problendoПроблемы ЭндокринологииProblems of Endocrinology0375-96602308-1430Endocrinology Research Centre10.14341/probl201157657-63problendo-4634Research ArticleСтатьиArticlesТиазолидиндионы: долгая дорога в клиникуThiazolidinediones: a long way to clinical practiceAleksandrovA A-KukharenkoS S-IadrikhinskaiaM N-ShatskaiaO A-DrozdovaE N-201115122011576ТОМ 57, №6 (2011)5763Copyright © Aleksandrov A.A., Kukharenko S.S., Iadrikhinskaia M.N., Shatskaia O.A., Drozdova E.N., 20112011Aleksandrov A.A., Kukharenko S.S., Iadrikhinskaia M.N., Shatskaia O.A., Drozdova E.N.Aleksandrov A.A., Kukharenko S.S., Iadrikhinskaia M.N., Shatskaia O.A., Drozdova E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.probl-endojournals.ru/jour/article/view/4634

Клиническое использование тиазолидиндионов насчитывает около 12 лет. Коррекция углеводного обмена при их применении сопровождается улучшением многих факторов риска ИБС и прогноза больных сахарным диабетом 2-го типа. Обсуждаются возможные механизмы осложнений, выявленных в клинике при применении ряда тиазолидиндионов.

The clinical application of thiazolidinediones has an almost 12 year history. The correction of carbohydrate metabolism achieved by the treatment with hiazolidinediones is associated with the reduction of many risk factors of coronary heart disease and the improvement of prognosis for the patients presenting with type 2 diabetes mellitus. The possible mechanisms underlying complications encountered in the clinical practice in connection with the use of thiazolidinediones are discussed.

сахарный диабет 2-го типатиазолидиндионыпероксисомысвободнорадикальное окислениеинсулинорезистентностьсердечно-сосудистые осложнениягепатитинфаркт миокардаtype 2 diabetes mellitusthiazolidinedionesperoxisomesfree radical oxidationinsulin resistancecardiovascular complicationshepatitismyocardial infarctionReferencesIkeda H. Discovery of The Thiazolidinediones Class and its Distinct Futures. Insulin Resistence, Dyslipidemia, and Type 2 Diabetes. Opportunities Offered by the Thiazolidinediones. 36th Annual Meeting of the European Association for The Study of Diabetes. Report 2000; 3.Ikeda H. Discovery of The Thiazolidinediones Class and its Distinct Futures. Insulin Resistence, Dyslipidemia, and Type 2 Diabetes. Opportunities Offered by the Thiazolidinediones. 36th Annual Meeting of the European Association for The Study of Diabetes. Report 2000; 3.Rosen E.D., Spiegelman B.M. PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth. J Biol Chem 2001; 276: 37731-37734.Rosen E.D., Spiegelman B.M. PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth. J Biol Chem 2001; 276: 37731-37734.Desvergne В., Wahli W. Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocrine Rev 1999; 20: 649-688.Desvergne В., Wahli W. Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocrine Rev 1999; 20: 649-688.Kelly D.P. The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway. Circulat Res 2001; 89: 935-937.Kelly D.P. The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway. Circulat Res 2001; 89: 935-937.Guan Y.F., Breyer M.D. Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease. Kidney Int 2001; 60: 14-30.Guan Y.F., Breyer M.D. Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease. Kidney Int 2001; 60: 14-30.Willson T.M., Brown P.J., Sternbach D.D., Henke B.R. The PPARs: From Orphan Receptors to Drug Discovery. J Med Chem 2000; 43: 4: 527-550.Willson T.M., Brown P.J., Sternbach D.D., Henke B.R. The PPARs: From Orphan Receptors to Drug Discovery. J Med Chem 2000; 43: 4: 527-550.Lehmann J.M., Moore L.B., Smith-Oliver T.A., Wilkison W.O., Willson T.M., Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-acntivated receptor ? (PPARγ). J Biol Chem 1995; 270: 12953-12956.Lehmann J.M., Moore L.B., Smith-Oliver T.A., Wilkison W.O., Willson T.M., Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-acntivated receptor ? (PPARγ). J Biol Chem 1995; 270: 12953-12956.Kawasaki J., Hirano K., Nishimura J., Fujishima M., Kanaide H. Mechanisms of vasorelaxation induced by troglitazone, a novel antidiabetic drug, in the porcine coronary artery. Circulation 1998; 98: 2446-2452.Kawasaki J., Hirano K., Nishimura J., Fujishima M., Kanaide H. Mechanisms of vasorelaxation induced by troglitazone, a novel antidiabetic drug, in the porcine coronary artery. Circulation 1998; 98: 2446-2452.Nakajama Т., Iwasawa K., Oonuma H., Imuta H., Hazama H., Asano M., Morita Т., Nakamura F., Suzuki J., Suzuki S., Kawakami Y., Omata M., Okuda Y. Troglitazone inhibits voltagt-dependent calcium currents in guinea pig cardiac myocytes. Circulation 1999; 99: 2942-2950.Nakajama Т., Iwasawa K., Oonuma H., Imuta H., Hazama H., Asano M., Morita Т., Nakamura F., Suzuki J., Suzuki S., Kawakami Y., Omata M., Okuda Y. Troglitazone inhibits voltagt-dependent calcium currents in guinea pig cardiac myocytes. Circulation 1999; 99: 2942-2950.Mirakami Т., Mizuno S., Ohsato K., Moriuchi I., Arai Y., Nio Y., Kaku В., Takahashi Y., Ohnaka M. Effects of Troglitazone on frequency of coronary vasospastic-induced angina pectoris in patient with diabetes mellitus. Am J Cardiol 1999; 84: 92-95.Mirakami Т., Mizuno S., Ohsato K., Moriuchi I., Arai Y., Nio Y., Kaku В., Takahashi Y., Ohnaka M. Effects of Troglitazone on frequency of coronary vasospastic-induced angina pectoris in patient with diabetes mellitus. Am J Cardiol 1999; 84: 92-95.Takagi Т., Akasaka Т., Yamamuro A., Honda Y., Hozumi Т., Morioka S., Yoshida K. Troglitazone reduces neointimal Tissue proliferation after coronary stent impantation in patients with non-insulin dependent diabetes mellitus. J Am Coll Cardiol 2000; 36: 1529-1535.Takagi Т., Akasaka Т., Yamamuro A., Honda Y., Hozumi Т., Morioka S., Yoshida K. Troglitazone reduces neointimal Tissue proliferation after coronary stent impantation in patients with non-insulin dependent diabetes mellitus. J Am Coll Cardiol 2000; 36: 1529-1535.Sinon S., Loke Y.K., Furrberg C.D. Thiazolidintdiones and heart Failure. Diabetes Care 2007; 30: 2148-2153.Sinon S., Loke Y.K., Furrberg C.D. Thiazolidintdiones and heart Failure. Diabetes Care 2007; 30: 2148-2153.Boyle P., King A.B., Olansky L., Marchetti A., Lau H., Magar R., Martin J. Effects of pioglitazone and Rosiglitazone on blood lipid levels and glycemic control in patient with type 2 diabetes mellitus: aretrospective review of randomly selected medical records. Clin Ther 2002; 24: 3: 378-396.Boyle P., King A.B., Olansky L., Marchetti A., Lau H., Magar R., Martin J. Effects of pioglitazone and Rosiglitazone on blood lipid levels and glycemic control in patient with type 2 diabetes mellitus: aretrospective review of randomly selected medical records. Clin Ther 2002; 24: 3: 378-396.Haffner S.M., Greenberg A.S., Weston W.M., Chen H., Williams K., Freed M.I. Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus. Circulation 2002; 106: 679-684.Haffner S.M., Greenberg A.S., Weston W.M., Chen H., Williams K., Freed M.I. Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus. Circulation 2002; 106: 679-684.Albertini J.P. et al. Markers of Endothelial Dysfunction and Insulin Resistance. Beneficial Effects of Rosiglitazone in Type 2 Diabetes (abstract 494 P). Diabetes 2004; 53: Suppl 2: A117.Albertini J.P. et al. Markers of Endothelial Dysfunction and Insulin Resistance. Beneficial Effects of Rosiglitazone in Type 2 Diabetes (abstract 494 P). Diabetes 2004; 53: Suppl 2: A117.Sidhu J.S., Kaposzta Z., Markus H.S., Kaski J.C. Effect of Rosiglitazone on Common Carotid Intima-Media Thickness Progression in Coronary Artery Disease Patients Without Diabetes Mellitus. Arterioscler Thromb Vasc Biol 2004; 24: 930-934.Sidhu J.S., Kaposzta Z., Markus H.S., Kaski J.C. Effect of Rosiglitazone on Common Carotid Intima-Media Thickness Progression in Coronary Artery Disease Patients Without Diabetes Mellitus. Arterioscler Thromb Vasc Biol 2004; 24: 930-934.Freed M. et al. Effect of combination therapy with rosiglitazone and Glibenclamide on PAI-1 antigen, PAI-1 activity, and tPA in patients with type 2 diabetes. Diabetologia 2000; 43: Suppl: A267; Abstract 1024+poster.Freed M. et al. Effect of combination therapy with rosiglitazone and Glibenclamide on PAI-1 antigen, PAI-1 activity, and tPA in patients with type 2 diabetes. Diabetologia 2000; 43: Suppl: A267; Abstract 1024+poster.Sutton M., Rendell M., Dandona P., Dole J.F., Murphy K., Patwardhan R., Patel J., Freed M. A Comparison of the Effects of Rosiglitazone and Glyburide on Cardiovascular Function and Glycemic Control in Patients With Type 2 Diabetes. Diabetes Care 2002; 25: 2058-2064.Sutton M., Rendell M., Dandona P., Dole J.F., Murphy K., Patwardhan R., Patel J., Freed M. A Comparison of the Effects of Rosiglitazone and Glyburide on Cardiovascular Function and Glycemic Control in Patients With Type 2 Diabetes. Diabetes Care 2002; 25: 2058-2064.Choi D., Kim S.-K., Choi S.-H., Ко Y.-G., Ahn C.-W., Jang Y., Lim S.-K., Lee H.-C., Cha B.-S. Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation inChoi D., Kim S.-K., Choi S.-H., Ко Y.-G., Ahn C.-W., Jang Y., Lim S.-K., Lee H.-C., Cha B.-S. Preventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation inSrikanthan P. et al. Impact of Rosiglitazone on Vascular Events, Atherosclerosis and Allograft Rejection in Cardiac Transplant Patients with Diabetes (abstract 615 P). Diabetes 2004; 53: Suppl 2: A146.Srikanthan P. et al. Impact of Rosiglitazone on Vascular Events, Atherosclerosis and Allograft Rejection in Cardiac Transplant Patients with Diabetes (abstract 615 P). Diabetes 2004; 53: Suppl 2: A146.Rosenblatt S., Miskin В., Glazer N.M., Prince M.J., Roberson K.E. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001; 12: 413-423.Rosenblatt S., Miskin В., Glazer N.M., Prince M.J., Roberson K.E. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001; 12: 413-423.Kipnes M.S., Krosnick A., Rendell M.S., Egan J.W., Mathisen A.L., Schneider R.L. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001; 111: 10-17.Kipnes M.S., Krosnick A., Rendell M.S., Egan J.W., Mathisen A.L., Schneider R.L. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001; 111: 10-17.Einhorn D., Rendell M., Rosenzweig J., Egan J.W., Mathisen A.L., Schneider R.L. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000; 22: 1395-1409.Einhorn D., Rendell M., Rosenzweig J., Egan J.W., Mathisen A.L., Schneider R.L. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000; 22: 1395-1409.Rubin C., Egan J., Schneider R. Combination therapy with pioglitazone and insulin in patients with type 2 diabetes. Diabetes 1999; 48: Suppl 1: A110: Abstract.Rubin C., Egan J., Schneider R. Combination therapy with pioglitazone and insulin in patients with type 2 diabetes. Diabetes 1999; 48: Suppl 1: A110: Abstract.Winkler K., Friedrich I., Nauck M. et al. Pioglitazone reduces dens LDL-particles in patients with type 2 diabetes (abstract 592p). Diabetes 2001; 50: Suppl 2: A147.Winkler K., Friedrich I., Nauck M. et al. Pioglitazone reduces dens LDL-particles in patients with type 2 diabetes (abstract 592p). Diabetes 2001; 50: Suppl 2: A147.Prince M.J., Zagar A.J., Robertson K.E. Effect of pioglitazone on HDL-C, a cardiovascular risk factor in type 2 diabetes (abstract 514p). Diabetes 2001; 50: Suppl 2: A128.Prince M.J., Zagar A.J., Robertson K.E. Effect of pioglitazone on HDL-C, a cardiovascular risk factor in type 2 diabetes (abstract 514p). Diabetes 2001; 50: Suppl 2: A128.Miyazaki Y., Mahankali A., Matsuda M., Mahankali S., Hardies J., Cusi K., Mandarino L.J., DeFronzo R.A. Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients. J Clin Endocrinol Metab 2002; 87: 2784-2791.Miyazaki Y., Mahankali A., Matsuda M., Mahankali S., Hardies J., Cusi K., Mandarino L.J., DeFronzo R.A. Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients. J Clin Endocrinol Metab 2002; 87: 2784-2791.Koshiyama H., Shimono D., Kuwamura N., Minamikawa J., Nakamura Y. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 3452-3456.Koshiyama H., Shimono D., Kuwamura N., Minamikawa J., Nakamura Y. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 3452-3456.Thiemermann C., Wayman N.S. Menarini Academy Cardiovascular Research Awards in Basic Science 2001: ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size. Med Sci Monit 2001; 7: 787-789.Thiemermann C., Wayman N.S. Menarini Academy Cardiovascular Research Awards in Basic Science 2001: ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size. Med Sci Monit 2001; 7: 787-789.Dormandy J.A., Charbonnel В., Eckland D.J. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in the macro Vascular Events): a randomized controlled Trial. Lancet 2005; 366: 1279-1289.Dormandy J.A., Charbonnel В., Eckland D.J. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in the macro Vascular Events): a randomized controlled Trial. Lancet 2005; 366: 1279-1289.Nesto R.W., Bell D., Bonow R.O. et al. Thiazolidinedione use, fluid retention, and congestive heart failure; a consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108: 23: 2941-2948.Nesto R.W., Bell D., Bonow R.O. et al. Thiazolidinedione use, fluid retention, and congestive heart failure; a consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108: 23: 2941-2948.Nesto R.W., Bell D., Bonow R.O., Fonseca V., Grundy S.M., Horton E.S., Le Winter M., Porte D., Semenkovich C.F., Smith S., Young L.H., Kahn R. Thiazolidinedione Use. Fluid Retention, and Congestive Heart Failure: A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27: 256-263; doi: 10.2337/diacare.27.1.256.Nesto R.W., Bell D., Bonow R.O., Fonseca V., Grundy S.M., Horton E.S., Le Winter M., Porte D., Semenkovich C.F., Smith S., Young L.H., Kahn R. Thiazolidinedione Use. Fluid Retention, and Congestive Heart Failure: A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27: 256-263; doi: 10.2337/diacare.27.1.256.Kaul S., Bolger A.F., Herrington D., Giugliano R.P., Eckel R.H. Thiazolidinedione drugs and cardiovascular risk: a science advisory from the American Heart Association and American College of Cardiology foundation. J Am Coll Cardiol 2010; 55: 1885-1894.Kaul S., Bolger A.F., Herrington D., Giugliano R.P., Eckel R.H. Thiazolidinedione drugs and cardiovascular risk: a science advisory from the American Heart Association and American College of Cardiology foundation. J Am Coll Cardiol 2010; 55: 1885-1894.Carey D.G., Cowin G.J., Galloway G.J. et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002; 10: 1008-1015.Carey D.G., Cowin G.J., Galloway G.J. et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002; 10: 1008-1015.Tollman K.G. Thiazolidinedione hepatotoxity: a class effect? Int J Clin Practice 2000; Suppl 113: 29-34.Tollman K.G. Thiazolidinedione hepatotoxity: a class effect? Int J Clin Practice 2000; Suppl 113: 29-34.Singh S., Lake Y.K., Fuberg C.D. Long-term risk of Cardiovascular events with rosiglitazone: a metaanalysis. JAMA 2007; 298: 1189-1195.Singh S., Lake Y.K., Fuberg C.D. Long-term risk of Cardiovascular events with rosiglitazone: a metaanalysis. JAMA 2007; 298: 1189-1195.Gerrits С.М., Bhattacharya M., Manthena S., Baran R., Peres A., Kupfer S.A. A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes. Farmacoepidemiol Drug Saf 2007; 16: 10: 1065-1071.Gerrits С.М., Bhattacharya M., Manthena S., Baran R., Peres A., Kupfer S.A. A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes. Farmacoepidemiol Drug Saf 2007; 16: 10: 1065-1071.Walker A.M., Коrо С.Е., Landon J. Coronary heart disease outcomes in patients receiving antidiabetic agents in the PharMetrics database 2000-2007. Pharmacoepidemiol Drug Saf 2008; 17: 8: 760-768.Walker A.M., Коrо С.Е., Landon J. Coronary heart disease outcomes in patients receiving antidiabetic agents in the PharMetrics database 2000-2007. Pharmacoepidemiol Drug Saf 2008; 17: 8: 760-768.Winkelmayer W.C., Setoguchi S., Levin R., Solomon D.H. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Argh Int Med 2008; 168: 21: 2368-2375.Winkelmayer W.C., Setoguchi S., Levin R., Solomon D.H. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Argh Int Med 2008; 168: 21: 2368-2375.Doormuth C.R., Maclure M., Carney C., Schneeweiss S., Wright J.M. Rosiglitazone and myocardial infarction in patients previously prescribed metformin. PloS One 2009; 4: 6:e6080.Doormuth C.R., Maclure M., Carney C., Schneeweiss S., Wright J.M. Rosiglitazone and myocardial infarction in patients previously prescribed metformin. PloS One 2009; 4: 6:e6080.Juurink D.N., Gomes Т., Lipscombe L.L., Austin P.C., Них J.E., Mandani M.M. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohord study. BMJ 2009; 339: b2942.Juurink D.N., Gomes Т., Lipscombe L.L., Austin P.C., Них J.E., Mandani M.M. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohord study. BMJ 2009; 339: b2942.Ziyadeh N., McAfee A.T., Коrо С., Landon J., Arnold Chan K. The thiazolidobnediones rosiglitazone and pioglitazone and the risk of coronary heart disease: a retrospective cohort study using a US health insurance database. Clin Ther 2009; 31: 11: 2665-2677.Ziyadeh N., McAfee A.T., Коrо С., Landon J., Arnold Chan K. The thiazolidobnediones rosiglitazone and pioglitazone and the risk of coronary heart disease: a retrospective cohort study using a US health insurance database. Clin Ther 2009; 31: 11: 2665-2677.Brownstein J.S., Murphy S.N., Goldin A.B. et al. Rapid identification of myocardial infarction risk associated with diabetes medication using electronic medical records. Diabetes Care 2010; 33: 3: 526-531.Brownstein J.S., Murphy S.N., Goldin A.B. et al. Rapid identification of myocardial infarction risk associated with diabetes medication using electronic medical records. Diabetes Care 2010; 33: 3: 526-531.Graham D., Ouellrt-Hellstrom R., MaGurdy Т.Е., Ali F., Sholley C., Worral C., Kelman J.A. Risk of acute myocardial Infarction, Stroke, heart failure, and Death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010; 304: 4: 411-418.Graham D., Ouellrt-Hellstrom R., MaGurdy Т.Е., Ali F., Sholley C., Worral C., Kelman J.A. Risk of acute myocardial Infarction, Stroke, heart failure, and Death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010; 304: 4: 411-418.Rhodin J. Correlation of ultrastructure organization and function in normal and experimentally treated proximal convoluted tubule cells of the mouse kidney. Doctoral thesis. Stockholm: Karolinska Institute 1954.Rhodin J. Correlation of ultrastructure organization and function in normal and experimentally treated proximal convoluted tubule cells of the mouse kidney. Doctoral thesis. Stockholm: Karolinska Institute 1954.Gartner J. Organelle disease: peroxisomal disorders. Eur J Pediatr 2000; 159: Suppl 3: S236-S239.Gartner J. Organelle disease: peroxisomal disorders. Eur J Pediatr 2000; 159: Suppl 3: S236-S239.

The authors declare that there are no conflicts of interest present.