawal of GEM treatment, MDA levels in all tissue levels of both rat strains were less in comparison with GEM treatment. GEM caused a significant drop of PON1 activity in serum and liver of Fisher rats, and in liver of Wistar rats. We suggest that GEM, through induction of lipid peroxidation, caused the damage of hepatocytes with consequent reduction of PON1 synthesis. The increase in PON1 activity in serum and tissues of both rat strains 10 days after withdrawal of GEM treatment shows the fast recovery of enzyme synthesis.

Effects of high sucrose diet, gemfibrozil, and their combination on plasma paraoxonase 1 activity and lipid levels in rats.

We investigated the influence of high sucrose diet (HSD) after 3 or 5 weeks of administration on paraoxonase 1 (PON1) activity in plasma of normolipidemic rats and the relationship between serum PON1 activity, triacylglycerides (TGs), HDL and total cholesterol vs. the control group of rats fed normal, control diet (CD). Because the data about the influence of gemfibrozil (GEM) on PON1 activity are controversial, we also investigated its effects (administration in the 4th and 5th week in rats on HSD and CD) on plasma PON1 activity and lipid levels in normolipidemic rats, and in rats with hypertriglyceridemia caused by HSD. Our results obtained in rats on HSD show a significant increase of plasma TGs levels by 47% (P<0.05) after 5 weeks of treatment, and PON1 activity by 32% and 23% (P<0.05) after 3 and 5 weeks, but without change in lipid levels vs. rats on CD. In the rats on CD and HSD, GEM caused a significant decrease of PON1 activity by 44% and 33%, while a significant decrease of TGs level by 38% (P<0.05) was measured only in rats on CD. The effects of GEM on total cholesterol, HDL and LDL in both groups of rats were typical for its action on lipoprotein metabolism. Because GEM in the rat liver stimulates proliferation of peroxisomes, ß oxidation, and production of H2O2, it is possible that the oxidative stress induced by GEM damages hepatocytes and lowers the synthesis of PON1.

Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk.

The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

Clinical study on the effect of simvastatin on paraoxonase activity.

Human paraoxonase (PON1) is a serum high-density lipoprotein-associated phosphotriesterase. High-density lipoprotein (HDL) plays the role of a carrier and the site of action of this enzyme. According to a majority of authors, PON1 acts as an antioxidant, preventing low-density lipoprotein (LDL) peroxidation. However, due to the fact that in vivo serum PON1 is predominantly associated with HDL, its major physiological role might be to protect HDL, rather than LDL, from oxidation. Nevertheless, the physiological substrate of PON1 still remains to be discovered. The objective of this study was to determine changes in PON1 activity during treatment with simvastatin (CAS 79902-63-9, Lipex) in patients with type IIa and/or IIb hyperlipoproteinemia. PON1 activity was assessed in 32 patients with hyperlipoproteinemia type IIa or IIb with an LDL cholesterol concentration higher than 4.2 mmol/l. Patients received simvastatin in a daily dose of 20 mg. The lipid status and PON1 activity were assessed at baseline, as well as 3 and 6 months after the beginning of treatment. The study demonstrated a statistically significant lipid lowering effect of simvastatin on total and LDL cholesterol, and an increase in PON1 activity in patients with both types of hyperlipoproteinemia. No statistically significant correlation was observed either between changes in PON1 activity and HDL, HDL2, HDL3 and LDL cholesterol and triglyceride levels, or between their first differences in patients with both type IIa and IIb hyperlipoproteinemia. The obtained results suggest that the antioxidant properties of simvastatin might be caused by a mechanism independent of apoAI-containing lipoprotein concentration. The antioxidant properties of simvastatin, which play an important role in HDL protection from oxidation, could be the mechanism inducing the increase in PON1 activity.

Changes in butyrylcholinesterase activity and serum lipids after oxprenolol and glibenclamide treatments in non-diabetic rats.

The effects of chronic treatment with oxprenolol (CAS 6452-72-7, OXP, 15 mg/ kg/ day) or glibenclamide (CAS 10238-21-8, GL, 2.5 mg/kg/day), or their combination administered for 6 and 12 weeks, on the butyrylcholinesterase (BuChE) activity in plasma and liver and on the plasma levels of triglycerides, total cholesterol and high density lipoprotein (HDL)-cholesterol were studied in normal, non-diabetic female rats. In all treated groups a significant increase of plasma BuChE activity was obtained after 6 weeks of either OXP (46 %), or GL (36 %) treatment, or of their concurrent application (24 %). After 12 weeks of treatment, the increase in enzyme activity was significant only in the OXP group. The BuChE activity in the liver was increased (between 3-25 %) in all treated groups except in one during 6 and 12 weeks of treatment. These effects of either OXP or GL, or their combination on BuChE activity in liver suggest their stimulating effects on enzyme synthesis. The changes of total plasma cholesterol in all groups were insignificant. On the other hand, HDL-cholesterol was significantly decreased in all treated groups. After 6 weeks of treatment, GL, OXP, or their combination caused a decrease in plasma HDL cholesterol by 19, 50 or 22 % respectively, when compared with the control group. After 12 weeks of GL, OXP, or GL+OXP administration, HDL-cholesterol plasma levels in treated groups were 32, 25 and 22 % lower than in the control group. Treatment with GL, OXP, or GL+OXP during 6 weeks had no significant effect on triglycerides level. However, after 12 weeks of GL, OXP, or GL+OXP administration, the triglycerides levels were significantly increased (9, 47 and 36 %) when compared with the control group. These results showed that the increase in BuChE activity might be the first sign of altered triglyceride and lipoprotein metabolism.

Butyrylcholinesterase activity and plasma lipids in dexamethasone treated rats.

The paper describes the effect of glucocorticoid dexamethasone (DM) given intraperitoneally on the catalytic activity of butyrylcholinesterase (BuChE) measured in plasma, liver and white adipose tissue of rats of both sexes. Effects of DM on the concentration of plasma lipids and lipoproteins were also tested. Rats were given multiple (2 and 4) pharmacological doses (0.4 and 3.0 mg kg(-1) body mass) of DM. All animals were sacrificed 48 hours after the last dose. Administration of DM significantly decreased the catalytic activity of BuChE in plasma and liver of all treated groups regardless of sex. BuChE catalytic activity in white adipose tissue differed depending on the dose and frequency of administration. In contrast to liver where both doses caused significant BuChE inhibition, the lower DM dose did not inhibit BuChE activity in adipose tissue, and the inhibition achieved by the higher dose was not as strong as in liver. This result corroborates an earlier hypothesis that BuChE is also synthesized in the adipose tissue. DM significantly increased plasma concentrations of triglycerides, total cholesterol and high-density lipoprotein (HDL) cholesterol and decreased the low-density lipoprotein (LDL) cholesterol concentration. Neither positive correlation between BuChE and triglycerides nor negative correlation between BuChE and HDL was found. Changes in lipid profile during DM treatment were not sex- and time-dependent.

Clinical study on the effect of simvastatin on butyrylcholinesterase activity.

Although the physiological function of serum butyrylcholinesterase (BuChE) has not yet been clarified, there is evidence that this enzyme is involved in serum lipoprotein metabolism. It has been suggested that serum BuChE is positively correlated with LDL (low-density lipoprotein) and negatively with HDL (high-density lipoprotein) levels. The objective of this study was to determine whether the activity of BuChE changes during treatment with simvastatin (CAS 79902-63-9). The effects of simvastatin therapy on serum lipoproteins and plasma BuChE activity were studied in 15 patients with type IIa and 17 patients with type IIb hyperlipoproteinemia. Beside the expected influence on serum lipid concentration, a statistically significant decrease in BuChE activity in patients with hyperlipoproteinemia type IIa and IIb during treatment with simvastatin was not observed.

Adamantyl tenocyclidines--adjuvant therapy in poisoning with organophosphorus compounds and carbamates.

The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl- D-aspartate and muscarinic receptors showed low acute toxicity, having LD50 values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD50 of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD50 of aldicarb to >16.00 LD50 for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD50 of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.

The effect of dichlorvos treatment on butyrylcholinesterase activity and lipid metabolism in rats.

This paper describes the effects of dichlorvos (DDVP) on butyrylcholinesterase (BuChE) activity with possible consequences for lipid and lipoprotein metabolism in rats. The rats of both sexes were given a single and multiple doses of DDVP (8.0 mg/kg body weight) with two-day intervals between administrations, ensuring the continuous inhibition of BuChE activity without lethal outcome. BuChE activity was measured in plasma, liver, and white and brown adipose tissue. The recovery of BuChE activity was observed only in white adipose tissue of female rats 10 days after treatment. Our results show that DDVP significantly decreases BuChE activity in female and male rat plasma (40-60%; P < 0.05), and significantly increases triglycerides (60-600%; P < 0.05) and total cholesterol (35-75%; P < 0.05). In contrast to the increased HDL-cholesterol (20-30%; P < 0.05), LDL-cholesterol decreased (30-40%; P < 0.05). The decrease of BuChE activity and the changes in concentrations of lipids and lipoproteins were observed throughout the experiment. Our results contribute to the hypothesis that BuChE may play a role in lipid and lipoprotein metabolism.

The effect of cycloheximide on butyrylcholinesterase activity in vivo.

The paper describes the catalytic activity of butyrylcholinesterase (BuChE) measured in plasma, liver, white adipose tissue, heart, and brain of rats intraperitoneally administered a single non-lethal dose of cycloheximide (2.0 mg/kg body weight; CHM). The BuChE assay was performed on rats of both sexes either administered CHM or saline (controls), and killed 2, 3, 4, 5, 10 days later. A significant decrease of BuChE catalytic activity was observed in all tested tissues except plasma. In animals of both sexes, the lowest BuChE catalytic activity was found in the liver (2-6%), while it was higher in white adipose tissue, heart, and brain. However, the respective values remained significantly different from controls (33-67%, 49-62%, and 14-71% in males, and 24-82%, 72-86%, and 33-67% in females). Since there was no effect of CHM on BuChE catalytic activity in plasma, the data suggest that CHM inhibits the synthesis of BuChE rather than its active site.