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Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia

C U R RE N T M E D IC A L RE S E AR CH AN D O P IN I O N ® 1 0 . 1 1 8 5 /0 3 0 0 7 9 9 0 2 1 2 5 0 0 0 3 7 2
V O L . 1 8 , N O . 3 , 2 0 0 2 , 1 2 5 – 1 2 8
Mixed HyperlipidemiaGeorge Liamis1, Anna Kakafika1, Eleni Bairaktari2, George Miltiadous1, Vasilios Tsimihodimos1, John Goudevenos1, Apostolos Achimastos3and Moses Elisaf11Department of Internal Medicine, University of Ioannina, Greece2Laboratory of Biochemistry, Medical School, University of Ioannina, Greece3Third Department of Medicine, University of Athens, Greece Address for correspondence: Prof. Moses Elisaf, Professor of Medicine, Department of Internal Medicine,
University of Ioannina, 451 10 Ioannina, Greece. Tel. 06510–097509; Fax 06510–097016

Key words: Atorvastatin – Fibrates – Combination therapy – Mixed hyperlipidemia
Combined statin and fibrate therapy is often The administration of the fibrates resulted in imperative for the improvement of the serum cholesterol levels, as wel as in triglycerides , hyperlipidemia . However, the potential risk of and an increase in HDL-cholesterol levels. The myopathy has limited the widespread use of addition of atorvastat in (5 mg/day) resulted in a such therapy. Preferably this treatment should further decrease in total and LDL-cholestero l levels. Consequently, the hypolipide mic therapy hypolipide mic drugs. Thus, we undertook a study target was achieved in most of the patients.
Combination therapy was wel tolerated and no combination therapy with fibrates and smal significant increases in serum liver and muscle doses of atorvastat in. Twenty-two patients with mixed hyperlipide mia were started on a fibrate We conclude that the careful administration of regimen (micronised fenofibrate 200 mg/day or small doses of atorvastat in in patients with ciprofibrate 100 mg/day). Because after 12 weeks of therapy the fibrate failed to normalise associated with a significant amelioration of lipid atorvastat in (5 mg/day) were added for a further12 weeks.
Introduction
and/or rhabdomyolysis, has been reported after suchcombination regimens3,4. Ideally, combination Mixed hyperlipidemia with elevations of both LDL- therapy requires the careful administration of low cholesterol and triglycerides is commonly optimally tolerable doses of hypolipidemic drugs2.
encountered in patients with premature coronary The most potent triglyceride-lowering agents heart disease (CHD)1. Patients with mixed lipid available – fibrates – are the drugs of choice in disorders are often refractory to lipid-lowering patients with raised triglycerides5,6. However, LDL- monotherapy and warrant a more aggressive cholesterol levels often remain inappropriately high treatment through combination regimens2. However, after their administration7–9. There are limited data an increased risk of side-effects, mainly myopathy concerning the combination of atorvastatin with fibrates. In all these studies, conventional doses of atorvastatin (10–40 mg/day) were used8,10. We Concentrations of total cholesterol and triglycerides undertook the present study to assess the safety and were determined enzymatically on the Olympus efficacy of combination treatment with fibrates and AU600 clinical chemistry analyser (Olympus small doses of atorvastatin (5 mg/day) in patients Diagnostica, Hamburg, Germany). High-density lipoprotein (HDL)-cholesterol was determined inthe supernatant, after precipitation of the ApoB-containing lipoproteins with dextran sulphate–Mg2+(Sigma Diagnostics, St. Louis, Mo, USA). Low- Materials and Methods
density lipoprotein (LDL)-cholesterol was calculatedusing the Friedewald formula. Apolipoproteins A1, B Twenty-two patients with primary mixed hyper- and E were measured with a Behring Nephelometer lipidemia, consisting of elevated total and LDL- BN100, and reagents (antibodies and calibrators) cholesterol levels {> 240 mg/dl (6.22 mmol/l) and from Dade Behring Holding GmbH (Liederbach, > 160 mg/dl (4.14 mmol/l), respectively} and triglycerides {> 250 mg/dl (2.82 mmol/l)} after a 3- calibrated according to the International Federation month hypolipidemic diet, were included in our of Clinical Chemistry (IFCC) standards.
study. Patients with diabetes mellitus {fasting glucose Lipoprotein(a) {Lp(a)} levels were determined by > 126 mg/dl (6.93 mmol/l)}, renal failure {serum the enzyme immunoassay Macra Lp(a) (Trinity creatine > 1.6 mg/dl (142 m mol/l)}, liver disease Biotech, Jamestown, NY, USA). The lower limit of (increased serum liver enzymes more than twice the detectability was 0.8 mg/dl (0.008 g/l). Liver and muscle enzymes were measured using conventional {TSH > 4.8 m U/ml (4.8 mU/l)}, increased levels of creatinine kinase (CK) (more than twice the uppernormal limits), as well as patients on drugs that couldaffect serum lipid parameters, were excluded.
triglycerides, patients were started on a fibrate(micronised fenofibrate 200 mg/day, n = 11 or The administration of fibrates was followed by a ciprofibrate 100 mg/day, n = 11). As after 12 weeks small, though significant, decrease in total and LDL- of therapy the fibrate failed to achieve the desired cholesterol levels (11.6% and 8%, respectively), a considerable decrease in serum triglycerides (43%), (3.37 mmol/l)}, small doses of atorvastatin and a marked increase in HDL-cholesterol levels (5 mg/day) were added for a further 12 weeks.
(19.4%). Furthermore, a significant decrease in Fibrate was given in the morning, while atorvastatin serum alkaline phosphatase was evident, though the was given in the evening. Before treatment, as well as other liver or muscle enzymes were unchanged. No after 12 and 24 weeks of therapy, blood samples were significant differences in the changes of serum lipid obtained after a 14 h overnight fast for the parameters were observed between the two fibrates determination of the serum lipid profile, as well as used (fenofibrate and ciprofibrate).
liver and muscle enzymes. Hepatic toxicity was The addition of atorvastatin (5 mg/day) resulted in defined as the marked elevation of the transaminase a significant further decrease in total cholesterol (by levels to more than three times the upper limit of 21.5%) and LDL-cholesterol (by 21.9%). A small normal. Myopathy was defined as symptomatic decrease in serum triglycerides was also observed (by myositis associated with a CK elevation greater than ten times the upper limits of normal.
Fifteen out of the 22 patients achieved the desired LDL-cholesterol levels {< 130 mg/dl (3.37mmol/l)} according to the recently published NCEP ATP IIIguidelines11.
Descriptive statistics were performed and all data Combination therapy was well tolerated. No were expressed as mean ± standard deviation (SD).
episodes of myopathy or profound aminotransferases Treatment effects were tested with a paired t-test for elevation of more than three times the upper limit of normally distributed data or with the Wilcoxon normal occurred. Furthermore, small insignificant signed-rank test for non-normally distributed data, increases in the activity of muscle and liver enzymes which included serum triglycerides, alanine was observed. The results are summarised in Table 1.
aminotransferase (SGPT), aspartate aminotrans- Unlike ciprofibrate administration, fenofibrate ferase (SGOT), gamma-glutamyl transpeptidase administration caused a significant decrease in serum uric acid levels {6.4 ± 1.6 mg/dl vs. 4.5 ± 1.2 mg/dl 126 Combined Treatment with Fibrates and Smal Doses of Atorvastatin in Patients with Mixed Hyperlipidemia Liamis et al.
Table 1. Effect of hypolipdemic drugs on the serum lipid profile and serum liver and muscle enzymes
g -GT (IU/l) {reference range 10–52 IU/l} Alkaline phosphatase (IU/l) {reference range 30–125 IU/l} CPK (IU/l) {reference range 90–190 IU/l} 1p < 0.001 compared to values obtained after fibrate administration 2p < 0.05, 3p < 0.01, 4p < 0.001 compared to baseline values To convert to mmol/l, multiply by 0.0259 for cholesterol and by 0.0113 for triglycerides To convert to m kat/l, multiply by 0.01667 for AST, ALT, g -GT, alkaline phosphatase and CPK (381 ± 95.2 m mol/l vs. 267.8 ± 71.4 m mol/l), p < combination regimens reported in the literature2.
0.005}. The addition of atorvastatin was followed by The small further decrease in serum triglycerides a small insignificant decrease in serum uric acid levels after atorvastatin administration could be related to {5.3 ± 1.3 mg/dl vs. 5.0 ± 0.9 mg/dl (315.3 ± the low dose of the drug used, since the triglyceride- 77.3 m mol/l vs. 297.5 ± 53.5 m mol/l)}. Fibrate lowering effect of statins is dose dependent24.
administration resulted in a significant increase in However, it could also be ascribed to the co- serum creatinine levels {1 ± 0.18 mg/dl vs. 1.2 ± administration of fibrates, which may limit the ability 0.12 mg/dl (88.4 ± 15.9 m mol/l vs. 106.1 ± of atorvastatin to further affect the metabolism of 10.6 m mol/l), p = 0.05}, while no significant triglyceride-rich lipoproteins. Further studies are differences in the changes of serum creatinine were needed to clarify this issue better. It is worth observed between the two fibrates used. No mentioning that low-dose combination therapy in significant changes in serum creatinine levels were patients with normal renal function, who are not found after atorvastatin initiation.
given medications that could increase the circulatinglevels of either the statin or the fibrate, is inagreement with the recent NCEP ATP IIIguidelines11.
Discussion
The significant decrease in serum uric acid levels noticed after fenofibrate administration has been Our study showed for the first time that even small previously documented and has been related to a doses of atorvastatin (5 mg/day) could significantly considerable increase in fractional urate excretion25,26.
improved the serum lipid profile of patients with It has been suggested that conventional doses of mixed hyperlipidemia receiving fibrates. The absence atorvastatin (10–80 mg/day) can significantly of toxicity, possibly related to the low statin dose, decrease serum uric acid levels27. In our study, even permits the use of this combination therapy in though there was a tendency towards the lowering of patients at high risk of atherosclerotic complications.
serum uric acid levels, this decrease was not Even though a number of studies have demonstrated significant, possibly due to the low dose of the drug that statin–fibrate regimens markedly ameliorate used. An increase in serum creatinine levels, which mixed lipid disorders2,12–23, atorvastatin was has been recently reported after the administration infrequently used in these combinations, and when of fibrates, was also evident in our study28,29. We have used, higher doses (20–40 mg) of this statin were recently found that atorvastatin can decrease serum administered8,10. In the present study, the low dose creatinine levels only in patients who also exhibit a combination therapy conferred lipid-altering benefits significant decrease in serum uric acid levels, which of a similar magnitude with those reported in the literature after combination therapy with conventional doses of statins and fibrates12–23. Thus, dyslipidemia, who do not achieve target level with monotherapy, may benefit from combination approximately 30%, a pronounced increase in HDL- regimens. In this setting, the careful administration cholesterol by 22% was observed; the latter increase of small doses of atorvastatin, in patients with mixed is in turn superior to that observed after most of the dyslipidemia receiving fibrates, is associated with a Combined Treatment with Fibrates and Smal Doses of Atorvastatin in Patients with Mixed Hyperlipidemia Liamis et al. 127 significant amelioration of lipid abnormalities. This 13. Athyros VG, Papageorgiou AA, Hatzikonstantinou HA, Didangelos TP, Carina MV, Kranitsaw DF, Kontopoulos AG.
low-dose combination therapy is possibly associated Safety and efficacy of long-term statin–fibrate combinations in with improved safety and tolerability profile in patients with refractory familial combined hyperlipidemia. Am comparison with escalation doses of monotherapy 14. Leitersdorf E, Muratti EN, Eliav O, Meiner V, Eisenberg S, with each compound. However, such treatment Dann EJ, Sehayek E, Peters TK, Stein Y. Efficacy and safety of should be administered with appropriate caution and a combination fluvastatin–bezafibrate treatment for familialhypercholesterolemia: comparative analysis with a combined clinical and laboratory monitoring. Even fluvastatin–cholestyramine combination. Am J Med though combination drug treatment was well 15. Eliav O, Schurr D, Pfister P, Freidlander Y, Leitersdorf E. High- tolerated in our study with either of the fibrates dose fluvastatin and bezafibrate combination treatment for used, micronized fenofibrate may be preferable since heterozygous familial hypercholesterolemia. Am J Cardiol1995;76:76A-79A its half-life is shorter (20–22 h) than ciprofibrate 16. Smit JW, Jansen GH, de Bruin TW, Erkelens DW. Treatment (80 h). This is of special importance taking into of combined hyperlipidemia with fluvastatin and gemfibrozil, account the increased half-life of atorvastatin alone or in combination, does not induce muscle damage. AmJ Cardiol 1995;76:126A-128A 17. Farnier M, Dejager S for the French Fluvastatin Study Group.
Effect of combined fluvastatin–fenofibrate therapy comparedwith fenofibrate monotherapy in severe primaryhypercholesterolemia. Am J Cardiol 2000;85:53-7 18. Pauciullo P, Brognino C, Paoletti R, Mariani M, Mancini M.
References
Efficacy and safety of a combination of fluvastatin andbezafibrate in patients with mixed hyperlipidaemia (FACT 1. Pajukanta P, Porkka KV Genetics of familial combined hyper- lipidemia. Curr Atheroscler Rep 1999;1:79-86 19. Spieker LE, Noll G, Hannak M, Luscher TF. Efficacy and 2. Jacobson TA. Combination lipid-altering therapy: an emerging tolerability of fluvastatin and bezafibrate in patients with treatment paradigm for the 21st century. Curr Atheroscler Rep hyperlipidemia and persistently high triglyceride levels. J 3. Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to 20. Tuzgol S, Wang LD, Kastelein JJ. Tolerability and efficacy of combination therapy with cerivastatin and gemfibrozil. Am J gemfibrozil and simvastatin combination therapy in 263 dyslipidemic patients attending a lipid clinic. 66th Congress of the European Atherosclerosis Society 1996;Florence, Italy 4. Bays HE, Dujovne CA. Drug interactions of lipid-altering 21. Ellen RL, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined 5. Fruchart JC, Staels B, Duriez P. The role of fibric acids in ath- hyperlipidemia. Am J Cardiol 1998;81:60B-65B erosclerosis. Curr Atheroscler Rep 2001; 3:83-92 22. Iliadis EA, Rosenson RS. Long-term safety of 6. Milionis HJ, Elisaf MS, Mikhailidis DP. Treatment of dyslipi- pravastatin–gemfibrozil therapy in mixed hyperlipidemia. Clin daemias in patients with established vascular disease: a revival of the fibrates. Curr Med Res Opin 2000;16:21-32 23. Gavish D, Leibovitz E, Shapira I, Rubinstein A. Bezafibrate and 7. Fruchart JC, Brewer HB Jr, Leitersdorf E for the Fibrate simvastatin combination therapy for diabetic dyslipidaemia: Consensus Group. Consensus for the use of fibrates in the efficacy and safety. J Intern Med 2000;247:563-9 treatment of dyslipoproteinemia and coronary heart disease.
24. Bakker-Arkema RG, Davidson MH, Goldstein RJ, Diagnon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, 8. Kiortsis DN, Milionis H, Bairaktari E, Elisaf MS. Efficacy of Shurzinske LJ, Black DM. Efficacy and safety of a new HMG- combination of atorvastatin and micronised fenofibrate in the CoA reductase inhibitor in patients with hypertriglyceridemia.
treatment of severe mixed hyperlipidemia. Eur J Clin 25. Elisaf M, Tsimichodimos V, Bairaktari E, Siamopoulos KC.
9. Caslake MJ, Packard CJ, Gaw A, Murray E, Griffin BA, Effect of micronized fenofibrate and losartan combination on Vallance BD, Shepherd J. Fenofibrate and LDL metabolic het- uric acid metabolism in hypertensive patients with erogeneity in hypercholesterolemia. Arterioscler Thromb hyperuricemia. J Cardiovasc Pharmacol 1999;34:60-63 26. Achimastos A, Liberopoulos E, Nikas S, Bairaktari E, 10. Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane Miltiadous G, Tsimihodimos V, Elisaf M. The effects of the AM, Kersten ME, Joyo DM, Ganter SE. Long-term safety and addition of micronized fenofibrate on uric acid metabolism in patients receiving indapamide. Curr Med Res Opin efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am 27. Kakafika A, Tsimihodimos V, Elisaf M. Effect of atorvastatin on serum uric acid levels. Atherosclerosis 2001;158:255 11. Executive Summary of the Third Report of the National 28. Tsimihodimos V, Kakafika A, Elisaf M. Fibrate treatment can Cholesterol Education Program (NCEP) Expert Panel on increase serum creatinine levels. Nephrol Dial Transplant Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 29. Tsimihodimos V, Miltiadous G, Bairaktari E, Elisaf M. Possible mechanisms of the fibrate-induced increase in serum 12. Papadakis JA, Ganotakis ES, Jagroop IA, Winder AF, Mikhailidis DP. Statin + fibrate combination therapy 30. Kakafika A, Liamis G, Elisaf M, Mikhailidis D. Effect of fluvastatin with bezafibrate or ciprofibrate in high risk patients atorvastatin on serum creatinine levels. Curr Med Res Opin with vascular disease. Int J Cardiol 1999;69:237-44 128 Combined Treatment with Fibrates and Smal Doses of Atorvastatin in Patients with Mixed Hyperlipidemia Liamis et al.

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