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Policosanol

Common Name(s): Policosanol , polycosanol

Uses

Cholesterol-lowering effects previously attributed to policosanol have not been validated by more recent trials. Policosanol has been studied in platelet aggregation and intermittent claudication, but data are insufficient to support this use.

Dosing

Policosanol is typically initiated at 5 mg/day and titrated up to 20 mg/day for hypercholesterolemia.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Studies in rats and mice demonstrated no adverse effects on fertility, reproduction, teratogenesis, or development at doses equivalent to 1,500 times the normal human dose of 20 mg/kg/day.

Interactions

Because of policosanol's possible effects on platelet aggregation, caution is warranted if policosanol is used concurrently with anticoagulants (eg, warfarin) or antiplatelet agents (eg, aspirin, clopidogrel, prasugrel). In a study in healthy men, policosanol did not affect the pharmacokinetics of warfarin.

Adverse Reactions

Animal and human studies have demonstrated few adverse reactions from policosanol.

Toxicology

Limited animal and human studies have found policosanol to be safe.

Policosanol, as reviewed in this monograph, is a mixture of high molecular weight, primary aliphatic alcohols (waxy substances), of which octacosanol (1-octacosanol) is the main component (approximately 60%). For information regarding the octacosanol component, refer to the Octacosanol monograph. Policosanol is isolated from sugar cane wax or beeswax, but these sources may have different proportions of policosanol components. Octacosanol and related substances also are found in wheat germ oil, vegetable oils, alfalfa, and animal products. 1 , 2 , 3

History

Policosanol has been used most often for cholesterol-lowering effects.

Chemistry

Policosanol is derived through hydrolysis of wax esters and isolation of the alcohol constituent. 4 Reports to determine constituents in policosanol from raw materials have been published. Eight aliphatic fatty alcohols in 1 study were 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, 1-nonacosanol, 1-triacontanol, 1-dotriacontanol, and 1-tetratriacontanol, 4 , 5 , 6 each having 24 to 34 carbons. 4 Three compounds isolated from Chinese beeswax were identified as dotriacontanol, triacontanol, and octacosanol in another report. 2 The saturated carbon structure results in policosanol being hydrophobic. 4

Uses and Pharmacology

Cholesterol reduction

Policosanol's impact on cholesterol is mediated through a reduction in the synthesis and degradation of the rate-limiting step of cholesterol biosynthesis, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. In comparison, statins competitively inhibit this enzyme. 7 In hepatoma cells and mouse liver, policosanol promoted the phosphorylation of adenosine monophosphate kinase, the principle enzyme for catalyzing the phosphorylation of HMG CoA reductase, thereby reducing its activity. 8 Policosanol has affected low-density lipoprotein (LDL) metabolism through increasing LDL binding, uptake, and degradation. 7

Animal data

In a study of normocholesterolemic rabbits, total, non–high-density lipoprotein (HDL), and HDL cholesterol increased following supplementation with sugar cane policosanol. 9 However, in a study of LDL receptor knock-out mice, individual policosanol components, as well as the natural mixture, did not lower serum cholesterol concentrations. 10 Similarly, plasma lipid levels were not reduced in golden Syrian hamsters supplemented with policosanol. 11

Clinical data

Despite the proliferation of studies primarily conducted by researchers in Cuba in the late 1990s and early 2000 proclaiming the efficacy of policosanol in lowering cholesterol, more recent studies have failed to validate early expectations. 4 , 12 , 13 , 14 , 15 , 16 , 17 , 18 In a study of patients with HIV-related dyslipidemia, policosanol 20 mg/day for a period of 12 weeks did not significantly affect patient lipid profiles or lipoprotein size or concentration. 19 In a study in which investigators modified the policosanol formulation in an effort to make it more effective, the product was not associated with a reduction in cholesterol parameters. 20 However, a small study in Italy found a reduction in total cholesterol, LDL, and Human Omeostatic Assessment Index in 52 patients with nonalcoholic fatty liver disease who were taking Frilipid , a policosanol supplement. 21 A more recent study found that policosanol in combination with tomato extract, grape procyanidins, and Oenothera biennis oil marketed as Cholactiv , given for 6 weeks, reduced LDL and total cholesterol levels. Reductions in C-reactive protein, malondialdehyde, and superoxide dismutase levels also occurred but were not statistically significant. 22

Trials published in 2006 in the United States, Germany, Netherlands, Canada, and South Africa found no effect on blood lipid profiles at dosages of 10 to 80 mg daily over 4 to 12 weeks. Additionally, no synergy with atorvastatin was demonstrated in one of these trials. 13 , 23 , 24 , 25 , 26 , 27

Intermittent claudication

Platelet aggregation is believed to be reduced with policosanol through a reduction in the synthesis of thromboxane B2. 7

Animal data

In rabbits with arterial wall damage, policosanol was found to reduce platelet adhesion. 28

Clinical data

Multiple trials, all published by the same authors, suggest a role for policosanol in intermittent claudication and platelet aggregation inhibition. Independent validation of these trials is needed. 29 , 30 , 31 , 32 , 33 , 34 , 35 In a 10-week, randomized, comparative study, policosanol 10 mg/day was increased the initial and absolute claudication distances in patients with intermittent claudication. This effect was not noted with aspirin 100 mg/day. 36 In another 20-week, randomized, double-blind comparative study, policosanol 10 mg twice daily was associated with improvements in initial and absolute claudication distances. Ticlopidine 250 mg twice daily was the comparator drug that exhibited similar improvements with no differences between treatment groups. 37

Other uses

Policosanol has been used to reduce smooth muscle proliferation and improve symptoms associated with cardiovascular disease. 7 In combination with omega-3 fatty acid supplementation, the use of policosanol was associated with an improvement in mood state and a reduction in reaction time in athletes given supplements for 21 days. 38

Dosage

Policosanol is typically initiated at 5 mg/day and titrated up to 20 mg/day for hypercholesterolemia. 4

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Studies in rats and mice demonstrated no adverse effects on fertility, reproduction, teratogenesis, or development at doses equivalent to 1,500 times the normal human dose of 20 mg/kg/day. 7

Interactions

Because of policosanol's potential effects on platelet aggregation, caution is warranted if it is used concurrently with anticoagulants (eg, warfarin) or antiplatelet agents (eg, aspirin, clopidogrel, prasugrel). 7 However, a study in 11 healthy men receiving warfarin 25 mg before and after 2 weeks of administration of policosanol 10 mg twice daily found no effect of policosanol on the pharmacokinetics of (S)- or (R)-warfarin. 39 Policosanol also did not alter the response to warfarin on platelet aggregation. Animal studies suggest policosanol may increase the hypotensive effects of beta-blockers 40 and nitroprusside. 41

Adverse Reactions

Policosanol was generally well tolerated in human trials, with adverse reactions including rash, fatigue, headache, weight loss, excess urination, and insomnia. 23 , 24 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 A surveillance study of 2,252 elderly patients taking policosanol supplementation found long-term tolerability with the supplements. 42

Toxicology

Limited animal and human studies have found policosanol to be safe. In rats, administration of the drug did not adversely effect reproductive performance and fetal development. 43 Policosanol was also nonteratogenic in rats and rabbits. 44 No evidence of carcinogenicity was observed in mice 45 or rats, 46 even at doses equivalent to 1,500 times the human dose of 20 mg/kg/day. 7

Bibliography

1. Gouni-Berthold I , Berthold HK . Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent . Am Heart J . 2002;143(2):356-365.
2. Liu F , Sun D . Active constituents lowering blood-lipid in beeswax [in Chinese] . Zhongguo Zhong Yao Za Zhi . 1996;21(9):553-554, 576.
3. Saint-John M , McNaughton L . Octacosanol ingestion and its effects on metabolic responses to submaximal cycle ergometry, reaction time and chest and grip strength . Int Clin Nutr Rev . 1986;6:81-87.
4. Marinangeli CP, Jones PH, Kassis AN, Eskin MN. Policosanols as nutraceuticals: fact or fiction. Crit Rev Food Sci Nutr . 2010;50(3):259-267.
5. Gonzalez VL , Magraner J , Otero T , Garcia E . Validation and interlaboratory study of a new GC analytical method for the determination of policosanol in raw material [in Spanish] . Rev CENIC Cienc Quim . 1999;30:148-152.
6. Gonzalez CV , Magraner HJ . Validation of a gas chromatographic method for determining fatty alcohols that compose policosanol in five-milligram film-coated tablets . J AOAC Int . 1999;82(4):834-839.
7. Policosanol. Altern Med Rev . 2004;9(3):312-317.
8. Banerjee S, Ghoshal S, Porter TD. Activation of AMP-kinase by policosanol requires peroxisomal metabolism. Lipids . 2011;46(4):311-321.
9. Murphy KJ, Saint DA, Howe PR. Lack of effect of sugar cane and sunflower seed policosanols on plasma cholesterol in rabbits. J Am Coll Nutr . 2008;27(4):476-484.
10. Dullens SP, Mensink RP, Bragt MC, Kies AK, Plat J. Effects of emulsified policosanols with different chain lengths on cholesterol metabolism in heterozygous LDL receptor-deficient mice. J Lipid Res . 2008;49(4):790-796.
11. Kassis AN, Marinangeli CP, Jain D, Ebine N, Jones PJ. Lack of effect of sugar cane policosanol on plasma cholesterol in golden Syrian hamsters. Atherosclerosis . 2007;194(1):153-158.
12. Policosanol: a sweet nothing for high cholesterol. Harv Heart Lett . 2006;17(1):7.
13. Lin Y , Rudrum M , van der Wielen RP , et al. Wheat germ policosanol failed to lower plasma cholesterol in subjects with normal to mildly elevated cholesterol concentrations . Metabolism . 2004;53(10):1309-1314.
14. Chen JT , Wesley R , Shamburek RD , Pucino F , Csako G . Meta-analysis of natural therapies for hyperlipidemia: plant sterols and stanols versus policosanol . Pharmacotherapy . 2005;25(2):171-183.
15. Francini-Pesenti F, Brocadello F, Beltramolli D, Nardi M, Caregaro L. Sugar cane policosanol failed to lower plasma cholesterol in primitive, diet-resistant hypercholesterolaemia: a double blind, controlled study. Complement Ther Med . 2008;16(2):61-65.
16. Kassis AN, Jones PJ. Changes in cholesterol kinetics following sugar cane policosanol supplementation: a randomized control trial. Lipids Health Dis . 2008;7:17.
17. Castaño G, Fernández L, Mas R, Illnait J, Mesa M, Fernández JC. Comparison of the effects of policosanol and atorvastatin on lipid profile and platelet aggregation in patients with dyslipidemia and type 2 diabetes mellitus. Clin Drug Invest . 2003;23(10):639-650.
18. Castano G, Mas R, Fernandez L, et al. A comparison of the effects of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia: a randomized, double-blinded study. Drugs Exp Clin Res . 2005;(31 suppl);31-44.
19. Swanson B, Keithley JK, Sha BE, et al. Policosanol for managing human immunodeficiency virus-related dyslipidemia in a medically underserved population: a randomized, controlled clinical trial. Altern Ther Health Med . 2011;17(2):30-35.
20. Backes JM, Gibson CA, Ruisinger JF, Moriarty PM. Modified-policosanol does not reduce plasma lipoproteins in hyperlipidemic patients when used alone or in combination with statin therapy. Lipids . 46(10):923-929.
21. Musto D, Martorelli L, Russo M, et al. Non-alcoholic hepatic steatosis: the role of policosanols in associated hyperlipidemia. Minerva Gastroenterol Dietrol . 2010;56(4):389-395.
22. Gupta H, Pawar D, Riva A, Bombardelli E, Morazzoni P. A randomized, double-blind, placebo-controlled trial to evaluate efficacy and tolerability of an optimized botanical combination in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Phytother Res . 2011 Jun 14. 10.1002/ptr.3542 . [Epub ahead of print].
23. Cubeddu LX , Cubeddu RJ , Heimowitz T , Restrepo B , Lamas GA , Wienberg GB . Comparative lipid-lowering effects of policosanol and atorvastatin: a randomized, parallel, double-blind, placebo-controlled trial . Am Heart J . 2006;152(5):982. e1.5.
24. Dulin MF , Hatcher LF , Sasser HC , Barringer TA . Policosanol is ineffective in the treatment of hypercholesterolemia: a randomized controlled trial . Am J Clin Nutr . 2006;84(6):1543-1548.
25. Kassis AN , Jones PJ . Lack of cholesterol-lowering efficacy of Cuban sugar cane policosanols in hypercholesterolemic persons . Am J Clin Nutr . 2006;84(5):1003-1008.
26. Greyling A , De Witt C , Oosthuizen W , Jerling JC . Effects of a policosanol supplement on serum lipid concentrations in hypercholesterolaemic and heterozygous familial hypercholesterolaemic subjects . Br J Nutr . 2006;95(5):968-975.
27. Berthold HK , Unverdorben S , Degenhardt R , Bulitta M , Gounti-Berthold I . Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: a randomized controlled trial . JAMA . 2006;295(19):2262-2269.
28. Noa M, Rás M, Lariot C. Protective effect of policosanol on endothelium and intimal thickness induced by forceps in rabbits. J Med Food . 2007;10(3):452-459.
29. Arruzazabala ML , Valdés S , Más R , Carbajal D , Fernández L . Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers . Pharmacol Res . 1997;36(4):293-297.
30. Arruzazabala ML , Valdés S , Más R , Fernández L, Carbajal D . Effect of policosanol successive dose increases on platelet aggregation in healthy volunteers . Pharmacol Res . 1996;34(5-6):181-185.
31. Arruzazabala ML , Más R , Molina V , et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients . Int J Tissue React . 1998;20(4):119-124.
32. Carbajal D , Arruzazabala ML , Valdés S , Más R . Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers . Prostaglandins Leukot Essent Fatty Acids . 1998;58(1):61-64.
33. Valdés S , Arruzazabala ML , Fernández L , et al. Effect of policosanol on platelet aggregation in healthy volunteers . Int J Pharmacol Res . 1996;16(2-3):67-72.
34. Castaño G , Más R , Roca J , et al. A double-blind, placebo-controlled study of the effects of policosanol in patients with intermittent claudication . Angiology . 1999;50(2):123-130.
35. Castaño G , Más Ferreiro R , Fernández L , Gámez R , Illnait J , Fernández C . A long-term study of policosanol in the treatment of intermittent claudication . Angiology . 2001;52(2):115-125.
36. Illnait J, Castano G, Alvarez E, et al. Effects of policosanol (10 mg/d) versus aspirin (100 mg/d) in patients with intermittent claudication: a 10-week, randomized, comparative study. Angiology . 2008;59(3):269-277.
37. Castaño G, Más R, Gámez R, Fernández L, Illnait J. Effects of policosanol and ticlopidine in patients with intermittent claudication: a double-blinded pilot comparative study. Angiology . 2004;55(4):361-371.
38. Fontani G, Lodi L, Migliorini S, Corradeschi F. Effect of omega-3 and policosanol supplementation on attention and reactivity in athletes. J Am Coll Nutr . 2009;(28 suppl):473S-481S.
39. Abdul MI, Williams KM, Day RO, et al. Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. BJCP . 2010;69(5):508-515.
40. Molina Cuevas V , Arruzazabala ML , Carbajal Quintana D , Más Ferrerio R , Valdés García S . Effect of policosanol on arterial blood pressure in rats. Study of the pharmacological interaction with nifedipine and propranolol . Arch Med Res . 1998;29(1):21-24.
41. Arruzazabala ML , Carbajal D , Más R , Valdés S , Molina V . Pharmacological interaction between policosanol and nitroprusside in rats . J Med Food . 2001;4(2):67-70.
42. Fernández S, Más R, Gámez R, et al. A pharmacological surveillance study of the tolerability of policosanol in the elderly population. Am J Geriatr Pharmacother . 2004;2(4):219-229.
43. Rodríguez MD , García H . Evaluation of peri- and post-natal toxicity of Policosanol in rats . Teratog Carcinog Mutagen . 1998;18(1):1-7.
44. Rodríguez MD , García H . Teratogenic and reproductive studies of policosanol in the rat and rabbit . Teratog Carcinog Mutagen . 1994;14(3):107-113.
45. Alemán CL , Puig MN , Elías EC , et al. Carcinogenicity of policosanol in mice: an 18-month study . Food Chem Toxicol . 1995;33(7):573-578.
46. Alemán CL , Más Ferreiro R , Noa Puig M , Rodeiro Guerra I , Hernández Ortega C , Capote A . Carcinogenicity of policosanol in Sprague Dawley rats: a 24-month study . Teratog Carcinog Mutagen . 1994;14(5):239-249.

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