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Policosanols as Nutraceuticals: Fact or Fiction

a a a a
Christopher P. F. Marinangeli , Peter J. H. Jones , Amira N. Kassis & Michael N. A. Eskin
a
Richardson Centre for Functional Foods and Nutraceuticals, Departments of Food Science
and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
Published online: 17 Mar 2010.

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 Critical Reviews in Food Science and Nutrition, 50:259–267 (2010)
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ISSN: 1040-8398
DOI: 10.1080/10408391003626249

Policosanols as Nutraceuticals: Fact

or Fiction

CHRISTOPHER P. F. MARINANGELI, PETER J. H. JONES, AMIRA N. KASSIS,

and MICHAEL N. A. ESKIN
Richardson Centre for Functional Foods and Nutraceuticals, Departments of Food Science and Human Nutritional Sciences,
Downloaded by [University of Saskatchewan Library] at 08:50 05 May 2013

University of Manitoba, Winnipeg, Manitoba, Canada

Policosanols (PC) are very long chain aliphatic alcohols derived from the wax constituent of plants. In the early 1990s,
researchers at Dalmer Laboratories in La Habana Cuba isolated and produced the first PC supplement from sugarcane
wax. The original PC supplement has been approved as a cholesterol-lowering drug in over 25 countries throughout the
Caribbean and South America. Cuban studies claim that 1 to 20 mg/day of the original PC supplement are effective at
producing significant reductions in total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). These studies
also show that PC supplements are potent antioxidants, promote proper arterial endothelial cell function, inhibit platelet
aggregation and thrombosis, and serve as effective treatments for intermittent claudication. However, for the most part, those
studies reporting therapeutic efficacy of PC were carried out by one research group situated in Cuba. Conversely, research
groups outside of Cuba have failed to validate the cholesterol-lowering and antioxidant efficacy of PC. Cuban researchers,
however, continue to claim that the efficacy is attributed to the unique purity and composition of the original PC preparation,
a mixture not found in PC products used by external research groups. The absence of independent and external studies
confirming the therapeutic benefits of PC in disease prevention and treatment raises questions regarding their true efficacy.

Keywords policosanols, long chain alcohols, sugar cane, therapeutic properties

INTRODUCTION population which varies between 12 and 40 mg/d. Logically,

Plant waxes consist of very long chain fatty acids esteri-
fied to very long chain alcohols. Policosanols (PC) are ob-
tained by hydrolyzing wax esters and isolating the alcohol
constituent. PC are classified as very long chain alcohols with
carbon backbones ranging from 24 to 34 carbons and include—
tetracosanol (C24), hexacosanol (C26), heptacosanol (C27), oc-
tacosanol (C28), nonacosanol (C29), triacontanol (C30), dotri-
acontanol (C32), and tetratriacontanol (C34) (Gouni-Berthold
and Berthold, 2002; Mas, 2000; ThorneResearch, 2004). Due to
their long saturated carbon structure, PCs are very hydrophobic.
Although PC therapeutic efficacy has been based primarily
on PC derived from sugarcane wax, PC can also be isolated
from other sources such as beeswax, cereal grains, and grasses
(Hargrove et al., 2004). PCs are also found in the leaves, fruits,
nuts, and seeds of many foods (Hargrove et al., 2004). Very
little is known regarding PC levels in foods; however, estima-
tions have been made on hexacosanoic acid intake in the US
Address all correspondence to: Michael N. A. Eskin, University of Mani-
toba, Human Ecology Bldg, room 406, Winnipeg, MB, R3T 2N2, Telephone:
(204) 474 8078, Fax: (204) 474-7592. Email: eskin@ms.umanitoba.ca
259
the question arises “why supplement with PC when they are
readily available in the food supply?” Unfortunately, the hu-
man digestive system has yet to find a way to effectively hy-
drolyze wax esters. Of the small amount of dietary PC available
for absorption, their extreme hydrophobic nature limits solubi-
lization and movement across the intestinal mucosa (Hargrove
et al., 2004). The observation that chloroform, a very non-polar
solvent, is the only chemical able to effectively solubilize PC to
a maximum concentration of 1.25 mg/ml (25◦ C) and 2.5 mg/ml
(40◦ C), illustrates the extent of their hydrophobic nature (Urib-
arri et al., 2002). Studies using medium and long chain fatty
acids have shown that as the carbon chain length (Sallee, 1979;
Sallee and Dietschy, 1973) and the degree of saturation increase
(Jones et al., 1985a, 1985b), intestinal absorption is significantly
decreased. Due to the structural similarities between PC and
fatty acids, the problems associated with the absorption of long
chain length and saturated fatty acids could be extrapolated to
PC. Studies examining tissue distribution of radiolabelled octa-
cosanol in rats found 31 to 33% of the administered radioactivity
was in the feces (Kabir and Kimura, 1993; 1995), which fur-
ther suggested the low bioavailability of PC (Kabir and Kimura,
1993; 1995).
 260 C. P. F. MARINANGELI ET AL.
Despite low bioavailability, numerous studies originating in
Cuba have shown PC supplements to be efficacious treatments
for various cardiovascular-related ailments including hyperc-
holesterolemia, poor arterial function, poor antioxidant status,
and intermittent claudication. Nonetheless, in many instances,
studies outside of Cuba have not been able to reproduce previous
evidence regarding PC as adjunctive treatment for cardiovascu-
lar disease risk factors. The purpose of the present review is
to provide a detailed, objective overview of evidence regarding
supplemental PC efficacy in treating or decreasing symptoms
and risk factors associated with cardiovascular disease in hu-
mans.
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COMPOSITION AND STABILITY OF THE ORIGINAL
POLICOSANOL SUPPLEMENT
Only the original PC supplement produced by Dalmer Labo-
ratories has been shown to possess health promoting properties.
Currently, its main indication is for the treatment of hyperc-
holesterolemia. Researchers owe its irreproducible efficacy to
that of its unique PC composition (Castano et al., 2002a). The
product is reported to have ≥90% PC purity relative to the
total lipid fraction. The proportions of the major PC include
hexacosanol (4.5%–10%), octacosanol (60–70%) and triacon-
tanol (10%–15%) (Fig. 1) (Castano et al., 2002a; Mas, 2000).
The other alcohols are present in much smaller quantities—
tetracosanol (≤2%), heptacosanol (≤5%), nonacosanol (≤2%),
dotriacontanol (3%–8%), and tetratriacontanol (≤2%) (Castano
et al., 2002a; Mas, 2000). The original research group hypoth-
esized that octacosanol is the major active PC responsible for
efficacy since it is present in the largest quantity (Castano et al.,
2002a; Mas, 2000).
Studies testing the stability of the original PC supplement re-
port that when subjected to environments that favor acid hydrol-
ysis, basic hydrolysis, oxidation, photolytic degradation, and
thermolysis for 9 months, the PC content remained unchanged
(Cabrera et al., 2002; Cabrera et al., 2003). The researchers in-
dicate that the original PC supplement should have a shelf-life
of 5 years.
Supplementation Regimen for Treatment of
Hypercholesterolemia
The original PC supplement is manufactured by the Dalmer
Laboratories in La Habana Cuba and is available commercially
OH
A.
B.
C.
Figure 1 Chemical structures of A. Hexacosanol(C26), B. Octacosanol (C28)
and C. triacontanol (C30).
in tablet form in Central and South America, the Caribbean,
and Canada (Gouni-Berthold and Berthold, 2002; Marinangeli
et al., 2007). The patients who elect to use PC as a means of treat-
ing hypercholesterolemia are instructed to initiate treatment at
5 mg/day. If ineffective, the treatment dose should be gradually
increased to a maximum of 20 mg/day (ThorneResearch, 2004).
THERAPEUTIC PROPERTIES OF THE ORIGINAL
POLICOSANOL SUPPLEMENT
Cholesterol Lowering Efficacy
Compared to the baseline, supplemental PC have been shown
to elicit significant decreases in TC and LDL-C levels ranging
from 12.8 to 23% and 11.3 and 31.2% respectively (Aneiros
et al., 1993; 1995; Batista et al., 1996; Canetti et al.,
1995a; 1995b; Castano et al., 1995a; 2001b; 2001c; 2005;
1995b;1996; Mas et al., 1999; Mirkin et al., 2001; Pons et
al., 1992;1994a;1994b; Torres et al., 1995). Cholesterol reduc-
tions are dose-dependent and are consistent across a range of
populations including postmenopausal women (Castano et al.,
2000b; Mirkin et al., 2001) and those who have also been diag-
nosed with coronary heart disease (Batista et al., 1996), diabetes
(Torres et al., 1995), hypertension (Castano et al., 1996), and
multiple coronary risk factors (Mas et al., 1999). A summary of
studies outlining PC cholesterol lowering efficiacy can be found
in Table 1.
Although PC cholesterol-efficacy is dose dependent, its ther-
apeutic effects plateau at 20 mg/day (Arruzazabala et al., 2002;
Castano et al., 2001c). A study comparing the effectiveness
of 20 mg/day and 40 mg/day doses of PC in treating type II
hypercholesterolemia reported a 15.6 and 17.3% decrease in
TC, coupled with 27.4 and 28.1% decrease in LDL-C respec-
tively. PC efficacy in reducing TC and LDL-C was not statisti-
cally significant between volunteers receiving the two doses.
The researchers concluded that PC supplementation reaches
its maximum level of efficacy at 20 mg/day (Castano et al.,
2001c).
Studies in Cuba also compared the cholesterol-lowering effi-
cacy of PC supplementation with cholesterol-lowering prescrip-
tion medications. One such study compared the lipid-lowering
effects of 10 mg/day PC with 10mg/day of simvastatin for 6 wks.
TC and LDL-C significantly decreased with both treatments. PC
and simvastatin produced reductions in TC of 14.7 and 15.2%,
alongside a decrease in LDL-C of 17.9 and 19.8% respectively.
(Ortensi et al., 1997). Comparatively, the results between groups
were statistically similar (Ortensi et al., 1997). PC has also been
shown to be more effective than prescription medications in
OH
reducing serum cholesterol levels. When the effectiveness of
10 mg/day of PC was compared to 20 mg/day of lovastatin
for 12 wks, PC decreased TC and LDL-C by 22.4 and 32.4%,
OH
respectively (Castano et al., 2000a) while patients receiving lo-
vastatin displayed 19.8 and 27.6% decreases in TC and LDL-C,
respectively (Castano et al., 2000a). Between-group statistical
 POLICOSANOLS: FACT OR FICTION 261

Table 1 Summary of Cuban studies showing cholesterol-lowering efficacy using the original Cuban PC supplement

Effects of Original Cuban PC on Lipid Levels

Study Dose
Reference Subjects Duration mg/day Protocol TC LDL-C HDL-C

Batista et al., 1999 23 14 mo 2 Parallel-arm design. Subjects received 2 mg/d ↓TC 14.8%, ↓LDL-C 15.6% n/c
HL, CHD PC or placebo for 14 months.
Mas et al., 1999 437 12 wks 5 Parallel-arm design. Subjects received 5 mg/d ↓TC 13.0% ↓LDL-C 18.2% ↑HDL-C 15.5%
HC, CR 10 PC or placebo for 12 weeks. At the end of ↓TC 17.4% ↓LDL-C 25.6% ↑HDL-C 28.4%
the study period the PC dose was increased
to 10 mg/d for another 12 weeks.
Menendez et al., 2000 69 8 wks 5 Parallel-arm design. Subjects received 5 mg /d ↓TC 10.5% ↓LDL-C 16.7% ↑HDL-C 9.0%
NC 10 PC, 10 mg/d PC or placebo for 8 weeks. ↓TC 12.4% ↓LDL-C 20.2% ↑HDL-C 15.2%
Castano et al., 2001b 179 12 wks 5 Parallel-arm design. Subjects received 5 mg/d ↓TC 12.8% ↓LDL-C 16.9% ↑HDL-C 14.6%
HC, CR 10 PC or placebo for 12 weeks. At the end of ↓TC 16.2% ↓LDL-C 24.4% ↑HDL-C 29.1%
the study period the PC dose was increased
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to 10 mg/d for another 12 weeks.

Mirkin et al., 2001 56 8 wks 5 Parallel-arm design. Subjects received 5 mg/d ↓TC 12.9% ↓LDL-C 17.3% n/c
PM, HC 10 PC or placebo for 8 weeks. At the end of the ↓TC 19.5% ↓LDL-C 26.7% ↑HDL-C 7.4%
study period the PC dose was increased to
10 mg/d for another 12 weeks.
Castano et al., 2002a 110 5 wks 5 Parallel-arm design. Subjects received 5 mg/d ↓TC 13.4% ↓LDL-C 18.6% ↑HDL-C 5.6%
HC 10 Cuban sugarcane PC or non-Cuban ↓TC 20.4% ↓LDL-C 30.2% ↑HDL-C 12.5%
sugarcane PC for 5 weeks. At the end of the
study period PC dosages was increased to
10 mg/d for another 5 weeks.
Castano et al., 2003a 40 8 wks 10 Parallel-arm design. Subjects received 10 mg/d ↓TC 18.2% ↓LDL-C 25.7% ↑HDL-C 11.1%
DL, TIID PC or 10 mg/d atorvastatin for 8 weeks.
Castano et al., 2001c 89 24 wks 20 Parallel-arm design. Subjects received 20 mg ↓TC 15.6% ↓LDL-C 27.4% ↑HDL-C 17.6%
HC 40 PC, 40 mg/d PC or placebo for 24 weeks. ↓TC 17.3% ↓LDL-C 28.1% ↑HDL-C 17.0%
Arruzazabala et al., 2002 45 30 d 20 Parallel-arm design. Subjects received 20 mg/d ↓TC 12.4% ↓LDL-C 15.9% ↑HDL-C 5.4%
NC, HC 40 PC, 40 mg/d PC or placebo for 30 d. ↓TC 12.3% ↓LDL-C 17.0% ↑HDL-C 5.1%

Abbreviations: CHD, coronary heart disease, CR, coronary risk factors; DL, dyslipidemia; HC, hypercholesterolemic; HDL-C, high density cholesterol; HL,
hyperlipidemic; NC, normocholesterolemic; PM, postmenopausal; TIID, type II diabetes; PC, policosanol; TC, total cholesterol; LDL-C, low-density lipoprotein
cholesterol.

analysis indicated that the reduction in cholesterol levels in the
PC group were greater than those observed in the lovastatin
group (Castano et al., 2000a). Similar results for cholesterol-
lowering efficacy have been obtained when PC efficacy was
compared to pravastatin (Benitez et al., 1997; Castano et al.,
1999a), atorvastatin (Castano et al., 2003a; 2003b), acipimox
(Alcocer et al., 1999), and probucol (Pons et al., 1997).
Proposed Mechanism of Action
Policosanols are thought to elicit their cholesterol-lowering
effects by inhibiting endogenous cholesterol biosynthesis. An in
vitro study using tritium labeled water indicated that 3 H2 O in-
corporation into synthesized cholesterol was inhibited by 43.7%
with 50 µg/ml PC (Menendez et al., 2001a). When fibroblasts
containing either 14 C-acetate or 14 C-mevalonate were incubated
with PC at doses of 0.5 µg/ml, 5.0 µg/ml, and 50 µg/ml,
the incorporation of 14 C from acetate into cholesterol was in-
hibited in a dose-dependent manner (Menendez et al., 2001a;
1994). Acetate and mevalonate are two biochemical interme-
diates found within the endogenous cholesterol biosynthesis
pathway. Acetate is transformed to mevalonate by 3-hydroxy-
3-methyl-glutaryl CoA (HMG-CoA) reductase (Stryer, 1995).
The above results show that PC affect HMG-CoA reductase
activity and thus slowing endogenous cholesterol biosynthesis
prior to the production of mevalonate, but after acetate genera-
tion. Researchers indicate that PC does not competitively inhibit
HMG-CoA reductase activity (Menendez et al., 2001a; 1994).
Instead, it has been suggested that PC could reduce synthesis
of HMG-CoA reductase or enhance its degradation (Menendez
et al., 2001a; Menendez et al., 1994). Researchers propose that
PC could be manipulating the activity of HMG-CoA reductase
by affecting the physio-chemical properties of certain cellular
organelle membranes (Menendez et al., 2001b). During hepatic
metabolism of PC, PC are thought to be transformed to their
corresponding acids in the endoplasmic reticulum (ER) and are
subsequently chain shortened in the peroxisome (Hargrove et al.,
2004). The peroxisome and ER contain the highest levels of
HMG-CoA reductase (Olivier and Krisans, 2000). Moreover, di-
etary fatty acids have been shown to affect HMG-CoA reductase
activity by altering the membrane fluidity of cellular organelles
(Davis and Poznansky, 1987; Whitcomb et al., 1988). Although
evidence has yet to be published, it is possible that PC corre-
sponding acids are incorporated into the membranes of the ER
and peroxisome, downregulating HMG-CoA reductase activity.
 262 C. P. F. MARINANGELI ET AL.
In a recent in vitro study conducted outside Cuba (Singh
et al., 2006), PC reduced 14 C-acetate incorporation into synthe-
sized cholesterol by 30%. When the effects of individual PC
components were tested, triacontanol, not octacosanol, was the
only PC showing any efficacy (Singh et al., 2006). The results
of the study also showed a significant decrease in HMG-CoA
reductase activity, coupled with an increase in phosphorylated
AMP-kinase (Singh et al., 2006). These researchers suggested
that PC activation of AMP-kinase could be one of the mech-
anisms responsible for PC cholesterol-lowering efficacy since
phosphorylated AMP-kinase is a known inhibitor of HMG-CoA
reductase (Singh et al., 2006). However, these results have yet to
be verified as observed in vivo by independent clinical studies.
Despite the above theory linking PC metabolism to reduc-
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tions in HMG-CoA reductase activity, it could be hypothesized
that PC supplementation should have the opposite effect on
blood cholesterol levels. PC could be metabolized to their cor-
responding saturated fatty acids. The relationship between sat-
urated fat and its promotion of increased levels of circulating
cholesterol has been well established (“Third Report of the Na-
tional Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel III) final report,” 2002).
Coupled with reducing HMG-CoA reductase activity, PC
have also been shown to increase LDL-C uptake by the liver.
In an in vitro study using 125 I-LDL-C, PC supplementation
significantly increased the cell binding, internalization, and
degradation of 125 I-LDL-C in a dose dependent manner
(Menendez et al., 1994). Similar results have been noted in rab-
bits, whereby the half-lifeof serum 125 I-LDL-C was significantly
reduced in animals supplemented with 50 mg/day of PC for 30
days (Menendez et al., 1997). The observed increase in LDL-C
uptake with PC supplementation could be related to PC effect
on cholesterol levels. As circulating cholesterol levels decrease
the hepatic uptake of LDL-C increases to facilitate endogenous
cholesterol synthesis (Stryer, 1995). Overall, the reduced
HMG-CoA reductase activity and enhanced hepatic clearance
of LDL-C are hypothesized as the primary cholesterol-lowering
mechanisms of action induced by PC supplements.
Evidence Disputing the Cholesterol-lowering Efficacy of
Policosanol Supplements
As mentioned above, previous studies reported significant
reductions in serum cholesterol levels with PC supplemen-
tation have originated from Cuban research groups. External
researchers attempting to confirm the cholesterol-lowering
efficacy with PC have failed in both animal (Kassis et al., 2007;
Murphy et al., 2004; Y. Wang et al., 2005; Y. W. Wang et al.,
2003) and human models (Berthold et al., 2006; Cubeddu et al.,
2006; Dulin et al., 2006; Francini-Pesenti et al., 2008; Greyling
et al., 2006; Kassis and Jones, 2006; Lin et al., 2004; Reiner
et al., 2005).
Most external studies testing PC efficacy, however, did not
use sugarcane derived products (Lin et al., 2004; Murphy et al.,
2004; Reiner et al., 2005; Y. Wang et al., 2005; Y. W. Wang et
al., 2003). If sugarcane PC supplements were used, PC prepa-
rations were different from the original product used in Cuban
studies (Cubeddu et al., 2006; Dulin et al., 2006; Greyling et al.,
2006). The original research group has published a study com-
paring original PC supplement and another sugarcane derived


R
PC product called Lesstanol . The results indicated that orig-
inal PC significantly reduced TC and LDL-C in hypercholes-
terolemic patients by 20.4% and 30.2%, respectively (Castano et
al., 2002a). Reductions in TC and LDL-C were less prominent


R
in the Lesstanol group at 10.0 and 8.7% respectively (Cas-
tano et al., 2002a). The original research group indicated that


the disparity between products was due to Lesstanol having
R
a significantly lower PC purity and octacosanol concentration
relative to other PC within the mixture (Castano et al., 2002a).
They also indicated that the original PC supplement has a spe-
cific purity and composition capable of producing significant re-
ductions in cholesterol levels. Hence, these authors questioned
the validity of external studies using alternative sugarcane and
non-sugarcane PC supplements that fail to report any thera-
peutic effect with PC supplementation (Castano et al., 2002a).
Nonetheless, Marinangeli et al. (2007) compared the original
Cuban PC supplement with alternative non-Cuban sugarcane


R
derived PC formulations, including Lesstanol , and showed that
all preparations possessed a similar purity and very long chain
alcohol composition. The similarity in composition across PC
preparations calls into question whether variations in the make-
up of different sources of PC exists as a valid explanation of
why some are effective in lowering LDL-C and some are not.
Other recent publications examining the effect of PC on blood
lipid levels also dispute the claim of the original research groups
that the original PC supplement has unique properties. For ex-
ample, Greyling et al. (2006), Berthold et al. (2006), Kassis
et al. (2006), and Francini-Pesenti et al. (2008) conducted hu-
man clinical trials to evaluate PC efficacy for the treatment of
hypercholesterolemia. In the study by Greyling et al. (2006),
hypercholesterolemic and hyperlipidemic patients were supple-


R

R
mented with 20 mg/day of Lesstanol for 12 weeks. Lesstanol
failed to produce any significant decrease in cholesterol levels
(Greyling et al., 2006). Berthold et al. (2006), failed to observe
any cholesterol-lowering efficacy when hypercholesterolemic
patients were administered either a placebo or the original PC
supplement at 10, 20, 40, or 80 mg/day for 12 wks. Similar
results were noted by Kassis et al. (2006) and Francini-Pesenti
et al. (2008) using the authentic Cuban PC mixture at 10 and
20 mg/day, respectively. Table 2 provides a summary of hu-
man clinical trials conducted outside of Cuba that evaluated the
cholesterol-lowering efficacy of PC. The above studies confirm
that the original and an alternative sugarcane PC supplement
were equally ineffective at reducing cholesterol levels in hy-
percholesterolemic patients, refuting the claim by the original
Cuban research group that the original supplement has a unique
alcohol composition that confers cholesterol-lowering efficacy.
Another external study by Reiner et al. (2005) also adminis-
tered 10 mg/day of rice PC to hypercholesterolemic patients. TC
was reduced by 5%, although no significant change in LDL-C
was observed (Reiner et al., 2005). The slight decrease in TC
 POLICOSANOLS: FACT OR FICTION 263

Table 2 Summary of non-Cuban studies showing minimal cholesterol-lowering efficacy amongst hypercholesterolemic patients supplemented with PC

Effects of PC on Lipid Levels

Study Dose
Reference Subjects Duration mg/day PC Source Study Protocol TC LDL-C HDL-C

Reiner et al., 2005 70 8 wks 10 Rice PC Crossover design. Subjects received ↓TC 5% n/c n/c
HC either 10 mg/d PC or placebo for 8
wks. Subjects received the
opposing treatment for the
following 8 wks.
Greyling et al., 2006 19 12 wks 20 Alternative non-Cuban Crossover design. Subjects received n/c n/c n/c
FHC,HC sugarcane PC 20 mg/d PC or placebo for 12 wks.
Following a 4 wk washout,
subjects received the opposing
treatment for 12 wks.
Cubeddu et al., 2006 99 12 wks 20 Alternative non-Cuban Parallel-arm design. Subjects n/c n/c n/c
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HC sugarcane PC received 20 mg/d PC, 10 mg/d

atorvastatin, combination therapy
or placebo for 12 wks.
Dulin et al., 2006 39 8 wks 20 Alternative non-Cuban Parallel-arm design. Subjects n/c n/c n/c
HC sugarcane PC received either 20 mg/d PC or
placebo for 8 wks.
Berthold et al., 2006 143 12 wks 10 Cuban sugarcane PC Parallel-arm design. Subjects n/c n/c n/c
received wither 10 mg/d PC, 20
HC, HL 20 mg/d PC, 40 mg/d, PC, 80 mg/d or n/c n/c n/c
40 placebo for 12 wks. n/c n/c n/c
80 n/c n/c n/c
Kassis and Jones. 2006 21 4 wks 10 Cuban sugarcane PC Crossover design. Subjects received n/c n/c n/c
HC 10 mg/d PC or placebo for 4 wks.
Following a 4 wk washout,
subjects received the opposing
treatment for 4 wks.
Francini-Pesenti et al., 2008 63 8 wks 20 Cuban sugarcane PC Parallel-arm design. Subjects n/c n/c n/c
HC received wither 20 mg/d PC or
placebo for 8 wks.

Abbreviations: HL, hyperlipidemic; HC; hypercholesterolemic; HDL-C, high-density lipoprotein cholesterol; FHC; familial hypercholesterolemia; LDL-C,
low-density lipoprotein cholesterol; n/c, no change; PC, policosanol; TC, total cholesterol.

was considerably less extreme than that reported by the origi-
nal research group in Cuba outlined above. Another study that
fed hamsters diets containing 0.38, 0.75, 1.5 g/kg of PC for 6
wks, reduced TC 15 to 25% (Ng et al., 2005). The decrease in
cholesterol levels was attributed to an increase in fecal bile acid
secretion (Ng et al., 2005), a departure from the mechanism
outlined by original research group and Singh et al. (2006).
However, the PC administered was not incorporated into the
diet as a PC supplement. Instead, PC were added to the diet as
pure standards of octacosanol, hexacosanol, and triacontanol.
Administering pure PC to the gastrointestinal tract would be ex-
pected to have a different physiological effect compared to the
tabulated supplement. Therefore, claims attributed to the effect
of PC on reducing cholesterol levels cannot be extrapolated to
PC supplements. Nonetheless, the effect of PC supplementation
on bile acid secretion warrants further investigation.
Policosanol Supplements as Potent Antioxidants
PC were also reported to be potent inhibitors of LDL-C per-
oxidation. A Cuban study examining the effects of PC supple-
mentation at 5 and 10 mg/day for 8 wks, reported a significant
reduction in LDL-C peroxidation in a dose dependent manner
(Menendez et al., 2000). Patients receiving 5 and 10 mg/day
increased the time of the lag phase for conjugated diene produc-
tion from 83.8 to 94.9 min and 82.7 to 129.9 min, respectively
(Menendez et al., 2000). Moreover, malondialdehyde (MDA)
production was decreased from 8.5 to 7.5 nmol/mg protein in
patients administered 5 mg/day of PC, while individuals receiv-
ing 10 mg/day of PC reduced MDA production from 8.5 to 5.8
nmol/mg protein, respectively (Menendez et al., 2000).
Another Cuban study compared the inhibition LDL-C per-
oxidation between patients receiving 10 mg/day of PC and
20 mg/day lovastatin (Castano et al., 2002b). PC supplemen-
tation increased the time of the lag phase for conjugated diene
production 20.9%, from 57.7 to 68.6 min, while lovastatin had
no effect (Castano et al., 2002b). However, both PC and lovas-
tatin similarly reduced the propagation rate for conjugated diene
production by 44.3 and 42.9%, respectively, while the maximal
diene production was reduced by 10.9 and 7.1%, respectively
(Castano et al., 2002b).
Mechanisms underlining the antioxidant properties of PC
remain to be delineated. Researchers have ascertained, however,
 264 C. P. F. MARINANGELI ET AL.
that PC do not act as reducing agents (Menendez et al., 2000).
It has been suggested that modification of the LDL-C structure,
such as the incorporation of PC or a saturated metabolite, may
render LDL-C particles less susceptible to peroxidation since
the total number of double bonds would be reduced (Menendez
et al., 2000). However, evidence to support the above mechanism
has yet to be published.
The antioxidant properties of PC are convincing. However,
similar to the evidence showing cholesterol-lowering efficacy
with PC supplementation, antioxidant efficacy was also reported
by the same research group in Cuba. To date, only one external
study has been published examining the effects of PC supple-
mentation on LDL peroxidation. An ex vivo study by Ng et al.
(2005) examined the effects of the individual PC constituents,
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tetracosanol, hexacosanol and octacosanol on LDL peroxidation
in blood samples. PC had neither effects on LDL peroxidation
nor free radical scavenging activity (Ng et al., 2005). The authors
raised serious questions regarding the true efficacy of PC as an
antioxidant. However, one cannot discount that the antioxidant
efficacy of PC supplements could depend on a synergy been the
various PC components, rendering the effect of individual PC
components ineffective.
Policosanol Supplements as Promoters of Endothelial
Function, Inhibitors of Platelet Aggregation and
Thrombosis, and Treatment for Intermittent Claudication
PC treatment has been shown to improve cardiovascular
health by improving risk factors associated with arteriosclerosis.
First, the original PC supplement has been shown to improve
the functionality of the endothelial cells lining arterial walls.
Malfunctioning or damaged endothelial cells can cause the ar-
terial wall to become irregular. This irregularity can promote
the formation of blood clots and/or atherosclerotic plaques by
encouraging inflammation, platelet aggregation and the release
of clotting factors (Elkind, 2006; Guyton and Hall, 1996). In
a study feeding 25 mg/kg of PC to rats, the level of circulat-
ing endothelial cells was significantly lower than controls after
a venous injection of sodium citrate (Noa et al., 1997). The
same results were seen when spontaneously hypertensive rats
were given a 5 mg/kg dose of PC. Moreover, rats treated with
5 mg/day noted fewer aortic lesions versus control animals (Noa
et al., 1997). These results have also been observed in humans.
After hypercholesterolemic patients had received 10 mg/day of
original PC for 6 wks, the levels of circulating endothelial cells
had significantly decreased from 556 to 462 cells/ml platelet-
rich plasma (Castano et al., 1999a).
PC are also shown to significantly reduce platelet aggre-
gation. Platelets play an integral role in blood clot formation,
which can lead to a reduction in blood flow, and eventually a
stroke or embolism. People with atherosclerosis are especially
at risk. A study where blood samples were taken from rats prior
to, and 2, 4, and 24 hours after, PC supplementation found that
2 and 4 hours after treatment, the levels of thromboxane B2 was
significantly reduced (Arruzazabala et al., 1993). Thromboxane
B2 is a stable metabolite of thromboxane A2 , a clotting factor
released by platelets during aggregation (Arruzazabala et al.,
1993; Guyton and Hall, 1996). Thus, thromboxane B2 is used to
indirectly measure thromboxane A2 levels (Arruzazabala et al.,
1993). Prior to receiving PC, animals had circulating thrombox-
ane B2 levels of 310 µg/L. After 2 hours, PC had significantly
decreased circulating thromboxane B2 levels. However, 4
hours after treatment, thromboxane B2 increased, reaching
141 µg/L. After 24 hours, levels were no longer significantly
different from the baseline value of 218.7 µg/L (Arruzazabala
et al.,1993). These results suggest that the effects of PC on
thromboxane A2 are short-lived, and PC effect on platelet
aggregation could only be effective with persistent PC therapy.
Similar results have been observed in humans. Compared to the
baseline, healthy volunteers receiving 10 mg/day of original
PC for 15 days significantly reduced platelet aggregation by
arachidonic acid and collagen by 25.6 and 10.1 %, respectively
(Carbajal et al., 1998). No significant differences were noted
in patients receiving the placebo. Further analysis indicated
that the significant reduction in platelet aggregation seen in
the treatment group was accompanied by a 15.4% reduction in
thromboxane B2 compared to baseline (Carbajal et al., 1998).
The protective effects of PC supplementation mentioned
above regarding vascular health may serve as an adjunctive
treatment for patients diagnosed with intermittent claudication,
a condition associated with peripheral vascular disease. Due to
the narrowing of arteries and reduced blood flow, patients ex-
perience pain in the lower extremities during physical activity
(Elkind, 2006). Patients diagnosed with intermittent claudica-
tion receiving 20 mg/day of PC for 6 months were able to
increase their walking distance before the onset of pain from
132.5 to 205.7 m (Castano et al., 1999b). Furthermore, patients
receiving PC treatment were able to increase the walking dis-
tance associated with the onset of intolerable pain such that the
activity was stopped from 230 to 365 m (Castano et al., 1999b).
Walking distances in the placebo group remained unchanged
(Castano et al., 1999b). In another study, 20 mg/day of PC were
administered over the course of 24 months. At baseline, the dis-
tance patients were able to walk before the onset of pain was 126
m. After 24 months of treatment, this distance had increased to
334 m (Castano et al., 2001a). The distance in which patients
were forced to stop walking due to intolerable pain increased
from 220 to 649 m. Again, no changes in walking distances were
noted in patients receiving the placebo (Castano et al., 2001a).
Although the benefits of PC on vascular health appear con-
vincing, the lack of external validation by external laboratories,
using either the original or alternative PC supplements, raises
further questions regarding their efficacy. In a recent study by
Reiner et al. (2007), 10 mg/d of rice PC had no effect on blood
coagulation after 8 wks of treatment. Again, clinical research
from independent laboratories is needed to substantiate a role
for PC supplements in promoting vascular health.
Side Effects and Safety of Policosanol Supplementation
To date, no study has reported any toxic or carcinogenic
effects secondary to PC supplementation. The toxicity of the
 POLICOSANOLS: FACT OR FICTION
original PC supplement has been assessed in many animal
models including mice (Aleman et al., 1995), rats (Rodriguez
and Garcia, 1998), dogs (Mesa et al., 1994), and monkeys
(Rodriguez-Echenique et al., 1994), using doses ranging from
0.25 mg/kg to 500mg/kg. In one study using beagle dogs, 180
mg/kg of original PC was administered daily for one year. The
results indicated no histological or biochemical abnormalities
in animals receiving the treatment compared to controls (Mesa
et al., 1994). Similar results obtained in a study examining the
carcinogenicity of the original PC supplement in mice receiv-
ing 500 mg/kg of PC for 18 months. The frequencies of benign
and malignant lesions were similar between controls and those
receiving PC treatment. Furthermore, PC supplementation did
not accelerate tumor growth (Aleman et al., 1995).
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The prescription medications that are used for treating hyper-
cholesterolemia i.e. statins, can have side effects that are both
physical and biochemical. As outlined above, PC have been
shown to be just as effective as many hypercholesterolemic
medications for reducing circulating cholesterol levels. PC sup-
plements do not appear to produce biochemical changes that are
indicative of cell damage. Additionally, fewer patients report
adverse events such as headache, dizziness, abdominal pain,
nausea, and vomiting when receiving PC compared to prescrip-
tion drugs (Alcocer et al., 1999; Benitez et al., 1997; Castano
et al., 2000a). For example, a study comparing the cholesterol-
lowering effect of the original PC supplement to atorvastatin
noted that none of the patients receiving PC treatment expe-
rienced any adverse events (Castano et al., 2003b). However,
of the patients receiving atorvastatin, 7 reported adverse events
concerning the nervous system, cardiovascular system, gastroin-
testinal system, and musculature. As a result, 3 patients from
the atorvastatin group withdrew from the study (Castano et al.,
2003b). Moreover, PC supplementation resulted in a signifi-
cant reduction in circulating creatinine phosphokinase, alanine
transanimase, and aspartate transanimase, possibly indicating
improvements in cell health (Castano et al., 2003b). Atorvas-
tatin treatment resulted in a significant increase in creatinine
phosphokinase alluding to increased cell toxicity or inflamma-
tion (Castano et al., 2003b).
The current data show PC supplements to be safe compared to
other hypercholesterolemic treatments. However, once again, all
studies assessing the efficacy and safety of PC supplementation
have been conducted by a single research group. Nonetheless,
of the external studies outlined above that used authentic and
alternative PC preparations, none reported serious side-effects
that were attributed to PC treatment, thus supporting the notion
that chronic supplementation with PC is safe.
CONCLUSIONS
Studies conducted by researchers in Cuba report PC sup-
plementation as an effective means for combating hypercholes-
terolemia, LDL-C peroxidation, arterial endothelial cell dys-
function, platelet aggregation, and the symptoms associated
265
with intermittent claudication. However, the therapeutic effi-
cacy of PC supplementation has only been established by one
research group, using one brand of PC supplement. In general,
external research groups have been unable to reproduce the re-
ported cholesterol-lowering and antioxidant properties associ-
ated with PC supplementation. Recent publications question the
PC cholesterol-lowering efficacy data reported by the original
research group who claim that the original PC supplement has
a unique composition capable of reducing cholesterol levels.
Other therapeutic claims for the sugarcane PC including re-
duced platelet aggregation, improved endothelial function, and
improvements in symptoms related to intermittent claudication
also remain to be validated by independent laboratories. The
foundation of experimental science is based on other scientists
confirming or refuting the claims reported in peer reviewed jour-
nals. Currently, the inability for non-Cuban research groups to
publish studies that support the use of PC supplements as an
efficacious therapy for reducing cardiovascular risk factors is a
serious blow to the idea of using PC preparations as nutraceu-
ticals. Nonetheless, collaborative studies between Cuban and
non-Cuban laboratories should be engaged to rule out method-
ology differences and perhaps genetic differences in study pop-
ulations that could account for such a wide disparity in results
between research groups. Thereafter, conclusions regarding PC
supplements as beneficial nutraceuticals can be ascertained with
confidence.
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