Biomedical subjects

György Paragh

Publications and source records attributed to György Paragh.

At least 19 recordsLinked to original sources

PubMed2006

Neuropeptides induced a pronounced and statin-sensitive dysregulation of mevalonate cycle in human monocytes of patients with hypercholesterolemia.

Angiotensin II (Ang II) and leptin generate statin-inhibitable superoxide anion production that accounts for only part of the entire superoxide anion production. In our recent studies, we aimed at elucidating whether Ang II and leptin, affecting the intensity of the mevalonate cycle, are able to increase endogenous cholesterol synthesis. Furthermore, we compared the superoxide anion and cholesterol production capability of monocytes of healthy control volunteers and monocytes obtained from patients with hypercholesterolemia (HC). We also studied the differences of the produced statin-inhibitable superoxide anion and cholesterol synthesis in control and HC-monocytes, depending on the applied stimulating ligands. In control and HC-monocytes--stimulated by Ang II, leptin, fenyl-Me-Leu-Phe (FMLP), phorbol-12-myristate-13-acetate (PMA) and A23187--we determined the proportion of mevalonate cycle-dependent and -independent superoxide and cholesterol production, using lovastatin (Lov), and 25-hydroxycholesterol (25-HC). According to our results; (1) superoxide anion generation in HC-monocytes was elevated after Ang II, leptin and FMLP-stimulation, whereas PMA and A23187-stimulation had lower stimulating effect in HC than in control cells. (2) Cholesterol synthesis was increased only after stimulation with Ang II and leptin. (3) The Ang II and leptin-induced total superoxide anion generation and cholesterol synthesis were more elevated in HC than in control monocytes. (4) In contrast, the increase in Lov and 25-HC sensitive cholesterol synthesis were higher in resting, but lower in stimulated HC monocytes than in control cells. Summarizing our results, we concluded that Ang II and leptin are involved in enhancement of endogenous cholesterol synthesis through a statin-sensitive pathway.

Aged↗

PubMed2006

[The role and clinical importance of nitric oxide-endothelin system in hypertension].

This review summarises the role of the endothelium in the regulation of the vascular tone, emphasizes the importance of nitric oxide and endothelin at the vasodilator and vasoconstrictor physiological processes. Mainly, the nitric oxide is responsible for the basal tone of the vasculature, but plenty of modifying factors (endothelin, angiotensin-II, prostacyclin) have also important effects. Endothelial dysfunction observable in hypertension, which characterised by disorder of the endothelium-dependent relaxation, and predominance of the vasoconstrictor processes. Disorder of synthesis, decreased biological activity and increased degradation of the nitric oxide could play a role in the fall of the basal vasodilator tone, as well as other factors influencing the production of nitric oxide. Due to a relaxation disorder, the vasoconstrictor endothelin come to the front, following morphological changes of the vessels, afterwards. Endothelial dysfunction of the medium size arteries lead to thickening of the intima, what can follow by non-invasive measurements at the common carotid arteries. It is unambiguous in hypertensive patients that augmenting the tone of the resistance vessels, the peripheral vascular tone increases. It is proved in hypertensive adults that damaged function of the cerebral arterioles results in decrease of the vasoreactivity following a hypo- or hypercapnic stimuli. The imbalance of the nitric oxide-endothelin system is not only a process what helps to partly explain the pathophysiology of hypertension, but also a therapeutic aim preventing the process of atherosclerosis.

Atherosclerosis↗

PubMed2006

[Prevention of target organ damage with modern antihypertensive agents].

This review summarises the recent epidemiological data on hypertension, the aims of the treatment of hypertension, and emphasizes the importance of the modification of target organ damages and accelerated clinical conditions. Because the pathogenesis of hypertension is extremely complex, the therapy most likely requires a combined drug administration. The modern third generation dihydropyridine calcium channel blocker, amlodipine, not only has a favourable antihypertensive and anti-ischemic effect, but anti-atherosclerosis properties as well. There are plenty of evidence which demonstrate that lisinopril, a first line antihypertensive agent, has a positive effect in the treatment of left ventricular hypertrophy, retinopathy and nephropathy, and also has a favourable outcome after myocardial infarction and in heart failure. The combined administration of the two drugs leads to a favourable additive effect, with a decrease in the number and severity of side effects. The results of the ASCOT study proved a favourable effect with amlodipine based, combination therapy with an ACE-inhibitor, compared with the traditional beta-blockers and diuretics. The data of the CAFE sub-study showed, that in spite of the similar peripheral antihypertensive effect, the amlodipine based therapy decreased the central aortic pulse pressure to a greater extent. The central aortic pressure showed a good correlation with the end-points of the study, respectively. The results of the Hungarian multicenter study (HAMLET) proved the effective and safe administration of the two drugs in combination. Based on the above evidence, the fixed-dose combination of the CCB-ACE inhibitor (amlodipine-lisinopril) has not only effective blood pressure reducing properties, but also results in cardiovascular risk reduction, good tolerability and favourable compliance.

Amlodipine↗

PubMed2006

[New features in the recommendations of the Second Hungarian Therapeutic Consensus Conference].

The First Hungarian Therapeutic Consensus Conference took place on 3rd Nov. 2003 with the participation of 9 medical societies. Over the past 2 years the results of new major studies have been published and the American ATP III has also updated its guidelines issued in 2004. Based on the above proposals, the Second Hungarian Therapeutic Consensus Conference held on 3rd Nov. 2005 partly confirmed its earlier suggestions, but made some changes as well. Within the high risk category the Conference optionally created a very high risk group from those patients who - in addition to their cardiovascular disease--have either diabetes or metabolic syndrome or acut coronaria syndrome or who are chain smokers. We have included - as a complement - into the asymptomatic high risk category such newly emerging risk factors, one of which already in itself means high risk: ankle/arm index < or = 0.9, GFR <60 ml/min, microalbuminuria (30-300 mg), preclinical atherosclerosis (plaque). Besides, 4 other risk factors were also categorised such as Lp/a (> or = 30 mg/dl), CRP (> or = 3mg/l), homocysteine (> or = 12 micromol), familiarity--atherogenic gene constellation, but only the presence of at least two of these verify high risk. In very high risk group the goals of 3.5 mmol/l and 1.8 mmol/l were determined as therapeutic option. The goal in obese patients--expressed earlier only in BMI--can now be equally determined by the abdominal circumference (94 cm for men, 80 cm for women respectively). ACE inhibitors were recommended earlier as a preventive therapy in case of dysfunction of the left ventricle, while at present they are suggested for all patients with cardiovascular disease. In the recent recommendations guidelines related to nutrition, smoking, exercise have also been included.

Abdominal Fat↗

PubMed2006

Orlistat increases serum paraoxonase activity in obese patients.

BACKGROUND AND AIM: Previous studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity. METHODS AND RESULTS: A longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group. CONCLUSIONS: The 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.

Adult↗

PubMed2006

The effect of atorvastatin therapy on lecithin:cholesterol acyltransferase, cholesteryl ester transfer protein and the antioxidant paraoxonase.

OBJECTIVES: The aim of our study was to examine the influence of atorvastatin on lipid parameters, particularly on HDL, and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase. DESIGN AND METHODS: Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study. The patients received atorvastatin, 20 mg daily, for 3 months. We measured the serum paraoxonase activity and concentration, oxidized LDL, LCAT and CETP activities. RESULTS: Atorvastatin significantly reduced the levels of cholesterol, triglyceride, LDL-C and apoB, while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity, PON/HDL ratio and LCAT activity were significant, while oxLDL and CETP activities were significantly decreased. CONCLUSION: Atorvastatin may influence the composition and function of HDL, thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis.

Adult↗

PubMed2006

Target-organ damage in adolescent hypertension. Analysis of potential influencing factors, especially nitric oxide and endothelin-1.

BACKGROUND AND PURPOSE: To assess the role of the nitric oxide-endothelin imbalance in the development of target-organ damages (carotid intima-media thickness and left ventricular mass index) in adolescent hypertension. METHODS: 125 adolescents--67 hypertensive and 58 normotensive--underwent routine anthropology (height, weight) and blood pressure measurements, and laboratory (glucose, cholesterol and triglyceride levels) testing as well as sampling blood for determination of the plasma concentrations of nitric oxide (NOx) and endothelin-1 (ET-1), followed by measurement of the carotid intima-media thickness (IMT) and left ventricular mass index (LVMI). RESULTS: Plasma concentration of NOx was significantly lower (27.7+/-13.7 vs. 35.8+/-7.0 micromol/l, respectively, p<0.001) and ET-1 was higher (3.11+/-3.9 vs. 1.09+/-1.07 fmol/ml, respectively, p<0.001) in hypertensive adolescents than that of controls. NOx negatively, endothelin positively correlated with blood pressure values, especially with systolic BP. An inverse relationship has been found between NOx and ET-1 concentrations (r=-0.29, p<0.003). In this adolescent population body weight, systolic blood pressure and plasma ET-1 were the most important factors influencing IMT, whereas LVMI correlated with height and weight and systolic BP of the teenagers. CONCLUSIONS: NO/endothelin imbalance seems to play a role in the development of hypertension and target-organ damages in adolescence. Further studies are encouraged in order to clarify the pathophysiological role of NO/endothelin imbalance in adolescent hypertension.

Adolescent↗

PubMed2006

[A practicing physician's view on obesity].

Overweight and obesity are worldwide problems, its health and psychosocial burden on the individual and on society are tremendous. Diagnosing obesity is rather easy, and is based on simple anthropometric measurements, such as body weight, height and waist circumference. The different classes of obesity are determined by body mass index, which, together with waist circumference and comorbid conditions and other risk factors determine the individual risk for mortality and morbidity. Obesity is due to genetic and environmental factors, mainly is the consequence of excess calorie intake and sedentary lifestyle. The fat mass of the body is under neuroendocrine control, the central controller is the hypothalamus. Leptin, produced by adipocytes in proportion to fat mass, is the afferent signal to the hypothalamus. Decreasing or increasing levels of leptin result in orexigen and anorexigen neurotransmission, which mediate efferent activation towards food consumption and energy storage, or towards food restriction and energy expenditure, respectively. The balance of these events and/or the ,set point" of the controller--if leptin resistance is present--is shifted towards higher body/fat mass in obesity. Management of obesity is complex, however, in all stages of obesity lifestyle changes are mandatory--including diet, exercise and behavior modification. Pharmacotherapy might be needed if lifestyle changes alone do not result an acceptable weight loss. For the long-term treatment of obesity sibutramin and orlistat are the available approved drugs. In case of morbid obesity (body mass index > 40 kg/m2, or > 35 kg/m2 plus comorbid conditions and other risk factors) surgery might be the treatment of choice. There are different surgical methods, among those a widely used method nowadays is the laparoscopic adjustable gastric banding procedure.

Algorithms↗

PubMed2006

[Treatment of dyslipidemia in clinical practice].

The incidence of dyslipidemia is rising worldwide. Dyslipidemia combined with other factors represent the primary risk factors for the development of cardiovascular diseases. The National Cholesterol Education Program has recently updated the Adult Treatment Panel III guidelines and called for more intensive lipid lowering treatment, especially in patients at high risk for coronary heart disease. A statin and fibrate combination is a possible approach, moreover, niacin, particularly in combination with statins, might have a successful comeback. However, despite the existence of evidence-based treatment guidelines and effective antilipemic medications, recommended cardiovascular risk reduction rarely is achieved. This article summarises the mechanisms of action of available lipid lowering agents, their recommended dosing regiments and possible drug interactions.

Cholesterol↗

PubMed2006

[Metabolic syndrome in childhood and adolescence].

Metabolic syndrome has an outstanding impact on public health due to its increasing prevalence and poor prognosis. The development of insulin resistance, as a consequence of obesity, can be demonstrated even in childhood which has a pivotal role in the pathomechanism of the syndrome. Besides obesity, low birth weight, increased gain in body mass in early childhood, decreased pubertal insulin sensitivity and clinical markers of insulin resistance (acanthosis nigricans, polycystic ovarian syndrome, premature adrenarche) confer risk of metabolic syndrome. Currently, there are no consistent and consensus based diagnostic criteria of metabolic syndrome in children and adolescents. The most recent definition of the International Diabetes Federation [central obesity plus any two of four factors (raised triglyceride, reduced high-density lipoprotein-cholesterol, raised blood pressure and raised fasting plasma glucose)] is not approved for children and epidemiology data are not yet available. Applying the modified version of the most commonly used Adult Treatment Panel III diagnostic system for children and adolescents, the prevalence is given as 4.2% in the literature. As the components of the syndrome, frequency were as follows: 9.8-17.9% for abdominal obesity, 21.0-23.4% for elevated triglyceride, 18.3-23.3% for reduced high-density lipoprotein-cholesterol, 4.9-7.1% for elevated blood pressure and 0.8-1.7% for impaired fasting glucose. High frequency of morphological and functional disturbances of the vascular and endothelial systems seen frequently among children with signs of metabolic syndrome suggests early cardiovascular events and underlines the clinical significance of this entity. The most effective tool for prevention of metabolic syndrome is to avoid the development of childhood obesity. In case of established disease, the effective treatment should address the different components of the syndrome. The authors emphasize the need of elaboration of consensus based pediatric diagnostic criteria, national prevalence data, protocols for prevention, early recognition and effective treatment.

Abdomen↗

PubMed2006

[The role of transmembrane lipidtransporter molecules in the atherosclerotic process].

The role of transmembrane lipidtransporter molecules in the atherosclerotic process. The protective effect of high-density lipoprotein in the atherosclerotic process has been mainly attributed to its role in reverse cholesterol transport. Identification of mutations in the ATP-bindig casette transporter-A1 (ABCA1) as the genetic defect in genetic high-density lipoprotein-deficiency (Tangier disease) and selected patients with familiar hypoalphalipoproteinemia has generated interest in discovering the role of this lipid transporter molecule in the reverse cholesterol transport. It is well established, that the ABCA1 mediates cellular cholesterol efflux through transfer of phospholipids and cholesterol from the inner to the outer layer of the cell membrane, thus enabling the bindig to apolipoproteins. Previous studies showed that the ABCA1 is critically involved in cellular trafficking of cholesterol and phospholipids in total body of lipid homeostasis. In Tangier disease, the loss of the function of ABCA1, leads to an impaired formation of nascent high-density lipoprotein particles by preventing the release of cellular phospholipids and cholesterol to the acceptor apolipoprotein A1. This rare genetic disorder is characterized by a severe high-density lipoprotein deficiency, cholesterol deposition in macrophages and premature atherosclerosis. These findings implicate the ABCA1 as an important therapeutic target for preventing diseases that are associated with accelerated atherogenesis. The present review summarizes the current knowledge of the ABCA1, its pivotal role in the cholesterol homeostasis and preventing atherosclerosis.

ATP Binding Cassette Transporter 1↗

PubMed2006

Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress.

Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-kappaB), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2-/- mice develop more aberrant crypt foci and colon tumors than Ucp2+/+ littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8-12). This effect is primarily seen in the proximal colon of Ucp2-/- mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-kappaB activation (increased levels of phosphorylated IkappaB and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2'-deoxy-uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.

Animals↗

PubMed2006

Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression.

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2-/-) and UCP2-competent littermates (ob/ob:ucp2+/+) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2-/- mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2+/+ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.

Acute Disease↗

PubMed2006

Ciprofibrate increases paraoxonase activity in patients with metabolic syndrome.

AIMS: Diabetic dyslipidaemia with decreased high-density lipoprotein-cholesterol (HDL-C) concentration plays a key role in enhanced atherosclerosis. The antioxidant effect of HDL is due to the influence of human paraoxonase 1 (PON1) and several authors have described decreased activity of this enzyme in Type 2 diabetics and subjects with metabolic syndrome. The goal of this study was to examine the effect of daily ciprofibrate on serum PON1 and lipoprotein concentrations in patients with metabolic syndrome. METHODS: Fifty-one patients with metabolic syndrome were enrolled into the study. We examined the effect of 100 mg day(-1) ciprofibrate treatment on lipid concentrations, oxidized low-density lipoprotein (LDL), PON1 concentrations and activity. We also investigated the calculated size of LDL-cholesterol (LDL-C). RESULTS: During the 3-month study, it was observed that following treatment with ciprofibrate, the serum triglyceride concentration decreased significantly (from 2.76 +/- 0.9 mmol l(-1) to 2.27 +/- 1.6 mmol l(-1); -18%; P < 0.001), while HDL-C increased significantly (from 0.95 +/- 0.2 mmol l(-1) to 1.2 +/- 0.3 mmol l(-1); 26%; P < 0.001). The oxidatively modified LDL-C concentration decreased significantly (from 137 +/- 19 U l(-1) to 117 +/- 20 U l(-1); P < 0.001), while HDL-associated apolipoprotein A1 significantly increased (from 1.35 +/- 0.2 g l(-1) to 1.75 +/- 0.3 g l(-1); P < 0.001). The LDL-C/LDL-apoB ratio, which reflects the size of LDL, increased significantly (from 0.96 +/- 0.05 to 1.05 +/- 0.06; P < 0.05). Serum PON1 activity was significantly elevated (from 108 +/- 34 U l(-1) to 129 +/- 31 U l(-1); P < 0.05), while standardized values for HDL-C remained significantly unchanged (PON1/HDL-C) (from 114 +/- 21 to 107 +/- 20; NS). CONCLUSION: Three months of treatment with ciprofibrate favourably affected the lipid profile, increased LDL resistance to oxidation and improved antioxidant status by increasing serum paraoxonase activity in these patients.

Aryldialkylphosphatase↗

PubMed2005

[Analysis of paraoxonase activity and lipid profile in lupus patients].

INTRODUCTION: Immune-inflammatory processes play important role in the pathogenesis of atherosclerosis. Therefore, increasing attention is focused on rheumatic diseases with chronic inflammation, such as systemic lupus erythematosus. Besides direct influences, inflammation may modify the development of atherosclerosis by other mechanisms. AIMS: To examine paraaoxonase activity and lipid profile in lupus patients. METHODS: Authors entered 37 definitive lupus patients and 30 age- and sex-matched normal controls into the present study. Patients' age was 40.8 +/- 13.9 year, follow-up time 6.7 +/- 6.2 year, disease activity index 2.8 +/- 3.4. Lipid parameters (total cholesterol, LDL-C, HDL-C, Apo-AI and ApoB) were determined by an autoanalyser, paraoxonase and arylesterase activities were measured spectrophotometrically. Phenotypic distribution of the enzyme was determined by dual substrate method. Anti-oxLDL was measured by ELISA method, CRP by automatised immunoassay. Statistical analysis was performed by SPSS program. RESULTS: Despite of long disease duration and low inflammatory activity authors found significantly (p < 0.001) decreased paraoxonase activity (121.9 +/- 65.9 U/mL) (p < 0.001) in lupus as compared to control (188.1 +/- 78.9 U/mL), which correlated with the presence of atherothrombotic complications (p = 0.009). High activity BB phenotype did not occur in lupus. Lipid parameters and arylesterase activity were within normal range in both groups. No significant correlation was found between paraoxonase activity and disease activity index, dose of corticosteroid therapy, CRP and anti-oxLDL level. Arylesterase activity did not differ in lupus and control groups. CONCLUSIONS: Present results suggest that other mechanisms, e.g. antibodies, genetic factors, alteration in the distribution of HDL-subfractions or ensyme abnormalities in HDL remodelling may stand at the background of reduced paraoxonase activity in lupus.

Adult↗

PubMed2005

Identification of a novel deletion in the ABCC6 gene leading to Pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder, characterized by dermal, ocular and cardiovascular lesions. Genetic defects of the ABCC6 (MRP6) transporter are known to cause PXE. OBJECTIVES: The purpose of this study was to identify the genetic background of a PXE patient with a very early onset of the disease and severe systemic involvement. METHODS: Direct sequencing of genomic DNA obtained from peripheral whole blood. RESULTS: Our patient was found to be compound heterozygous with both ABCC6 alleles having genomic deletions. A novel exon 24-25 deletion was identified on one allele, while the frequently observed exon 23-29 deletion was found on the other allele. The novel deletion is 4.68 kb long and was shown to extend from intron 23 to 25. DNA-sequencing of a 2.03 kb fusion fragment revealed the deletion breakpoints within introns 23 and 25 originating in the middle of two Alu-repeats. CONCLUSION: In a patient with severe clinical symptoms, we found two genomic deletions in regions that might be important for function of the ABCC6 transporter. Genomic deletions in ABCC6 may occur more frequently in PXE patients than previously expected and future genetic analysis should focus on these mutations as well.

Adult↗

PubMed2005

Different anticancer effects of fluvastatin on primary hepatocellular tumors and metastases in rats.

Rats (FLF1) were pretreated with 2 and 20 mg/kg/day fluvastatin (Flu), and after 6 weeks, hepatocellular tumor cells were inoculated under the left renal capsule. At different times, growth and pyruvate kinase (PK) activity of the primary tumors and lymph node metastases were determined. Flu had a dose-dependent inhibitory effect on primary and metastatic tumors, and the inhibitory effect on growth and PK activity in metastases were higher than in primary tumors. Finally, Flu had an earlier inhibitory effect on the early appeared PK activity in metastases than in primary tumors.

Animals↗

PubMed2005

[Significance of cytochrome P450 2C9 genotype for the bleeding complications in patients treated with acenocoumarol].

INTRODUCTION: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the comorbidity, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. AIM: The influence of CYP2C9 polymorphism on the effectiveness of the--in Hungary for oral anticoagulation exclusively used--acenocoumarol therapy and on the occurrence of bleeding complications was investigated. METHODS: Genotyping of 421 patients including 183 men and 238 women, (mean age 66.2 +/- 11.8 years) who took acenocoumarol (Syncumar) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. RESULTS: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p < 0.001) lower than in patients with the wild type allele (2.12 +/- 0.96 mg/day and 2.90 +/- 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p < 0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnesis was significantly (p < 0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. CONCLUSIONS: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

Acenocoumarol↗