Hyperlipidemias: Poland

Kłosiewicz-Latoszek L, Cybulska B. · Instytut Zywności i Zywienia, Warszawa, Poland. · Kardiol Pol. · Pubmed #14560351 No free full text.

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Krysiak R, Okopień B, Herman Z. · Department of Clinical Pharmacology, Medical University of Silesia, Medyków 18, PL 40-752 Katowice, Poland. · Drugs. · Pubmed #12921488 No free full text.

Abstract: Recent large clinical trials have demonstrated that HMG-CoA reductase inhibitors, or statins, markedly reduce morbidity and mortality when used in the primary and secondary prevention of cardiovascular disease. It has been established that the benefits of statin therapy in cardiovascular disease can be explained not only by the lipid-lowering potential of statins but also by nonlipid-related mechanisms (so-called "pleiotropic effects") that contribute to the positive effect of statins on the incidence of cardiovascular events.The coagulation and fibrinolytic systems are two separate but reciprocally linked enzyme cascades that regulate the formation and breakdown of fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of atherosclerosis, and that they affect the incidence of atherosclerosis-related clinical events. High plasma levels or activities of fibrinogen, factor VII, factor VIII, von Willebrand factor (vWF), soluble thrombomodulin, tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to cardiovascular disease.Experimental studies and many clinical studies have recently shown that statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease. Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including tissue factor (TF) activity, conversion of prothrombin to thrombin and thrombin activity. In some studies, statins also reduced fibrinogen levels. By altering the levels and activities of tPA and PAI-1, statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with statins and other drugs on haemostasis are rather limited. They suggest that statins combined with fibric acid derivatives, omega-3 fatty acids and 17beta-estradiol are superior to statins alone. The only two clinical studies performed in patients with acute coronary syndromes showed a relatively weak effect of statins on haemostasis in those patients. Although various statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the lipid-lowering effect, statins suppress the synthesis of several important nonsterol isoprenoids derived from the mevalonate pathway, especially farnesyl and geranylgeranyl pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of statins on the mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and PAI-1, and perhaps they also control the generation and activity of thrombin.The beneficial effects of statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The lipid-independent effects of statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.

Chmielewski M, Zdrojewski Z, Rutkowski B. · Klinika Nefrologii, Transplantologii i Chorób Wewnetrznych Akademii Medycznej w Gdańsku. · Przegl Lek. · Pubmed #12516241 No free full text.

Abstract: The great importance of HMGCoA reductase inhibitors (statins) in treatment of hyperlipidemia is well known, and accepted. Numerous multicenter trials have shown the effectiveness of statins in lowering cholesterol concentration, slowing down progression of atherosclerosis, and in decreasing number of cardio-vascular incidents. However, since the discovery of statins experiments have been carried out showing other mechanisms of action of these drugs. Many circumstances expose the antiproliferative, and antiinflammatory influence of HMGCoA reductase inhibitors. This paper presents a review of the studies on these mechanisms with a special emphasis on their nephroprotective role.

Chmielewski M, Zdrojewski Z, Rutkowski B. · Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk. · Ann Transplant. · Pubmed #12416466 links to  free full text

Abstract: Hypercholesterolemia in patients after renal transplantation composes a significant risk factor of cardio-vascular disease, it may also worsen graft survival. Statins are the most potent drugs to lower blood cholesterol. They also posses numerous pleiotropic abilities. The paper presents benefits of the use of statins in patients after renal transplantation, as well as the dangers related to the side effects of these drugs. It underlines that adequate use of statins is worth considering in patients after renal transplantation, taking into account not only their ability to lower cholesterol but also their additional properties positively influencing graft survival.

Cybulska B. · Zakład Zywienia Klinicznego, Instytut Zywności i Zywienia w Warszawie. · Pol Arch Med Wewn. · Pubmed #12412248 No free full text.

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Malczewska B, Chotkowska E, Szwed H, Sadowski Z. · Instytut Kardiologii w Warszawie, Klinika Choroby Wieńcowej. · Pol Arch Med Wewn. · Pubmed #11505704 No free full text.

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Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Pereira JR, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. · Lung Disease Centre, Oncology Department, ul.Szamarzewskiego, Poznań, Poland. · J Clin Oncol. · Pubmed #18398154 No free full text.

Abstract: PURPOSE: This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted. RESULTS: A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm). CONCLUSION: The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.

Undas A, Celinska-Löwenhoff M, Domagala TB, Iwaniec T, Dropinski J, Löwenhoff T, Szczeklik A. · Dept. of Medicine, Jagiellonian University School of Medicine, 8 Skawinska Str., 31-066 Cracow, Poland. · Thromb Haemost. · Pubmed #16113803 No free full text.

Abstract: The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.

Wlodarczyk Z, Vitko S, Salmela K, Czajkowski Z, Margreiter R, Anonymous00149. · Transplantation Unit, Szpital Uniwersytecki CM UMK, Bydgoszcz, Poland. · Transplant Proc. · Pubmed #15919489 No free full text.

Abstract: INTRODUCTION: The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR). METHODS: For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions. RESULTS: Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months. CONCLUSION: Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.

Grodzińska L, Starzyk D, Bieroń K, Goszcz A, Korbut R. · Department of Pharmacology, Department of Clinical Pharmacology, Jagiellonian University School of Medicine, 31-531 Cracow, 16 Grzegorzecka, Poland. · Basic Clin Pharmacol Toxicol. · Pubmed #15910404 No free full text.

Abstract: Improvement of endothelial function caused by statin treatment is not related to lowering of the cholesterol levels but results primarily from statin pleiotropic effects. Accordingly, we designed a pilot study in 10 normocholesterolaemic and 10 hypercholesterolaemic patients with peripheral arterial occlusive disease to investigate potential biological effects of statins in relation to their effects on endothelial function. The patients were treated with simvastatin 40 mg/daily for 3 months. Simvastatin led to significant reduction in total cholesterol and trigliceride levels in normocholesterolaemic and hypercholesterolaemic patients. Elongation of pain-free and total walking distance was observed in both groups studied. Inconsiderable changes in rest ankle brachial index were seen. Flow-mediated dilation increased in normocholesterolaemic group by 153% and in the hypercholesterolaemic group by 180% after 3 months of treatment. Euglobulin clot lysis time was shortened significantly in both groups each time after drug intake. Platelet aggregates ratio was increased in normocholesterolaemic patients by 8.9% and in hypercholesterolaemic patients by 17.6% each time after intake and remained significantly increased during the observation after 1 and 3 months. Simvastatin inhibited platelet aggregation induced by collagen and ADP in both study groups 3 hr after intake, but the platelets of hypercholesterolaemic patients were less sensitive to these aggregatory agents after 3 months of treatment. Simvastatin therapy caused clinical improvement in normocholesterolaemic and hypercholesterolaemic patients with peripheral occlusive disease. It is suggested that this effect is due to the restoration of endothelial function.

Zubelewicz-Szkodzińska B, Szkodziński J, Romanowski W, Błazelonis A, Danikiewicz A, Muc-Wierzgoń M, Szkilnik R. · Department of Internal Medicine, Silesian Medical University, Bytom, Poland. · J Biol Regul Homeost Agents. · Pubmed #15786696 No free full text.

Abstract: Statins, HMG-CoA reductase inhibitors are drugs with a potent lipid-lowering effect. They are also able to inhibit proliferation of smooth muscle cells, T-lymphocytes, to restore endothelial activity and to inhibit inflammatory responses. These effects have been called the pleiotropic effect of statins. Statins have demonstrated contrast to the inflammatory activity of macrophages. The aim of the study was to assess the influence of simvastatin on serum levels of proinflammatory cytokines such as IL-2 and TNFalpha in hypercholesterolemic patients. METHODS: In 58 non-smoking men with total cholesterol (TC) >7.8 mmol/L, LDL-cholesterol>5.5 mmol/L and fasting triglycerides<4.6 mmol/L serum IL-2 and TNFalpha were determined at the beginning of the study, after 3 months diet and after 3 months of simvastatin therapy (20 mg/day). The control group was composed of 10 healthy volunteers with correct lipid values: TC<5.2 mmol/L, LDL-cholesterol <2.3 mmol/L, HDL-cholesterol >1.5 mmol/L and triglycerides<2.3 mmol/L. RESULTS: There were significant reductions in IL-2 concentration after 3 months diet (p=0.0059) and significant (p=0.0003) decrease of IL-2 after 3 months of simvastatin therapy. Meanwhile we observed a significant decrease of TNFalpha concentration after 3 months diet (p=0.0001) and no significant decrease after 3 months of simvastatin therapy.

Okopien B, Krysiak R, Haberka M, Herman ZS. · Department of Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. · J Cardiovasc Pharmacol. · Pubmed #15772519 No free full text.

Abstract: The aim of this study was to compare the effect of 30-day treatment with atorvastatin and fenofibrate on monocyte release and plasma levels of monocyte chemoattractant protein-1 (MCP-1). We studied 52 atherosclerotic patients with primary mixed dyslipidemia and 16 age-, sex-, and weight-matched control subjects with asymptomatic atherosclerosis. Dyslipidemic patients enrolled into the study were randomly divided into three groups, simultaneously treated with atorvastatin (20 mg/d, n = 18), fenofibrate (267 mg/d, n = 16), or placebo (n = 18). Plasma lipid-profile and content of MCP-1, and monocyte release of this chemokine were measured at baseline and after 30 days of therapy. Compared with the control subjects, dyslipidemic patients exhibited the increased plasma levels and monocyte MCP-1 release. Atorvastatin and fenofibrate not only improved lipid profile but also decreased monocyte secretion of this chemokine. Moreover, hypolipemic agents slightly reduced its plasma levels. MCP-1-lowering effect of atorvastatin and fenofibrate did not correlate with the lipid-lowering potential of these agents. Our results suggest that atorvastatin and fenofibrate produce their antiinflammatory effect partially via inhibiting monocyte release of MCP-1. The treatment-induced reduction in its secretion may contribute to the clinical effectiveness of statins and fibrates in the therapy for atherosclerosis and other chronic fibroproliferative diseases.

Okopień B, Krysiak R, Kowalski J, Madej A, Belowski D, Zieliński M, Labuzek K, Herman ZS. · Department of Clinical Pharmacology, Medical University of Silesia, Medyków 18, PL 40-752 Katowice, Poland. · Atherosclerosis. · Pubmed #15380456 No free full text.

Abstract: The aim of the study was to assess the effect of two major groups of hypolipemic drugs, HMG-CoA reductase inhibitors (statins) and PPARalpha activators (fibrates), on the secretory function of T-lymphocytes in patients with primary type II dyslipidemia. Sixty-three patients with type IIa dyslipidemia were randomized to fluvastatin (40 mg daily; n = 33) or simvastatin (20mg daily; n = 30), while 68 type IIb dyslipidemic patients were treated with micronized ciprofibrate (100mg daily; n = 34) or micronized fenofibrate (200mg daily; n = 34). Lipid profile and cytokine (interferon-gamma and interleukin-2) release by phytohemagglutinin-stimulated lymphocytes were determined at the beginning of the study and after 30 and 90 days of treatment. Compared to healthy subjects (n = 59), both type IIa and IIb dyslipidemic patients exhibited higher baseline release of interferon-gamma and interleukin-2. Fluvastatin, simvastatin and, to a less extent, ciprofibrate and fenofibrate inhibited the release of both cytokines, but this effect did not correlate with their lipid-lowering potential. Hypolipemic agents also slightly reduced plasma interleukin-2 levels. Our study suggests that the beneficial effect of hypolipemic drugs involves their inhibitory action on the secretory function of T-lymphocytes. This lipid-independent action is stronger for statins than for fibrates and probably results from their "class" effect. The treatment-induced reduction in the release of both cytokines may contribute to the clinical effectiveness of statins and fibrates in the therapy of atherosclerosis and in the management of organ transplant recipients.

Wysocki J, Belowski D, Kalina M, Kochanski L, Okopien B, Kalina Z. · Department of Internal Diseases and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. · Int J Clin Pharmacol Ther. · Pubmed #15124979 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Metabolic syndrome is characterized by insulin resistance (IR) as well as dyslipidemia, ventral overweight, hypertension and elevated fasting plasma glucose. Since diabetic and prediabetic states are commonly associated with hypertriglyceridemia, fenofibrates have been used in such patients. The aim of this pilot open trial was to study the influence of micronized fenofibrate on insulin resistance and plasma insulin levels in prediabetic and diabetic patients. SUBJECTS: From 114 dyslipidemic patients, 31 with dyslipidemia and insulin resistance were selected to take part in the study. Of the 31 patients, 20 were nondiabetic and only 11 had noninsulin-dependent diabetes mellitus. Eighteen dyslipidemic patients acted as controls. METHODS: Insulin resistance was assessed in a short-term insulin tolerance test. Plasma insulin, antiinsulin antibodies, lipid parameters and the insulin sensitivity index (ISI) were measured at entry and after a 3-month therapy with 200 mg micronized fenofibrate daily. RESULTS: Three-month therapy with micronized fenofibrate resulted in significant ISI increase and was accompanied by a decrease in plasma insulin levels in dyslipidemic patients with metabolic syndrome. ISI also improved in patients with type 2 diabetes mellitus and there was an unexpected increase in plasma insulin levels. Antiinsulin antibodies were unchanged throughout the trial. Reductions in plasma triglycerides and total cholesterol exceeding 50% and 20%, respectively, were observed in patients with metabolic syndrome. These changes were accompanied by an increase in mean levels of plasma high-density lipoprotein (HDL) cholesterol (above 35%). CONCLUSIONS: Micronized fenofibrate is an effective drug in normalizing lipid-lipoprotein levels in patients with metabolic syndrome. After a 3-month fenofibrate therapy, insulin resistance was reduced in a group of patients with dyslipidemia and metabolic syndrome.

Kłosiewicz-Latoszek L, Respondek W, Białobrzeska-Paluszkiewicz J, Grzybowska B, Jakóbisiak-Ostasz B, Stolarska I. · Poradnia Chorób Metabolicznych Instytutu Zywności i Zywienia w Warszawie. · Pol Merkur Lekarski. · Pubmed #14593958 No free full text.

Abstract: In most patients with mixed hyperlipidemia and coronary heart disease (CHD) the treatment targeted both at triglyceride and LDL cholesterol levels is very difficult, when one lipid-lowering drug is used. We performed a prospective study evaluating the efficacy and safety of statins (simvastatin 20 mg, fluvastatin 40 mg, lovastatin 20 mg, atorvastatin 10 mg) and fibrates (fenofibrate 200 mg, ciprofibrate 100 mg) used alone, and then compared with statin-fibrate combinations in 180 patients. Each of three periods of therapy lasted 8-12 weeks. All regimens of statins and fibrates normalised the lipid profile more effectively than monotherapy. Monotherapy with statins lowered total cholesterol by 23.8% in relation to the baseline; compared with 13% for fibrates monotherapy and 34.3% for statins plus fibrates combinations. Triglyceride concentration decreased by 25.5% with statins alone, 34.0% with fibrates alone and 44.5% with combined therapy. LDL cholesterol was reduced by 28.1%, 12.7%, 40.3%, respectively. Statins increased HDL cholesterol by 4%, fibrates by 18% and combined therapy by 15.2%. The target levels for LDL cholesterol were achieved in 3.7% patients on statins therapy, in 1.1% on fibrates and 21.7% on the combined therapy. For total cholesterol the changes were 8.3%, 2.2% and 41.7%, respectively and for triglycerides the were 27.7%, 45% and 66.7%, respectively. The safety of the treatment was assessed by recording adverse events and measuring clinical laboratory parameters. No significant increase in CPK or ALT levels was observed. Only 7 patients had a history of moderate ALT increase (< 3 times) and 27 of CPK increase (< 3 times) when receiving combined statins plus fibrates. CONCLUSIONS: We conclude that combined therapy with statins and fibrates can improve lipid abnormalities in mixed hyperlipidaemia more effective then statins or fibrates monotherapy. The combined therapy was well tolerated and safe.

Malyszko J, Malyszko JS, Hryszko T, Mysliwiec M. · Nephrology and Department of Internal Medicine, Medical University, Bialystok, Poland. · Perit Dial Int. · Pubmed #12938827 links to  free full text

Abstract: BACKGROUND: Patients on continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. Statins show beneficial effects on serum lipids and thrombogenesis in various groups of patients, but prospective studies have so far not been performed on CAPD patients. AIM: To determine the effects of 6 months' treatment with simvastatin on platelet function and some hemostatic parameters, markers of endothelial cell injury, in 14 CAPD patients with hypercholesterolemia. METHODS: Simvastatin was given in a dose of 10 mg at bedtime. Commercially available kits were used for all determinations. RESULTS: Cholesterol and low density lipoprotein fell significantly as early as after 1 month of the therapy (p < 0.001). Platelet aggregation in whole blood and platelet-rich plasma was transiently decreased by simvastatin therapy. The fibrinolytic activity index increased significantly after 6 months of simvastatin administration (p < 0.05), reaching values observed in the control group, whereas euglobulin clot lysis time, which was also significantly shortened after 6 months (p < 0.05), did not reach values obtained in healthy volunteers. Vascular cell adhesion molecule, thrombomodulin, and protein Z decreased significantly after 3 months of the therapy (p < 0.05, p < 0.05, and p < 0.01, respectively), whereas intercellular adhesion molecule decreased after 6 months (p < 0.05). Vascular endothelial growth factor and its receptor, protein Z, total tissue factor pathway inhibitor (TFPI),TFPI/Xa complexes, and thrombin activatable fibrinolysis inhibitor concentration and activity fell significantly after 6 months of treatment with simvastatin (all p < 0.05). Tissue plasminogen activator concentration increased after 1 month (p < 0.01 after 1 month, p < 0.05 after 3 and 6 months), whereas total homocysteine fell after 6 months of simvastatin therapy (p < 0.05).Truncated TFPI decreased significantly as early as after 1 month of therapy (p < 0.05 after 1 month, p < 0.01 after 3 and 6 months). CONCLUSION: Simvastatin is an effective hypolipemic agent in CAPD patients. It favorably affects platelet aggregation and the extrinsic coagulation pathway, improves fibrinolysis, and ameliorates endothelial dysfunction. Simvastatin might reduce the risk of thrombotic complications in CAPD patients.

Wójcicki J, Jaroszynska M, Droździk M, Pawlik A, Gawrońska-Szklarz B, Sterna R. · Department of Experimental and Clinical Pharmacology, Pomeranian Academy of Medicine, Szczecin, Poland. · Biopharm Drug Dispos. · Pubmed #12784321 No free full text.

Abstract: The lipophilic beta-adrenoreceptor antagonist propranolol and hydrophilic atenolol have been studied to define their pharmacokinetic and pharmacodynamic characteristics in obese patients. A total of 43 subjects were allocated into three study groups: (1) healthy, lean, normolipaemic volunteers, (2) obese normolipaemic subjects, and (3) obese patients with lipid disorders. A crossover method with an interval of 2 weeks was applied for oral 80 mg propranolol and oral 100 mg atenolol administration. Heart rate as well as systolic and diastolic blood pressure were recorded during 24 h. At each time-point of measurement blood serum concentration of propranolol and atenolol were evaluated. Pharmacokinetic parameters of the drugs were calculated using a one-compartment open model for extravascular administration. There were no statistically significant differences in blood serum concentrations of propranolol between the studied groups. The concentrations of atenolol were significantly lower in both normolipaemic and hyperlipidaemic obese subjects. A trend towards increase in Vd/F and Cl/F of propranolol in obese patients with hyperlipidaemia were noted. In the case of water-soluble atenolol, the AUC, C(max), Cl/(F x BW) were significantly lower in obese hyperlipidaemic and normolipaemic patients in comparison with lean subjects. The pharmacodynamic effects of propranolol and atenolol in obese and lean subjects were of similar magnitude. The observed differences between obese and non-obese persons were clinically not relevant.

Koter M, Franiak I, Broncel M, Chojnowska-Jezierska J. · Department of Biophysics of Environment Pollution, University of Lodz, 12/16 Banacha St., 90-347 Lodz, Poland. · Can J Physiol Pharmacol. · Pubmed #12774855 No free full text.

Abstract: Since hypercholesterolemia directly modifies the composition of erythrocytes plasma membrane, the influence of statins on erythrocytes has been researched. The beneficial effects of statins on clinical events may involve mechanisms that modify endothelial dysfunction, plaque stability, thrombus formation and inflammatory responses. The aim of the study was to evaluate the hypolipemic efficacy and effects of pravastatin and simvastatin on erythrocyte membrane fluidity and damage of erythrocytes in patients with type 2 hypercholesterolemia in comparison with a control group of healthy subjects. The study involved 53 patients affected by type 2 hypercholesterolemia (mean age, 53.3 +/- 10.3) with initial total serum cholesterol (TC) levels > 250 mg/dL, LDL-cholesterol (LDL-C) levels > 170 mg/dL, and triglycerides (TG) levels < 400 mg/dL. The control group consisted of 30 healthy individuals (mean age 56.9 +/- 6.3). Statins were given for 12 weeks. The dosages for oral administration of simvastatin and pravastatin were 20 mg/day. Laboratory tests were carried out before and after 4 and 12 weeks of the pharmacological treatment. The damage to plasma membrane of erythrocytes was measured on the basis of lipid peroxidation. The fluidity of plasma membrane of erythrocytes was determined by electron paramagnetic resonance (EPR) spectroscopy, using two spin labels: 5-DSA and 16-DSA. The cholesterol level in the membrane of red blood cells was estimated. Simvastatin and pravastatin reduced the total cholesterol concentration and LDL-cholesterol in plasma, as well as the cholesterol concentration in erythrocytes membranes. Hypercholesterolemia induced changes in the basic properties of human erythrocyte plasma membrane, including its fluidity and the intensity of lipid peroxidation. These results indicate that the simvastatin and pravastatin therapy reverses the alteration in the erythrocyte plasma membrane properties.

Kowalski J, Okopień B, Madej A, Zieliński M, Belowski D, Kalina Z, Herman ZS. · Department of Clinical Pharmacology, Medical University of Silesia, 40-752 Katowice, 18 Medyków, Poland. · Eur J Clin Pharmacol. · Pubmed #12756509 No free full text.

Abstract: OBJECTIVE: Monocytes that migrate into the arterial wall participate in the development and, eventually, rupture of the atherosclerotic plaque. The aim of this study was to evaluate the secretion of monocyte chemoattractant protein-1 (MCP-1) by monocytes from hyperlipidemic patients treated with hypolipidemic drugs, namely fenofibrate, simvastatin, or atorvastatin to determine what role is played by these drugs in the development and stabilization of the atherosclerotic plaque. METHODS: Fifty-four hyperlipidemic patients, who did not respond to a low-fat diet, were treated with fenofibrate, simvastatin, or atorvastatin (18 patients in each group) for 1 month. The control group included 18 normolipidemic, healthy, age-matched participants. Ten hyperlipidemic patients were effectively treated with hypolipidemic diet alone for 1 month. This group was compared with a control group of ten healthy subjects. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. Before and after treatment, monocytes were isolated from peripheral blood. After stimulation with lipopolysaccharide (LPS), MCP-1 secretion was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: MCP-1 levels were significantly higher in hyperlipidemic patients than controls: 15.8+/-0.47, 16.7+/-0.23, and 14.9+/-0.45 compared with 12.36+/-0.42 ng/ml. Fenofibrate, atorvastatin, and simvastatin significantly decreased MCP-1 levels from 15.8+/-0.47 to 8.79+/-0.89, from 16.7+/-0.23 to 7.46+/-0.73, and from 14.9+/-0.45 to 10.3+/-0.8 ng/ml, respectively. In the diet-treated group of hyperlipidemic patients, the level of MCP-1 before therapy was significantly higher than in controls (16.89+/-0.31 vs 12.45+/-0.36 ng/ml). The diet therapy caused a significant decrease in levels of MCP-1 to 15.1+/-0.36 ng/ml. There was a correlation between the decreased levels of lipids and the decreased release of MCP-1 in the patients treated with hypolipemic drugs. CONCLUSION: The drug-induced decrease in MCP-1 secretion in hyperlipidemic patients suggests that, apart from acting on lipids, the hypolipidemic drugs studied may directly inhibit the activity of monocytes.

Malyszko J, Malyszko JS, Mysliwiec M. · Department of Nephrology and Internal Medicine, Medical Academy Bialystok, Zurawia 14, 15-540 Bialystok, Poland. · Transpl Int. · Pubmed #12545342 No free full text.

Abstract: Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. Recently, attention has been drawn to the beneficial effects of statins on haemostasis in kidney patients prone to dyslipidaemia and with a high risk of cardiovascular death. The purpose of this study was to assess whether fluvastatin affects TAFI concentration in renal transplant recipients. We evaluated thrombin-antithrombin (TAT) complexes, prothrombin fragments 1+2, thrombomodulin, plasmin-antiplasmin (PAP) complexes, TAFI, P-selectin, and lipoprotein (a), 1, 2, and 3 months before and after fluvastatin treatment and in normolipaemic kidney transplant recipients and healthy volunteers. Cholesterol and LDL fell significantly as soon as 1 month after treatment had begun and remained lowered during the therapy. TAFI and prothrombin fragments 1+2 decreased significantly after 3 months of fluvastatin administration, whereas P-selectin decreased significantly after 2 months and remained significantly lower after 3 months of this therapy. We can conclude that fluvastatin is an effective hypolipaemic agent that favourably affects haemostasis.

Okopien B, Cwalina L, Lebek M, Kowalski J, Zielinski M, Wisniewska-Wanat M, Kalina Z, Herman ZS. · Department of Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. · Int J Clin Pharmacol Ther. · Pubmed #11770837 No free full text.

Abstract: OBJECTIVE: Increased levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) are associated with an increased risk of ischemic coronary disease and its complications. Since atherogenic dyslipidemias are well-known risk factors for coronary heart disease, this study aimed to determine whether Type IIb dyslipidemia, one of the most atherogenic dyslipidemias, is accompanied by increased PAI-1 and fibrinogen synthesis. The additional aim of this study was to evaluate the effect of micronized fibrates on the levels of PAI-1 and fibrinogen in patients with Type IIb dyslipidemia. SUBJECTS: Thirty patients with Type IIb dyslipidemia and 12 age-matched control subjects were studied. Fourteen patients were treated with fenofibrate and 16 were treated with ciprofibrate for 1 month. METHODS: Plasma PAI-1 levels were measured by the ELISA method with Diagnostica Stago kit. The level of fibrinogen was measured by the Clauss method. RESULTS: PAI-1 levels in dyslipidemic patients before treatment differed significantly in both the fenofibrate and ciprofibrate treatment groups (101.18 +/- 36.47 ng/ml, 87.64 +/- 32.06 ng/ml, respectively) from those in the control group (32.32 +/- 7.39 ng/ml, p < 0.001). Compared with the control subjects (2.91 +/- 0.35 g/l), fibrinogen levels before treatment were higher in patients with dyslipidemia treated with ciprofibrate (3.42 +/- 0.59 g/l, NS) and fenofibrate (3.65 +/- 1.10 g/l, p < 0.05). One-month ciprofibrate treatment resulted in an insignificant decrease in PAI-1 levels (76.28 21.60 ng/ml, NS) and in a significant decrease in fibrinogen levels (2.73 +/- 0.40 g/l, p < 0.01). After one-month fenofibrate treatment PAI-1 levels (81.22 +/- 25.01 ng/ml, p < 0.01) and fibrinogen levels (2.95 0.72 g/l, p < 0.01) decreased significantly. CONCLUSION: Type IIb dyslipidemic patients have increased levels of PAI-1 and fibrinogen. Micronized fibrates decreased not only lipid levels but also the levels of fibrinogen and PAI-1 in these patients.

Okopień B, Hyper M, Kowalski J, Belowski D, Madej A, Zieliński M, Tokarz D, Kalina Z, Herman ZS. · Department of Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. · Res Commun Mol Pathol Pharmacol. · Pubmed #11758653 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: The atherosclerotic arterial injuries lead to many life threatening vascular incidents. It has been well documented that inflammatory processes play an important role in atherogenesis. Intensive studies are undertaken to find a serum marker of inflammatory reaction correlated with arterial injuries. METHODS: In our study we measured the level of interleukin-6 (IL-6) in patients with dyslipidemia IIa and IIb biochemically confirmed. Control estimations were done in age-matched group. Arterial injuries were evaluated as a thickening of complex intima-media in common carotid arteries by means of Doppler ultrasonography. RESULTS: Levels of IL-6 were significantly higher in both groups of patients with dyslipidemia as compared with the healthy control persons (IIa vs control p<0.001, IIb vs control p<0.001). The plasma level of IL-6 is significantly correlated to intima-media complex thickness (r=0.68, p<0.0001). CONCLUSION: We conclude that increase of serum concentration of IL-6 may be related to arterial wall injuries in the course of the most atherogenic lipid disorders.

Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. · Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland. · Circulation. · Pubmed #11342472 links to  free full text

Abstract: BACKGROUND: The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury. METHODS AND RESULTS: Tissue factor-initiated coagulation was assessed in blood samples collected every 30 seconds from bleeding-time wounds of 17 patients who had advanced coronary artery disease and total cholesterol levels of 224.6+/-11.8 mg/dL (mean+/-SEM). Quantitative Western blotting for time courses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatment (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2+/-2.1%; P=0.004), formation of alpha-thrombin B-chain (27.4+/-1.8%; P=0.001), generation of factor Va heavy chain (29.7+/-3.1%; P=0.007) and factor Va light chain (18.9+/-1.2%; P=0.02), factor XIII activation (19.8+/-1.3%; P=0.001), and fibrinogen conversion to fibrin (72.2+/-3%; P=0.002). Posttreatment fibrinopeptides A and B concentrations, determined by using high-performance liquid chromatography, were reduced within the last 30 seconds of bleeding. The 30-kDa fragment of the factor Va heavy chain (residues 307 to 506), produced by activated protein C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 643) were released more rapidly after simvastatin treatment. The antithrombotic actions of simvastatin showed no relationship to its cholesterol-lowering action. CONCLUSIONS: Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.

Zaborska B, Kłoś J, Sikora-Frac M, Cybulska B, Ceremuzyński L. · Klinika Kardiologii Centrum Medycznego Kształcenia Podyplomowego w Warszawie. · Pol Arch Med Wewn. · Pubmed #11303327 No free full text.

Abstract: Elevated serum level of triglycerides is a classic indication for fibrates. Micronized fenofibrate is hypolipemic drug with proven safety and efficacy in a view of triglycerides reduction, but according to few papers published so far on the subject is also effective in decreasing elevated total and LDL cholesterol. The aim of study was to confirm results obtained from these few previous studies. Forty seven persons with lipid disturbances (25 males and 22 females, age range 34-71 yrs. mean 48.0) entered the study. Thirty two patients had a history myocardial infarction and fifteen persons without clinical symptoms of heart diseases. All of them were treated with micronized fenofibrate 200 mg daily. Micronized fenofibrate decreased serum concentration of total cholesterol by 13.4% (p < 0.01), LDL cholesterol by 21.2% (p < 0.001) and triglycerides by 39.5% (p < 0.001) in whole group of patients. Most beneficial effects were obtained in persons with mixed hyperlipidemia: reduction of total cholesterol, triglycerides and LDL cholesterol serum levels was 22.4% (p < 0.01), 52.5% (p < 0.0001), 25.4% (p < 0.01), respectively. In individuals with hypercholesterolemia a reduction of total cholesterol by 11% (p < 0.05) and LDL cholesterol by 15.4% (p < 0.05) was observed. In the group with hypertriglyceridemia or mixed hyperlipidemia reduction of serum triglycerides concentration by 33.5% (p < 0.05) was achieved. No significant change in serum HDL cholesterol level in any group was observed. The treatment with micronized fenofibrate was well tolerated. Our study shows that this drug is safe and seems to be effective in some cases with increased serum total and LDL cholesterol level as well.

Idzior-Walus B, Sieradzki J, Rostworowski W, Zdzienicka A, Kawalec E, Wójcik J, Zarnecki A, Blane G. · Collegium Medicum Jagiellonian University, Krakow, Poland, Laboratoires Fournier, Daix, France. · Eur J Clin Invest. · Pubmed #11029601 No free full text.

Abstract: BACKGROUND: This study investigated the effects of comicronised fenofibrate in patients with dyslipidemia and polymetabolic syndrome X. DESIGN: After a 6-week dietary run-in phase, 37 male patients eligible on lipid criteria entered a 12-week treatment phase consisting of diet plus one capsule daily containing 200 mg of comicronised fenofibrate (Lipanthyl(R)). RESULTS: A significant reduction in plasma concentrations of total cholesterol, LDL cholesterol and triglyceride was observed after 4, 8 and 12 weeks of treatment with fenofibrate. The improvement in the atherogenic index LDL/HDL cholesterol from a pretreatment 3.8 to 3.0 after treatment was highly statistically significant and may be judged as satisfactory. Significant changes were also observed in haemostatic factors (fibrinogen reduced by 19%, factor VII activity reduced by 18%). Fasting serum insulin levels and insulin response (area under the curve) after oral glucose load were significantly reduced by 26.8% and 18.7%, respectively, indicating an improvement of insulin sensitivity. Systolic and diastolic blood pressure were significantly reduced. Uric acid was significantly reduced by 21.6%. CONCLUSION: These favourable effects of comicronised fenofibrate both on lipid and non lipid parameters, including insulin sensitivity, may confer to this product a particular interest in the treatment of patients with polymetabolic syndrome X.