Статья
Биохимическим, структурный и клиническим анализ плейотропных эффектов статинов
Предпринята попытка на основании анализа результатов клинических и экспериментальных исследований выстроить доказательную линию плейотропного действия статинов, которое подразумевает включение нескольких механизмов реализации их активности. Понятие плейотропности предполагает: (а) влияние препарата на несколько мишеней, запускающее различные биохимические процессы в организме; (б) дивергенцию биохимических и патофизиологических процессов, исходящих от основной (единственной) мишени. Описаны патохимические механизмы эффектов статинов, как ингибиторов фермента редуктазы коэнзима А, с обоснованием того, что терапевтическое и побочное действия статинов не обязательно связаны с их влиянием на метаболизм липидов и снижением уровня холестерина.
1. ВНОК. Национальные клинические рекомендации “Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза”. Москва 2009; 231-50.
2. Gaspardone A, Area M. Atorvastatin: its clinical role in cerebrovascular prevention. Drugs 2007; 67 (Suppl 1): 55-62.
3. Scandinavian Simvastatin Survival Study Group.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.
4. Jacobson TA, Wertz DA, Hoy T, et al. Comparison of cardiovascular event rates in patients without cardiovascular disease in whom atorvastatin or simvastatin was newly initiated. Mayo Clin Proc 2008; 83(12): 1316-25.
5. Кухарчук В.В., Чазова И.Е. Статины при метаболическом синдроме и АГ по результатам программы “РОЗА” — Розувастатин у пациентов с артериальной гипертонией. Сист гиперт 2008; 1: 50-2.
6. Ballantyne CM, Raichlen JS, Cain VA. Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial. JACC 2008; 52(8): 626-32.
7. Кухарчук В.В., Бубнова М.Г., Кательницкая Л.И и др. Эффективность и безопасность симвастатина у пациентов с гиперхолестеринемией (результаты многоцентрового кли¬нического исследования). Кардиология 2003; 5: 42-7.
8. Соболева Г.Н., Ерпылова Е.А., Рябыкина Г.В. и др. Влияние симвастатина на показатели липидного обмена и толерантности к физической нагрузке у больных кардиальным синдромом. Атмосфера. Кардиология 2005; 3: 44-6.
9. Беляева О.Д., Волкова Е.В, Хромова Н.В., и др. Оценка эффективности терапии симвастолом у больных ишемичес¬кой болезнью сердца. Артер гиперт 2005; 11(2): ХХ.
10. Sola S, Mir M, Аtorvastatin improves left ventricular systolic func¬tion and serum markem: of inflammation in nonischemic heart failure. JA^ 2006; 47: 332-7.
11. Pellegrini CN, Vittinghoff E, Lin F, et al. Statin use is associated with lower risk of atrial fibrillation in women with coronary disease: the HERS trial. Program and abstracts from Heart Rhythm 2008: the Heart Rhythm Society (HRS) Annual Scientific Sessions; 2008, San Francisco, California.
12. Gissi-HF Investigators, Tavazzi L, Maggioni AP, et al. Collaborators (81). Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): randomised, double-blind, placebo-controlled trial. Lancet 2008; 372(9645): 1231-9.
13. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248-61.
14. Lowyck I, Fevery J. Statins in hepatobiliary diseases: effects, indications and risks. Acta Gastroenterol Belg 2007; 70(4): 381-8.
15. Paraskevas KI. Statin treatment for rheumatoid arthritis: a promising novel indication. Clin Rheumatol 2008; 27(3): 281-7.
16. Ten Cate R, Nibbering PH, Bredius RGM. Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins. Rheumatology 2004; 43: 934-5.
17. Okamoto H, Koizumi K, Kamitsuji S, et al. Beneficial action of statins in patients with rheumatoid arthritis in a large observational cohort. J Rheumatol 2007; 34(5): 964-8.
18. Haag MD, Hofman A, Koudstaal PJ, et al. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 2009; 80(1): 13-7.
19. Sparks DL, Lopez J, Connor D, et al. A position paper: based on observational data indicating an increased rate of altered blood chemistry requiring withdrawal from the Alzheimer’s disease cholesterol-lowering treatment trial (ADCLT). J Mol Neurosci 2003; 20: 407-10.
20. Davignon J, Leiter LA. Ongoing Clinical Trials of the Pleiotropic Effects of Statins. Vasc Health Risk Manag 2005; 1(1): 29-40.
21. Carlsson CM, Gleason CE, Hess TM, et al. Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimer disease. J Alzheim Dis 2008; 13(2): 187-97.
22. Zandi PP, Sparks DL, Khachaturian AS, et al. Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry 2005; 62(2): 217-24.
23. Arvanitakis Z, Schneider JA, Wilson RS, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 2008; 70(19 Pt 2): 1795-802.
24. "Vbllmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607-8.
25. Colman E, Szarfman A, Wyeth J, et al. An evaluation of a date minig signal for amyotrophic lateral sclerosis and statins detected in FDA’s spontaneous adverse event reporting system. Pharmacoepidemiol Drug Saf 2008; 17(11): 1068-76.
26. Lupattelli G, Scarponi AM, Vaudo G, et al. Simvastatin increas¬es bone mineral density in hypercholesterolemic postmenopausal women. Metabolism 2004; 53: 744-8.
27. Uzzan B, Cohen R, Nicolas P, et al. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone 2007; 40(60): 1581-7.
28. Bone HG, Kiel DP, Lindsay RS, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab 2007; 92(12): 4671-7.
29. Staal A, Frith JC, French MH, et al. The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG- CoA reductase activity. J Bone Miner Res 2003; 18(1): 88-96.
30. Ahn KS, Sethi G, Chaturvedi MM, Aggarwal BB. Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway. Int J Cancer 2008; 123(8): 1733-40.
31. Vughan CJ, Murphy MB, Buckley BM, et al. Statins do more than just lower cholesterol. Lancet 1996; 348: 1079-82.
32. Simes J, Furberg CD, Braunwald E, et al. Effects of pravastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels. Eur Heart J 2002; 23: 207-15.
33. Forst T, Wilhelm B, Pfutzner A, et al. Investigation ofthe vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk. Diab Vasc Dis Res 2008; 5(4): 298-303.
34. Singh U, Devaraj S, Jialal I, Siegel D. Comparison effect of atorvas¬tatin (10 versus 80 mg) on biomarkers of inflammation and oxidative stress in subjects with metabolic syndrome. Am J Cardiol 2008; 102(3): 321-5.
35. Ridker PM, Danielson E, Fonseca FA. Rosuvastatin to prevent vas¬cular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21): 2195-207.
36. Diomede L, Albani D, Sottocorno M, et al. In vivo anti-inflamma¬tory effect of statins is mediated by nonsterol mevalonate products. Arterioscler Thromb Vasc Biol 2001; 21: 1327-32.
37. Inoue I, Goto S, Mizotani K, et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: Reduction of mRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phlox by regulation of peroxisome proliferator-activated receptor (PPAR- alpha) in primary endothelial cells. Life Sci 2000; 67: 863-76.
38. Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000; 80: 1095¬100.
39. Yoshida M, Sawada T, Ishii H, et al. HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiologi¬cal flow conditions in vitro. Arterioscler Thromb Vsc Biol 2001; 21: 1165-71.
40. Hu YZ, Dong YG, Zhai YF, et al. Effects of simvastatin on homo¬cysteine-induced endothelial dysfunction and inflammatory response. Zhonghua Yi Xue Za Zhi 2006; 86(32): 2297-300.
41. Liang YJ, Shyu KG, Wang BW Lai LP. Simvastatin inhibits C-reactive protein-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products. Cardiology 2008; 110(3): 182-90.
42. Zhou Q, Zhou Y, Kummerow FA. High-dose lovastatin decreased basal prostacyclin production in cultured endothelial cells. Prostaglandins Other Lipid Mediat 2008.
43. Park SY, Lee JS, Ko YJ, et al. Inhibitory effect of simvastatin on the TNF-alpha- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgera- nyl isoprenoid-dependent ROS generation. Arch Pharm Res 2008; 31(2): 195-204.
44. Marino F, Guasti L, Cosentino M, et al. Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high- risk subjects: changes after treatment with simvastatin. J Cardiovasc Pharmacol 2007; 49(5): 299-305.
45. Marino F, Guasti L, Cosentino M, et al. Simvastatin treatment in subjects at high cardiovascular risk modulates AT1R expression on circulating monocytes and T lymphocytes. J Hypertens 2008; 26(6): 147-55.
46. Szarszoi O, Maly J, Ostadal P, et al. Effect of acute and chronic simvastatin treatment on post-ischemic contractile dysfunction in isolated rat heart. Physiol Res 2008; 57(5): 793-6.
47. Atar S, Ye Y, Lin Y, et al. Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2. Am J Physiol Heart Circ Physiol 2006; 290: H1960-8.
48. Von Zee CL, Richards MP, Bu P, et al. Lovastatin Increases RhoA and RhoB Protein Accumulation in Cultured Human. Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci 2009
49. Xu RX, Chen X, Hu SS, et al. Lovastatin protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis through activation of PI3K/Akt and ERK1/2 signal¬ing pathways. Zhonghua Xin Xue Guan Bing Za Zhi 2008; 36(8): 685-90.
50. Doggrell SA. Statins in the 21st century: end of simple history. Expert Opin Invest Drugs. 2001;10(9): 1755-66.
51. Tobert JA, Hitzenberger G; Kukovetz WR, et al. Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase. Atherosclerosis 1982; 41: 61-5.
52. Pfohl M, Naoumova RP, Kim KD, et al. Use of cholesterol precursors to assess changes in cholesterol synthesis under non¬steady-state conditions. Eur J Clin Invest 1998; 28: 491-6.
53. McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87(5A): 28B-32.
54. Corsin A. The use of statins in optimising reduction of cardiovas¬cular focus on fluvastatin. Int J Clin Pract 2004; 58: 494-503.
55. Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke 2004; 35(11 Suppl 1): 2708-11.
56. Yokota K, Miyazaki T, Hirano M, et al. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblastlike synoviocytes from patients with rheumatoid arthritis. J Rheumatol 2006; 33(3): 463-7.
57. Xu H, Liu P, Liang L, et al. RhoA-mediated, tumor necrosis factor alpha-induced activation of NF-kappaB in rheumatoid synoviocytes: inhibitory effect of simvastatin. Arthritis Rheum 2006; 54(11): 3441-51.
58. Lazzerini PE, Lorenzini S, Selvi E, et al. Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1beta-stimulated synoviocytes from rheumatoid arthritis patients. Clin Exp Rheumatol 2007; 25(5): 696-700.
59. Thelen KM, Laaksonen R, Piv H, et al. High-dose statin treatment does not alter plasma marker for brain cholesterol metabolism in patients with moderately elevated plasma chole¬sterol levels. J Clin Pharmacol 2006; 46(7): 812-6.
60. Elkind MS, Sacco RL, MacArthur RB, et al. The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke. Int J Stroke 2008; 3(3): 210-8.
61. Sugawara T, Ayer R, Jadhav V, et al. Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase. J Neurosci Res 2008; 88(16): 3635-43.
62. Maier O, De Jonge J, Nomden A, et al. Lovastatin induces the forma¬tion of abnormal myelin-like membrane sheets in primary oligodendrocytes. Glia 2009; 57(4): 402-13
63. Paintlia AS, Paintlia MK, Singh I, et al. Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 2009; 57(2): 182-93.
64. Renshaw PF, Parsegan A, Yang CK, et al. Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats. Pharmacol Biochem Behav 2009; 92(1): 88-92.
65. Scheen AJ, Radermecker RP, Sadzot B. Statin for the brain: update in 2008. Rev Med Liege 2008; 63(5-6): 287-92.
66. Sassano A, Platanias LC. Statins in tumor suppression. Cancer Lett 2008; 260(1-2): 11-9.
67. Collisson EA, Kleer C, Wu M, et al. Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells. Mol Cancer Ther 2003; 2(10): 941-8.
68. Kim W, Yoon JH, Kim JR, et al. Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma. Cancer Chemother Pharmacol 2008.
69. Liu H, Liang SL, Kumar S, et al. Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression. Cancer Chemother Pharmacol 2008
70. Horiuchi A, Kikuchi N, Osada R, et al. Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer. Cancer Sci 2008; 99(12): 2532-9.
71. Jakobisiak M, Golab J. Potential antitumor effects of statin. Int J Oncol 2003; 23(4): 1055-69.
72. Raggat l, Partrige N. HMG-reductase inhibitors as immunomodula- tors. Potential use in transplant rejection. Drug 2002; 62(15): 2185¬91.
73. Keogh A, Macdonald P, Kaan M, et al. Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation. J Heart Lung Transplant 2000; 19: 529-37.
74. Weis M, Pehlivanli S, Bruno M, et al. Simvastatin treatment is associated with improvement in coronary endothelial fonc-tion and decreased cytokine activation in patients after heart transplantation. JACC 2001; 38: 814-8.
75. Katznelson S, Wilkinson AH, Kobashigawa JA, et al. The effect of pravastatin on acute rejection after kidney transplantation: a pilot study. Transplantation 1996; 61: 1469-74.
76. Holdaas H, Jardine AG, Wheeler DC, et al. Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial. Kidney Int 2001; 60: 1990-7.
77. Kakkis JL, Ke B, Dawson S, et al. Pravastatin increases survival and inhibits natural killer cell enhancement factor in liver transplanted rats. J Surg Res 1997; 69: 393-8.
78. Koh CS. Effects of atorvastatin in multiple sclerosis. Nippon Rinsho 2003; 61(8): 1455-60.
79. Law M, Rudnicka AR. Statin safety: a systemic review. Am J Cardiol 2006; 97(Suppl): 52C-60.
80. Matsuzawa Y, Kita T, Mabuchi H, et al. Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients. Circ J 2003; 67: 287-94.
81. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292: 2585-90.
82. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/ NHLBI clinical advisory on the use and safety of statins. JACC 2002; 40: 567-72.
83. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 2002; 36(2): 288-95.
84. Kobayashi M, Chisaki I, Narumi K, et al. Association between risk of myopathy and cholesterol-lowering effect: a comparison of all statins. Life Sci 2008; 82(17-18): 969-75.
85. SEARCH Collaborative Group, Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy-a genomewide study. N Engl J Med 2008; 359(8): 789-99.
86. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001; 35: 1096-107.
87. Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004; 116: 408-16.
88. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97 (Suppl): 89C-94.
89. HPS (Heart Protection Study Collaborative Group). Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757-67.
90. PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002; 360: 1623-30.
91. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin-associated peripheral neuropathy: review of the literature. Pharmacotherapy. 2004; 24:1194-203.
92. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97(Suppl): 77C-81.
93. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long-term clinical trials. Circulation 2002; 105: 2341-6.
94. Jacobson TA. Statin safety: lessons from New Drug Applications for marketed statins. Am J Cardiol 2006; 97(Suppl): 44C-51.
95. Fried LF, Orchard TJ, Kasiske BL, for the Lipids and Renal Disease Progression Meta-Analysis Study Group. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001; 59: 260-9.
96. Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression ofrenal disease. Cardiology 2004; 102:52-60.
97. Kobayashi M, Chisaki I, Narumi K, et al. Association between risk of myopathy and cholesterol-lowering effect: a comparison of all statins. Life Sci 2008; 82(17-18): 969-75.
98. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007; 99(10): 1409-12.