The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Effects of D-002, a mixture of high molecular weight beeswax alcohols, on patients with nonalcoholic fatty liver disease

  • Illnait, Jose (Centre of Natural Products, National Centre for Scientific Research) ;
  • Rodriguez, Ivan (Surgical Medical Research Centre, National Centre for Scientific Research) ;
  • Mendoza, Sarahi (Centre of Natural Products, National Centre for Scientific Research) ;
  • Fernandez, Yolanda (Surgical Medical Research Centre, National Centre for Scientific Research) ;
  • Mas, Rosa (Centre of Natural Products, National Centre for Scientific Research) ;
  • Miranda, Mirtha (Surgical Medical Research Centre, National Centre for Scientific Research) ;
  • Pinera, Jesus (Surgical Medical Research Centre, National Centre for Scientific Research) ;
  • Fernandez, Julio Cesar (Centre of Natural Products, National Centre for Scientific Research) ;
  • Mesa, Meilis (Surgical Medical Research Centre, National Centre for Scientific Research) ;
  • Fernandez, Lilia (Centre of Natural Products, National Centre for Scientific Research) ;
  • Carbajal, Daisy (Centre of Natural Products, National Centre for Scientific Research) ;
  • Gamez, Rafael (Centre of Natural Products, National Centre for Scientific Research)
  • Published : 2013.07.01
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Abstract

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is intimately related to insulin resistance and ranges from a benign course to liver fibrosis and cirrhosis. NAFLD management mainly involves dietary modification and weight loss. Although no fully successful pharmacological intervention is available, alternative therapies to treat NAFLD have shown promising results. Experimental studies have shown that D-002, a mixture of beeswax alcohols with antioxidant effects, is hepatoprotective. The aim of this study was to investigate the efficacy and safety of D-002 in patients with NALFD. Methods: Fifty patients with NAFLD were randomized to receive a placebo or D-002 (100 mg/day) for 24 weeks. The primary endpoint was a significant ultrasonography-detected reduction of liver fat infiltration versus a placebo. Secondary endpoints were decreases in the homeostatic model assessment (HOMA) index, insulin levels, serum liver enzymes, increases in plasma total antioxidant status (TAS) and improved clinical symptoms versus the placebo recipients. Results: At randomization, all indicators were comparable in both groups. At study completion, seven (28.0%) D-002-patients, but none of the placebo recipients, exhibited a normal liver echo pattern on ultrasonography (p < 0.01). Also, D-002 significantly reduced (p < 0.01 vs. baseline and placebo) the HOMA index and insulin levels and increased the TAS, but did not affect other parameters. The proportion of D-002-patients (12/25, 48.0%) showing symptom improvement was higher (p < 0.001) than that of the placebo group (1/25, 4.0%). The treatment was safe and well tolerated. Three patients in each group withdrew from the study. Conclusions: D-002 (100 mg/day) improved ultrasonographic findings, indicators of insulin resistance, plasma TAS and clinical evolution on NAFLD patients. Further studies, however, are needed to confirm these results.

Keywords

References

  1. Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2007;25:883-889. https://doi.org/10.1111/j.1365-2036.2007.03246.x
  2. Mendez-Sanchez N, Arrese M, Zamora-Valdes D, Uribe M. Treating nonalcoholic fatty liver disease. Liver Int 2007;27:1157-1165.
  3. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53:372-384. https://doi.org/10.1016/j.jhep.2010.04.008
  4. Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci 2010;55:560-578. https://doi.org/10.1007/s10620-009-1081-0
  5. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005;288:E462-E468. https://doi.org/10.1152/ajpendo.00064.2004
  6. Kim HJ, Lee KE, Kim DJ, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004;164:2169-2175. https://doi.org/10.1001/archinte.164.19.2169
  7. Nagata K, Suzuki H, Sakaguchi S. Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis. J Toxicol Sci 2007;32:453-468. https://doi.org/10.2131/jts.32.453
  8. Caporaso N, Morisco F, Camera S, Graziani G, Donnarumma L, Ritieni A. Dietary approach in the prevention and treatment of NAFLD. Front Biosci 2012;17:2259-2268. https://doi.org/10.2741/4049
  9. Moscatiello S, Marzocchi R, Villanova N, Bugianesi E, Marchesini G. Which treatment for nonalcoholic fatty liver disease? Mini Rev Med Chem 2008;8:767-775. https://doi.org/10.2174/138955708784912193
  10. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000;6:998-1003. https://doi.org/10.1038/79697
  11. Hortander JC, Kwo PY, Cummings OW, Koukoulis G. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120(5 Suppl 1):A544. https://doi.org/10.1016/S0016-5085(08)82705-9
  12. Merat S, Malekzadeh R, Sohrabi MR, et al. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003;38:414-418.
  13. Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 2008;14:6395-6400. https://doi.org/10.3748/wjg.14.6395
  14. Musto D, Martorelli L, Russo M, et al. Non-alcoholic hepatic steatosis: the role of policosanols in associated hyperlipidemia. Minerva Gastroenterol Dietol 2010;56:389-395.
  15. Ohta Y, Ohashi K, Matsura T, Tokunaga K, Kitagawa A, Yamada K. Octacosanol attenuates disrupted hepatic reactive oxygen species metabolism associated with acute liver injury progression in rats intoxicated with carbon tetrachloride. J Clin Biochem Nutr 2008;42:118-125. https://doi.org/10.3164/jcbn.2008017
  16. Mas R. Policosanol. Drugs Future 2000;25:569-586. https://doi.org/10.1358/dof.2000.025.06.574693
  17. Mas R. D-002: a product obtained from beeswax. Drugs Future 2001;26:731-744. https://doi.org/10.1358/dof.2001.026.08.630956
  18. Menendez R, Amor AM, Gonzalez RM, Jimenez S, Mas R. Inhibition of rat microsomal lipid peroxidation by the oral administration of D002. Braz J Med Biol Res 2000;33:85-90. https://doi.org/10.1590/S0100-879X2000000100012
  19. Molina V, Valdes S, Carbajal D, Arruzazabala L, Menendez R, Mas R. Antioxidant effect of D-002 on gastric mucosa of rats with experimentally induced injury. J Med Food 2001;4:79-83. https://doi.org/10.1089/109662001300341734
  20. Perez Y, Oyarzabal A, Mas R, Molina V, Jimenez S. Protective effect of D-002, a mixture of beeswax alcohols, against indomethacin-induced gastric ulcers and mechanism of action. J Nat Med 2013;67:182-189. https://doi.org/10.1007/s11418-012-0670-y
  21. Menendez R, Mas R, Illnait J, et al. Effects of D-002 on lipid peroxidation in older subjects. J Med Food 2001;4:71-77. https://doi.org/10.1089/109662001300341725
  22. Lopez E, Illnait J, Molina V, et al. Effects of D-002 (beeswax alcohols) on lipid peroxidation in middle-aged and older subjects. Lat Am J Pharm 2008;27:695-703.
  23. Rodriguez I, Illnait J, Molina V, et al. Comparison of the antioxidant effects of D-002 (beeswax alcohols) and grape seed extract (GSE) on plasma oxidative variables in healthy subjects. Lat Am J Pharm 2010;29:255-262.
  24. Mendoza S, Noa M, Perez Y, Mas R. Preventive effect of D-002, a mixture of long-chain alcohols from beeswax, on the liver damage induced with CCl4 in rats. J Med Food 2007;10:379-383. https://doi.org/10.1089/jmf.2006.296
  25. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 2007;47:711-717. https://doi.org/10.1016/j.jhep.2007.06.020
  26. Csendes P, Paolinelli P, Bussel D, Venturelli V, Rodriguez J. Higado graso: ultrasonido y correlacion anatomopatologica. Rev Chil Radiol 2004;10:50-52.
  27. Rodriguez I, Illnait J, Terry H, et al. Effects of Abexol (beeswax alcohols) on gastrointestinal symptoms in middle-aged and older subjects. Rev CENIC Cien Biol 2009;40:147-154.
  28. Graif M, Yanuka M, Baraz M, et al. Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease. Invest Radiol 2000;35:319-324. https://doi.org/10.1097/00004424-200005000-00006
  29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
  30. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond) 2008;115:141-150. https://doi.org/10.1042/CS20070402
  31. Donati G, Stagni B, Piscaglia F, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004;53:1020-1023. https://doi.org/10.1136/gut.2003.027086
  32. Hsiao PJ, Kuo KK, Shin SJ, et al. Significant correlations between severe fatty liver and risk factors for metabolic syndrome. J Gastroenterol Hepatol 2007;22:2118-2123. https://doi.org/10.1111/j.1440-1746.2006.04698.x
  33. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev 2008;29:777-822. https://doi.org/10.1210/er.2008-0024
  34. Petta S, Handberg A, Craxi A. Non invasive indexes for the assessment of patients with non-alcoholic fatty liver disease. Curr Pharm Des. 2013 Feb 4 [Epub].
  35. Ruales F, Barbano J, Gomez E. Correlation between fatty infiltration of the liver and body mass index, triglycerides and transaminases. Acta Gastroenterol Latinoam 2012;42:278-284.
  36. Barsic N, Lerotic I, Smircic-Duvnjak L, Tomasic V, Duvnjak M. Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:3945-3954. https://doi.org/10.3748/wjg.v18.i30.3945
  37. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140:124-131. https://doi.org/10.1053/j.gastro.2010.09.038
  38. Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25:1135-1141. https://doi.org/10.2337/diacare.25.7.1135
  39. Singh DK, Li L, Porter TD. Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase. J Pharmacol Exp Ther 2006;318:1020-1026. https://doi.org/10.1124/jpet.106.107144
  40. Messina D, Perez Elizalde R, Soto C, Uvilla A, Lopez Laur JD, Lopez Fontana C. High intake of lycopene together with low intake of red meat increases the total antioxidant status. Arch Latinoam Nutr 2012;62:15-22.
  41. Ozgur P, Huseyin B, Ferhat C, Huseyin K, Nuri DB. Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease. J Clin Res Pediatr Endocrinol 2013;5:33-39. https://doi.org/10.4274/Jcrpe.825

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