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Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent.
Gouni-Berthold I, Berthold HK.
Medical Policlinic, University of Bonn, Bonn, Germany.
BACKGROUND: Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is octacosanol. The mixture has been shown to lower cholesterol in animal models, healthy volunteers, and patients with type II hypercholesterolemia. METHODS: We reviewed the literature on placebo-controlled lipid-lowering studies using policosanol published in peer-reviewed journals as well as studies investigating its mechanism of action and its clinical pharmacology. RESULTS: At doses of 10 to 20 mg per day, policosanol lowers total cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol by 21% to 29% and raises high-density lipoprotein cholesterol by 8% to 15%. Because higher doses have not been tested up to now, it cannot be excluded that effectiveness may be even greater. Daily doses of 10 mg of policosanol have been shown to be equally effective in lowering total or LDL cholesterol as the same dose of simvastatin or pravastatin. Triglyceride levels are not influenced by policosanol. At dosages of up to 20 mg per day, policosanol is safe and well tolerated, as studies of >3 years of therapy indicate. There is evidence from in vitro studies that policosanol may inhibit hepatic cholesterol synthesis at a step before mevalonate generation, but direct inhibition of the hydroxy-methylglutaryl-coenzyme A reductase is unlikely. Animal studies suggest that LDL catabolism may be enhanced, possibly through receptor-mediated mechanisms, but the precise mechanism of action is not understood yet. Policosanol has additional beneficial properties such as effects on smooth muscle cell proliferation, platelet aggregation, and LDL peroxidation. Data on efficacy determined by clinical end points such as rates of cardiac events or cardiac mortality are lacking. CONCLUSIONS: Policosanol seems to be a very promising phytochemical alternative to classic lipid-lowering agents such as the statins and deserves further evaluation.
Publication Types:

·  Review

Protective effect of policosanol on atherosclerotic plaque on aortas in monkeys.
Noa M, Mas R.
Center of Natural Products, National Center for Scientific Research, Havana City, Cuba.
BACKGROUND: Policosanol is a cholesterol-lowering drug isolated from sugar cane wax with concomitant antiplatelet effects. Previous studies have shown that policosanol prevents lipofundin-induced atherosclerotic lesions in rabbits and rats, including foam cell formation, as well as the development of foam cells in carrageenan-induced granulomas in rats. Policosanol also inhibits smooth muscle cells proliferation induced on rabbit cuffed artery and on forceps-induced arterial wall damage. Furthermore, policosanol administered long term lowered serum cholesterol and prevented the development of atherosclerotic lesions in Macaca arctoides monkeys. The present study was undertaken to determine whether policosanol could change some characteristic features of atherosclerotic lesions, such as macrophage number and immunohistochemical localization of apoA-1 and apoB in aortas of M. arctoides monkeys. METHODS: Fourteen adult male monkeys weighing 6-10 kg and receiving a low fat, protein-rich diet were randomly distributed in three groups: control group (six monkeys) and two other groups (four monkeys/group) treated with policosanol (2.5 and 25 mg/kg) for 54 weeks. Samples of arteries were examined by light microscopy. Monoclonal antibodies were used to evaluate the presence of macrophage, apoA-1 and apoB. RESULTS: Policosanol reduced the presence of macrophages and the occurrence of apoB, whereas increased apoA-1 localization in aortic atherosclerotic lesions compared with control monkeys. CONCLUSIONS: These results suggest the policosanol potential benefit on plaque composition and stability and could explain the protective effects of policosanol on atherosclerosis development.

Effects of addition of policosanol to omega-3 fatty acid therapy on the lipid profile of patients with type II hypercholesterolaemia.
Castano G, Fernandez L, Mas R, Illnait J, Gamez R, Mendoza S, Mesa M, Fernandez J.
Surgical Medical Research Center, Havana City, Cuba.
BACKGROUND: Policosanol is a mixture of higher aliphatic primary alcohols purified from sugar-cane wax. The mixture has cholesterol-lowering efficacy, its specific effects being to reduce serum total (TC) and low-density lipoprotein cholesterol (LDL-C), and to increase high-density lipoprotein cholesterol (HDL-C). The effects of policosanol on triglycerides (TG) are modest and inconsistent. Omega-3 fatty acids (FA) from fish oil protect against coronary disease, mainly through antiarrhythmic and antiplatelet effects. Omega-3 FA also have lipid-modifying effects, mostly relating to TG reduction. Thus, potential benefits could be expected from combined therapy with omega-3 FA and policosanol. OBJECTIVE: To investigate whether combined therapy with omega-3 FA + policosanol offers benefits compared with omega-3 FA + placebo with respect to the lipid profile of patients with type II hypercholesterolaemia. METHODS: This randomised, double-blind study was conducted in 90 patients with type II hypercholesterolaemia. After 5 weeks on a cholesterol-lowering diet, patients were randomised to omega-3 FA + placebo, omega-3 FA + policosanol 5 mg/day or omega-3 FA + policosanol 10 mg/day for 8 weeks. Omega-3 FA was supplied as 1g capsules (two per day); placebo and policosanol were provided in tablet form. Physical signs and laboratory markers were assessed at baseline and after 4 and 8 weeks on therapy. Drug compliance and adverse experiences (AEs) were assessed at weeks 4 and 8. The primary efficacy variable was LDL-C reduction; other lipid profile markers were secondary variables. RESULTS: After 8 weeks, omega-3 FA + policosanol 5 and 10 mg/day, but not omega-3 FA + placebo, significantly reduced LDL-C by 21.1% and 24.4%, respectively (both p < 0.0001). Omega-3 FA + policosanol 5 mg/day also significantly lowered TC (12.7%; p < 0.01) and TG (13.6%; p < 0.05), and significantly increased HDL-C (+14.4%; p < 0.001). Omega-3 FA + policosanol 10 mg/day significantly decreased TC (15.3%; p < 0.001) and TG (14.7%; p < 0.01), and significantly increased HDL-C (+15.5%; p < 0.0001). Omega-3 FA + placebo significantly reduced TG (14.2%; p < 0.05) but had no significant effect on other lipid profile variables. The proportion of randomised patients in the omega-3 FA + policosanol 5 or 10 mg/day groups that achieved LDL-C targets or reductions 15% was significantly greater than in the omega-3 FA + placebo group (p < 0.001). Combined therapy with omega-3 FA + policosanol 5 or 10 mg/day resulted in significantly greater changes in LDL-C, TC and HDL-C than treatment with omega-3 FA + placebo, but did not modify the TG response compared with the omega-3 FA + placebo group. Four patients (two in the omega-3 FA + placebo group and two in the omega-3 FA + policosanol 10 mg/day group) withdrew from the study; none of these withdrawals was due to AEs. Two patients reported mild AEs, namely nausea/headache (one in the omega-3 FA + placebo group) and heartburn (one in the omega-3 FA + policosanol 5 mg/day group). CONCLUSIONS: Policosanol 5 or 10 mg/day administered concomitantly with omega-3 FA 1 g/day improved LDL-C, TC and HDL-C, maintained the reduction in TG attributable to omega-3 FA monotherapy, and was well tolerated. Treatment with omega-3 FA + policosanol could be useful for regulating lipid profile in patients with type II hypercholesterolaemia, but further studies involving larger sample sizes are needed before definitive conclusions can be drawn.
PMID: 16050054 [PubMed - in process]

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An ezetimibe-policosanol combination has the potential to be an OTC agent that could dramatically lower LDL cholesterol without side effects.
McCarty MF.
NutriGuard Research, 1051 Hermes Avenue, Encinitas, CA 92024, USA.
Although many risk factors influence atherogenesis, LDL appears to play a primary role in this process. In prospective epidemiology, coronary risk increases as LDL cholesterol increases, throughout the entire range of concentrations encountered in healthy humans. Coronary risk is minimal in individuals and populations whose serum cholesterol remains quite low throughout life. Thus, practical strategies for achieving large reductions of LDL cholesterol in the general population could have a dramatic impact on coronary mortality rates. Dietary measures have limited potential in this regard; modest restriction of saturated fat has a rather trivial effect on LDL cholesterol, and the very-low-fat quasi-vegan diets that do have a notable effect in this regard currently have little appeal to the majority of the population. With respect to pharmacotherapy, most available hypolipidemic agents with reasonably potent activity entail side effects or compliance difficulties that would render their use too expensive or impractical for population-wide application. However, two agents may have great potential in this regard: policosanol and ezetimibe. The former, a mixture of long-chain alcohols derived from sugar cane wax, has effects on serum lipids comparable to those of statins, and may work by down-regulating expression of HMG-CoA reductase. However, unlike statins, policosanol appears to be devoid of side effects or risks. Ezetimibe is a newly approved drug that is a potent and highly specific inhibitor of an intestinal sterol permease; in daily doses as low as 10 mg, it suppresses intestinal absorption of cholesterol and decreases serum LDL cholesterol by approximately 18%. No side effects have been seen in clinical doses, and the fact that its hypolipidemic activity is additive to that of statins has generated considerable interest. Both policosanol and ezetimibe can be administered once daily. Future studies should determine whether policosanol, like statins, interacts additively with ezetimibe. If so, it may be feasible someday to produce a tablet combining policosanol and ezetimibe that could reduce LDL cholesterol by about 40%, without side effects, and that could be recommended to virtually anyone whose LDL cholesterol levels were not already ideal.

Role of policosanols in the prevention and treatment of cardiovascular disease.
Varady KA, Wang Y, Jones PJ.
School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.
Policosanols are a mixture of aliphatic alcohols derived from purified sugar cane. When administered at 5 to 20 mg/day, policosanols have been shown to decrease the risk of atheroma formation by reducing platelet aggregation, endothelial damage, and foam cell formation in animals. Additionally, policosanols have been shown to lower total and low-density lipoprotein (LDL) cholesterol levels by 13 to 23% and 19 to 31%, respectively, while increasing high-density lipoprotein (HDL) cholesterol from 8 to 29%. Policosanols are thought to improve lipid profiles by reducing hepatic cholesterol biosynthesis while enhancing LDL clearance. When compared with statins, policosanols exhibit comparable cholesterol-lowering effects at much smaller doses. The mixture is well tolerated when administered to animals; however, a more precise safety profile is needed for humans. In summary, policosanols are a promising resource in the prevention and therapy of cardiovascular disease (CVD), but these results need to be confirmed in independent laboratories.

A 6-Month Study on the Toxicity of High Doses of Policosanol Orally Administered to Sprague-Dawley Rats.
Gamez R, Aleman CL, Mas R, Noa M, Rodeiro I, Garcia H, Hernandez C, Menendez R, Aguilar C.
Center of Natural Products, National Center for Scientific Research, Cubanacan, Havana, Cuba.
Policosanol is a cholesterol-lowering drug purified from sugar cane. Previous toxicological studies have not demonstrated any policosanol-related toxicity, even with long-term oral administration at 500 mg/kg, a dose 1,724 times larger than the maximal therapeutic dose (20 mg/day) recommended to date. The present study was undertaken to investigate the oral toxicity of policosanol administered for 6 months in doses up to 5,000 mg/kg to Sprague-Dawley rats. Animals were randomly distributed in five groups (15 animals per dose per sex): a control and four groups given oral policosanol (50, 500, 2,500, or 5,000 mg/kg). Eight treated rats (6 males, 2 females) died during the study, five of them (4 males, 1 female) from among those receiving the highest dose (5,000 mg/kg). According to necropsy, all deaths were related to gavage manipulation of higher doses. Although the differences were not significant, body weight gain and food consumption in the groups receiving 2,500 or 5,000 mg/kg tended to be lower than in the control group. Nevertheless, no drug-related toxicity symptoms were detected. Analysis of blood biochemistry, hematology, organ weight ratios, and histopathological findings did not show significant differences compared with controls, nor any tendency with the dose. Therefore, the present study did not show any new evidence of oral toxicity of policosanol, and the findings observed were a consequence of long-term administration by gastric gavage of the highly concentrated suspensions needed to reach the higher doses. It is concluded that policosanol chronically administered by the oral route is safe and that no drug-related toxicity was demonstrated.

Efficacy of over-the-counter nutritional supplements.
Davidson MH, Geohas CT.
Department of Preventive Cardiology, Rush-Presbyterian-St. Luke's Medical Center, 1725 West Harrison Street, Suite 1159, Chicago, IL 60612, USA.
More than 100 million people in the United States report using nutritional supplements. Most people are under the impression that nutritional supplements offer health benefits and are closely regulated to ensure safety and efficacy. Unfortunately, the Dietary Supplement Health and Education Act of 1994 allows for the promotion of nutritional supplements without review by the United States Food and Drug Administration; therefore, it is important to evaluate the efficacy and safety of these supplements. There is strong scientific evidence supporting the use of plant sterols/stanols, omega-3 fatty acids, niacin, folate, vitamin B(6)/B(12), and tree nuts. There is potential evidence for the health benefits of soy protein, tea extracts, policosanol, guggulipids, coenzyme Q10, and L-arginine. There has been a lack of evidence for the health benefits of garlic and antioxidants.

Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia.
Castano G, Fernandez L, Mas R, Illnait J, Fernandez J, Mesa M, Alvarez E, Lezcay M.
Medical and Surgical Research Center, National Center for Scientific Research, Havana, Cuba.
This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol and Octa-60 in patients with type II hypercholesterolemia. After 4 weeks on a diet, 110 patients were randomized to policosanol or Octa-60 5 mg tablets once a day for 5 weeks. The dose was then doubled to 10 mg/day for the next 5 weeks. Policosanol 5 and 10 mg/day significantly lowered low-density lipoprotein-cholesterol (LDL-C) (p<0.0001 and p<0.00001), the main efficacy variable, by 18.6% and 30.2%, while Octa-60 significantly reduced (p<0.05) LDL-C by 10.0% at study completion only. The frequency of policosanol patients reaching reductions of LDL-C > or = 15% after 5 mg/day (37/55; 67.3%) and 10 mg/day (47/55; 88.7%) was greater (p<0.01 and p<0.01) than in the Octa-60 group, which was 5/55 (9.1%) and 20/55 (36.4%). Likewise, the frequency of patients reaching LDL-C values of <3.4 mmol/l at study completion was greater (p<0.001) in the policosanol group (39/55, 70.9%) than in the Octa-60 group (6/55, 10.9%). Policosanol 5 and 10 mg/day significantly lowered (p<0.00001) total cholesterol (TC) (13.4% and 20.4%), LDL-C/high-density lipoprotein-cholesterol (HDL-C) (22.1% and 37.0%) and TC/HDL-C (17.2% and 28.2%). Octa-60 at 10 mg/day lowered (p<0.05) TC (8.7%), LDL-C/HDL-C (12.6%) and TC/HDL-C (9.4%). HDL-C was increased (p<0.001 and 0.0001) by policosanol 5 and 10 mg/day (5.6% and 12.5%) but was unchanged by Octa-60. In both groups, triglycerides remained unchanged. Both treatments were safe and well tolerated. Octa-60, but not policosanol, significantly increased glucose and alanine aminotransferase, but individual values were within the normal range. Four patients (two from each group) discontinued the trial, but only one (in the Octa-60 group) did so because of an adverse event (AE) (skin rash). Overall, three patients (all from the Octa-60 group) reported AEs. In conclusion, original policosanol at 5 and 10 mg/day, but not Octa 60, was effective in patients with type II hypercholesterolemia. Thus, policosanol reached the efficacy criterion for LDL-C reduction in both steps, while Octa-60 failed to reach this goal. In addition, policosanol was better tolerated than Octa-60.