Michael Yatcilla, Ph.D.04.01.02
Pharmaceutical science often leads to an abundance of names. Consider the following four names: ([R-(R*,R*)]-2-(4-fluorophenyl)- beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-(hepatonic acid); CI-981; Atorvastatin calcium and Lipitor®. At various times since 1990, Pfizer has used one or more of these names to describe its synthetic cholesterol lowering drug. In this case, a well defined product is equally well described by four names. Also, in the last two cases, the name had to be approved by the autological agency known as the United States Approved Names (USAN).
By contrast, the nutraceuticals industry tends to have a paucity of names. Take the following three examples: a mixture of alcohols isolated from sugar cane, containing about 70% octacosanol, described in U.S. patent 5,633,156; a mixture of alcohols isolated from beeswax, containing about 45% octacosanol, described in U.S. patent 6,225,354 and a mixture of alcohols isolated from rice bran, containing about 20% octacosanol. All three of these products are being actively marketed in the U.S. as "policosanols"and all three of these products are presently being sold for their perceived value in reducing cholesterol levels. In the non-scientific literature these three incarnations of policosanols are seemingly interchangeable.
However, a review of the scientific literature (as recently published in the February, 2002 edition of the American Heart Journal) finds an entity known as policosanol (sometimes polycosanol) to have reduced cholesterol levels in thousands of subjects in over 60 published clinical trials. This policosanol deserves to be defined and explored.
Originally, policosanols was the trivial name given to a mixture of high molecular weight alcohols isolated from sugar cane, with octacosanol as the main component. Likely to the pharmaceutical research lab that named it, the name policosanol was akin to atorvastatin calcium in being scientific shorthand for a well-defined entity. In this regard, only sugar cane-derived alcohols with a specific profile can be considered policosanols because all the scientific literature on policosanols is based on this very specific definition.
Unfortunately, in a literal sense, the name poli- (or poly-) cosanol is totally ambiguous, as it is simply a clever shorthand for the group of tetra-, hexa-, octa- "cosanols" or "many –cosanols". In this regard, any of the naturally occurring sugar alcohols listed above (from sugar cane wax, rice bran wax or beeswax) may be considered policosanols.
As a definition that satisfies both scientific and commercial purposes, here policosanols refers to a collection of C24 to C34 primary alcohols found in the germ, kernel, seed coat, shell and skin (peel) of various nuts, seeds, fruits and cereals (table 1).
Owing to their considerable potential therapeutic use as hypocholesterolemic agents, policosanols have been sought in plants. These are found naturally in the waxes and germs of many plant species. However, the content of alcohols in oils and waxes is small compared to total hydrocarbons, esters and glycerides, and it is therefore chemically difficult to isolate the alcohols.
Higher levels of long chain aliphatic alcohols have been found in purified waxes available as byproducts of other agricultural commodities. In particular, sugar cane wax, rice bran wax, and beeswax have all shown very high levels of policosanols. Commercially, high policosanol waxes may be readily obtained using the byproducts of traditional sugar, rice or bee product processing.
The relative abundance of the various alcohols varies depending on the source material. As shown in figure 1, sugar cane wax has relatively higher levels of octacosanol than rice bran wax or beeswax.
In the early 1990s it was established that chronic administration of policosanols from sugar cane wax to laboratory animals reduced serum cholesterol levels. This cholesterol lowering effect was observed in both hypercholesterolemic (those animals with "naturally" higher cholesterol) and normocholesterolemic animals.
In 1994, (Rodriguez-Echenique, 1994 ) the long-term toxicity and effectiveness of policosanol was established at dosage levels of up to 25 mg/kg per day for 54 weeks. At dosage levels from 0.25 mg/kg to 25 mg/kg, statistically significant cholesterol reduction was observed after eight weeks.
The mechanisms of cholesterol-lowering by policosanols were established in the mid-1990s by incubating human cells with policosanols. It was observed that cholesterol synthesis was inhibited, and low density lipoprotein (LDL) cholesterol processing was enhanced through LDL binding, internalization and degradation. In the presence of policosanol, human cells could not make as much cholesterol, and in addition, LDL levels were lowered by various means.
Focusing on the ability for policosanol to lower cholesterol synthesis, a number of in vitro studies were performed. Cholesterol synthesis is a complicated mechanism involving many steps and involving many enzymes.
Most commercial pharmaceutical agents seek to reduce cholesterol manufacture in the body by inhibition of the key metabolic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The most popular pharmaceuticals (Mevacor®, Zoloft®, Lipitor®) inhibit cholesterol biosynthesis at this step.
Policosanols do not directly inhibit HMG-CoA reductase. They do, however, inhibit cholesterol synthesis at or near the HMG-CoA step, although the exact mechanism has not been elucidated.
Complicating such studies is the fact that these long chain alcohols by their chemical nature are difficult to study in vitro. As aliphatic long chains typically are, they do not dissolve in water or most biologically friendly media.
These various studies established the effectiveness, safety and rationale for benefit in treatment of high cholesterol. This set the stage for testing of policosanols on human subjects with elevated blood cholesterol levels.
In terms of clinical research, The Centro Nacional de Investigaciones Cientificas (CNIC), Havana, Cuba, has published dozens of trials since 1993 examining the clinical effects of policosanols from sugar cane wax on a number of cardiovascular conditions. Table 2 summarizes the findings of these studies.
By far the most promising aspect of the clinical research into policosanols observed in the Cuban research is the ability for policosanols, at dosages as low as 2 mg/day, to lower cholesterol levels in subjects with borderline to high cholesterol levels (table 3). Without any observed side-effects, the naturally-derived policosanols consistently performed as well as the "statin" HMG-CoA reductase inhibitors in lowering cholesterol levels over time.
Laboratorios Dalmer SA, the commercialization arm of CNIC, began selling policosanols from sugar cane wax as a prescription drug to treat hyperlipidemia in Latin American countries. Today, policosanols from sugar cane wax are approved pharmaceutical treatments available in over 20 countries.
As table 3 shows, policosanols have been studied on thousands of individuals at dosages ranging from 5-20 mg/day. Study durations ranged from 6 weeks to 2 years. Results show a dose-dependant reduction in total cholesterol in every case, with 10 mg/day dosages resulting in statistically-significant reductions in total cholesterol of 13.8-18% and reductions in LDL cholesterol of 18%–25.8%. In addition, statistically significant increases in HDL cholesterol and reduced serum triglycerides were observed in several cases.
When compared to synthetic pharmaceutical agents used widely in the treatment of high cholesterol, policosanols have shown similar to superior therapeutic effects with regards to total cholesterol lowering and LDL cholesterol lowering. Policosanols showed further increases in HDL cholesterol vs. "statin" type drugs, which show no increase in the HDL cholesterol (the "good" cholesterol). Finally, policosanols were uniformly better tolerated by subjects with a reduction in the number of reported adverse effect
Policosanols are also potent antioxidants. Several studies have shown the ability of policosanols to prevent lipid peroxidation, diene generation and overall LDL cholesterol oxidation.
This is a useful benefit to policosanols therapy for patients with high cholesterol levels. It is the high susceptibility of LDL cholesterol to oxidation that has caused it to be dubbed the "bad cholesterol." Oxidized LDL cholesterol has been implicated in free radical damage to the cardiovascular system, in particular leading to atherosclerosis or hardening of the arteries. Policosanols, like most antioxidants, have shown the ability to prevent LDL oxidation in vitro.
To further investigate the protective effect of policosanols, 69 human volunteers were fed 5 or 10 mg of policosanol per day. LDL-C oxidation was reduced by up to 50% in a dose-dependent fashion after 8 weeks (Menendez, 2000).
As policosanols become popular in the U.S. nutraceuticals market and the previously mentioned research is being widely cited by companies marketing policosanol-containing products, several points should be noted concerning the research findings.
First, all of the clinical trials were conducted using sugar cane wax-derived policosanols. Since the mechanism for action of policosanols is unclear, it is not scientifically justified to generalize these results to other mixtures of long-chain alcohols (e.g., from rice bran wax, beeswax or even pure octacosanol) with a different alcohol profile. This is not to say that such mixtures are ineffective, simply that one cannot make an a priori assumption of efficacy simply because the materials are policosanols in the absence of published clinical research.
Second, all the published clinical work on the efficacy was sponsored by Dalmer, and all clinical work has been performed in a very small number of clinics on a relatively homogeneous population in Cuba and Latin America. These results do not satisfy international regulations, specifically "Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data."As a result, much clinical work is required before pharmaceutical approval for policosanols could be extended to countries with substantially different ethnic populations than in those studied.
Third, all of the preclinical work was done at CNIC. Although peer-review is typically a fair "screen" to ensure some degree of impartiality in published work, independent verification of the biochemical studies needs to be completed. At this stage, the postulated mechanisms for cholesterol lowering are fairly weak.
Further complicating matters is the fact that there are several distinct types of policosanols available to the U.S. nutraceuticals market. Sugar cane wax policosanols, rice bran wax policosanols and beeswax policosanols are all available. Plus, pure octacosanol (the most abundant policosanol) is available from wheat germ oil.
Numerous U.S. patents have already been issued for the manufacture and use of policosanols and CNIC/Dalmer have several patents. Sugar cane wax policosanol is covered by manufacturing patents 5,663,156 and 5,856,316, both titled "Mixture of higher primary aliphatic alcohols, its obtention from sugar cane wax and its pharmaceutical uses" (1997 and 1999).
More recently, patent 6,225,354 was issued to a U.S. company entitled "High molecular weight primary aliphatic alcohols obtained from beeswax and pharmaceutical use thereof" (2001).
The many sources of policosanols and the proliferation of patents sounds a lot less like efficient development of a natural product to assist in the treatment of a serious medical problem, and a lot more like many companies "staking claims" to market share due to inevitable commoditization.
To address the controversy, a simple two step process is recommended. First, the exact mechanism of policosanol action must be defined and verified at multiple independent research laboratories and the relative effectiveness of the various plant species' unique alcohol profile needs to be compared. In this work it is possible that an "optimal" profile will be determined, and through any of several separation processes, an "optimal" policosanol mixture may be obtained from any waxy plant material.
Second, the various materials (alcohol mixtures in naturally-occurring ratios from sugar cane wax, rice bran wax, beeswax, or the hypothetical "optimal" blend) must be clinically tested and the results published in peer-reviewed journals.
This is a costly and time-consuming undertaking. However the potential reward, a natural solution that replaces a pharmaceutical problem, is very likely worth the trouble.
Recently policosanol was the subject of discussion in a major medical journal. To summarize the conclusion of the German review published in the February 2002edition of the American Heart Journal , the authors said, "Policosanol is in our opinion a fascinating new agent for the prevention and treatment of atherosclerotic disease."
There is great promise for effective cholesterol lowering products containing aliphatic long chain alcohols. High cholesterol as a medical condition requiring treatment will continue to rise over the next decades. The "statin" drugs are replete with side effects, are very costly and beg for a natural alternative. The clinical effectiveness of sugar cane wax policosanols is exciting and has never been challenged in published clinical work.
However, the ambiguity associated with the name and chemical makeup of the various products calling themselves policosanols portends problems. What our industry needs are effective products backed by unambiguous science. Policosanols are on the right track to meeting this need. However, product fragmentation, "borrowed" science, commoditization, and worst of all, the possibility of completely ineffective products bearing the name policosanol will hinder the availability of this potentially effective new treatment. Perhaps we should all learn a lesson from the pharmaceutical industry and realize that it is better to over name your product (e.g., Lipitor®, with projected sales of $8 billion in 2002), than under name your product (e.g., policosanols).NW
About the author:
Michael Yatcilla is senior chemist with Technica Consumer Health, Hayward, CA, which provides scientific and engineering expertise to the nutraceticals, pharmaceuticals and functional foods industries. He can be reached at yatcilla@hotmail.com.
By contrast, the nutraceuticals industry tends to have a paucity of names. Take the following three examples: a mixture of alcohols isolated from sugar cane, containing about 70% octacosanol, described in U.S. patent 5,633,156; a mixture of alcohols isolated from beeswax, containing about 45% octacosanol, described in U.S. patent 6,225,354 and a mixture of alcohols isolated from rice bran, containing about 20% octacosanol. All three of these products are being actively marketed in the U.S. as "policosanols"and all three of these products are presently being sold for their perceived value in reducing cholesterol levels. In the non-scientific literature these three incarnations of policosanols are seemingly interchangeable.
However, a review of the scientific literature (as recently published in the February, 2002 edition of the American Heart Journal) finds an entity known as policosanol (sometimes polycosanol) to have reduced cholesterol levels in thousands of subjects in over 60 published clinical trials. This policosanol deserves to be defined and explored.
Policosanols: A Working Definition
Originally, policosanols was the trivial name given to a mixture of high molecular weight alcohols isolated from sugar cane, with octacosanol as the main component. Likely to the pharmaceutical research lab that named it, the name policosanol was akin to atorvastatin calcium in being scientific shorthand for a well-defined entity. In this regard, only sugar cane-derived alcohols with a specific profile can be considered policosanols because all the scientific literature on policosanols is based on this very specific definition.
Unfortunately, in a literal sense, the name poli- (or poly-) cosanol is totally ambiguous, as it is simply a clever shorthand for the group of tetra-, hexa-, octa- "cosanols" or "many –cosanols". In this regard, any of the naturally occurring sugar alcohols listed above (from sugar cane wax, rice bran wax or beeswax) may be considered policosanols.
As a definition that satisfies both scientific and commercial purposes, here policosanols refers to a collection of C24 to C34 primary alcohols found in the germ, kernel, seed coat, shell and skin (peel) of various nuts, seeds, fruits and cereals (table 1).
Comparison of Naturally Occurring Policosanols
Owing to their considerable potential therapeutic use as hypocholesterolemic agents, policosanols have been sought in plants. These are found naturally in the waxes and germs of many plant species. However, the content of alcohols in oils and waxes is small compared to total hydrocarbons, esters and glycerides, and it is therefore chemically difficult to isolate the alcohols.
Higher levels of long chain aliphatic alcohols have been found in purified waxes available as byproducts of other agricultural commodities. In particular, sugar cane wax, rice bran wax, and beeswax have all shown very high levels of policosanols. Commercially, high policosanol waxes may be readily obtained using the byproducts of traditional sugar, rice or bee product processing.
The relative abundance of the various alcohols varies depending on the source material. As shown in figure 1, sugar cane wax has relatively higher levels of octacosanol than rice bran wax or beeswax.
Preclinical Research
In the early 1990s it was established that chronic administration of policosanols from sugar cane wax to laboratory animals reduced serum cholesterol levels. This cholesterol lowering effect was observed in both hypercholesterolemic (those animals with "naturally" higher cholesterol) and normocholesterolemic animals.
In 1994, (Rodriguez-Echenique, 1994 ) the long-term toxicity and effectiveness of policosanol was established at dosage levels of up to 25 mg/kg per day for 54 weeks. At dosage levels from 0.25 mg/kg to 25 mg/kg, statistically significant cholesterol reduction was observed after eight weeks.
The mechanisms of cholesterol-lowering by policosanols were established in the mid-1990s by incubating human cells with policosanols. It was observed that cholesterol synthesis was inhibited, and low density lipoprotein (LDL) cholesterol processing was enhanced through LDL binding, internalization and degradation. In the presence of policosanol, human cells could not make as much cholesterol, and in addition, LDL levels were lowered by various means.
Focusing on the ability for policosanol to lower cholesterol synthesis, a number of in vitro studies were performed. Cholesterol synthesis is a complicated mechanism involving many steps and involving many enzymes.
Most commercial pharmaceutical agents seek to reduce cholesterol manufacture in the body by inhibition of the key metabolic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The most popular pharmaceuticals (Mevacor®, Zoloft®, Lipitor®) inhibit cholesterol biosynthesis at this step.
Policosanols do not directly inhibit HMG-CoA reductase. They do, however, inhibit cholesterol synthesis at or near the HMG-CoA step, although the exact mechanism has not been elucidated.
Complicating such studies is the fact that these long chain alcohols by their chemical nature are difficult to study in vitro. As aliphatic long chains typically are, they do not dissolve in water or most biologically friendly media.
These various studies established the effectiveness, safety and rationale for benefit in treatment of high cholesterol. This set the stage for testing of policosanols on human subjects with elevated blood cholesterol levels.
In terms of clinical research, The Centro Nacional de Investigaciones Cientificas (CNIC), Havana, Cuba, has published dozens of trials since 1993 examining the clinical effects of policosanols from sugar cane wax on a number of cardiovascular conditions. Table 2 summarizes the findings of these studies.
Cholesterol Lowering by Policosanols
By far the most promising aspect of the clinical research into policosanols observed in the Cuban research is the ability for policosanols, at dosages as low as 2 mg/day, to lower cholesterol levels in subjects with borderline to high cholesterol levels (table 3). Without any observed side-effects, the naturally-derived policosanols consistently performed as well as the "statin" HMG-CoA reductase inhibitors in lowering cholesterol levels over time.
Laboratorios Dalmer SA, the commercialization arm of CNIC, began selling policosanols from sugar cane wax as a prescription drug to treat hyperlipidemia in Latin American countries. Today, policosanols from sugar cane wax are approved pharmaceutical treatments available in over 20 countries.
As table 3 shows, policosanols have been studied on thousands of individuals at dosages ranging from 5-20 mg/day. Study durations ranged from 6 weeks to 2 years. Results show a dose-dependant reduction in total cholesterol in every case, with 10 mg/day dosages resulting in statistically-significant reductions in total cholesterol of 13.8-18% and reductions in LDL cholesterol of 18%–25.8%. In addition, statistically significant increases in HDL cholesterol and reduced serum triglycerides were observed in several cases.
When compared to synthetic pharmaceutical agents used widely in the treatment of high cholesterol, policosanols have shown similar to superior therapeutic effects with regards to total cholesterol lowering and LDL cholesterol lowering. Policosanols showed further increases in HDL cholesterol vs. "statin" type drugs, which show no increase in the HDL cholesterol (the "good" cholesterol). Finally, policosanols were uniformly better tolerated by subjects with a reduction in the number of reported adverse effect
Antioxidant Effects of Policosanols
Policosanols are also potent antioxidants. Several studies have shown the ability of policosanols to prevent lipid peroxidation, diene generation and overall LDL cholesterol oxidation.
This is a useful benefit to policosanols therapy for patients with high cholesterol levels. It is the high susceptibility of LDL cholesterol to oxidation that has caused it to be dubbed the "bad cholesterol." Oxidized LDL cholesterol has been implicated in free radical damage to the cardiovascular system, in particular leading to atherosclerosis or hardening of the arteries. Policosanols, like most antioxidants, have shown the ability to prevent LDL oxidation in vitro.
To further investigate the protective effect of policosanols, 69 human volunteers were fed 5 or 10 mg of policosanol per day. LDL-C oxidation was reduced by up to 50% in a dose-dependent fashion after 8 weeks (Menendez, 2000).
Where is the Controversy?
As policosanols become popular in the U.S. nutraceuticals market and the previously mentioned research is being widely cited by companies marketing policosanol-containing products, several points should be noted concerning the research findings.
First, all of the clinical trials were conducted using sugar cane wax-derived policosanols. Since the mechanism for action of policosanols is unclear, it is not scientifically justified to generalize these results to other mixtures of long-chain alcohols (e.g., from rice bran wax, beeswax or even pure octacosanol) with a different alcohol profile. This is not to say that such mixtures are ineffective, simply that one cannot make an a priori assumption of efficacy simply because the materials are policosanols in the absence of published clinical research.
Second, all the published clinical work on the efficacy was sponsored by Dalmer, and all clinical work has been performed in a very small number of clinics on a relatively homogeneous population in Cuba and Latin America. These results do not satisfy international regulations, specifically "Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data."As a result, much clinical work is required before pharmaceutical approval for policosanols could be extended to countries with substantially different ethnic populations than in those studied.
Third, all of the preclinical work was done at CNIC. Although peer-review is typically a fair "screen" to ensure some degree of impartiality in published work, independent verification of the biochemical studies needs to be completed. At this stage, the postulated mechanisms for cholesterol lowering are fairly weak.
Further complicating matters is the fact that there are several distinct types of policosanols available to the U.S. nutraceuticals market. Sugar cane wax policosanols, rice bran wax policosanols and beeswax policosanols are all available. Plus, pure octacosanol (the most abundant policosanol) is available from wheat germ oil.
Numerous U.S. patents have already been issued for the manufacture and use of policosanols and CNIC/Dalmer have several patents. Sugar cane wax policosanol is covered by manufacturing patents 5,663,156 and 5,856,316, both titled "Mixture of higher primary aliphatic alcohols, its obtention from sugar cane wax and its pharmaceutical uses" (1997 and 1999).
More recently, patent 6,225,354 was issued to a U.S. company entitled "High molecular weight primary aliphatic alcohols obtained from beeswax and pharmaceutical use thereof" (2001).
The many sources of policosanols and the proliferation of patents sounds a lot less like efficient development of a natural product to assist in the treatment of a serious medical problem, and a lot more like many companies "staking claims" to market share due to inevitable commoditization.
A Proposed Solution
To address the controversy, a simple two step process is recommended. First, the exact mechanism of policosanol action must be defined and verified at multiple independent research laboratories and the relative effectiveness of the various plant species' unique alcohol profile needs to be compared. In this work it is possible that an "optimal" profile will be determined, and through any of several separation processes, an "optimal" policosanol mixture may be obtained from any waxy plant material.
Second, the various materials (alcohol mixtures in naturally-occurring ratios from sugar cane wax, rice bran wax, beeswax, or the hypothetical "optimal" blend) must be clinically tested and the results published in peer-reviewed journals.
This is a costly and time-consuming undertaking. However the potential reward, a natural solution that replaces a pharmaceutical problem, is very likely worth the trouble.
What Lies Ahead?
Recently policosanol was the subject of discussion in a major medical journal. To summarize the conclusion of the German review published in the February 2002edition of the American Heart Journal , the authors said, "Policosanol is in our opinion a fascinating new agent for the prevention and treatment of atherosclerotic disease."
There is great promise for effective cholesterol lowering products containing aliphatic long chain alcohols. High cholesterol as a medical condition requiring treatment will continue to rise over the next decades. The "statin" drugs are replete with side effects, are very costly and beg for a natural alternative. The clinical effectiveness of sugar cane wax policosanols is exciting and has never been challenged in published clinical work.
However, the ambiguity associated with the name and chemical makeup of the various products calling themselves policosanols portends problems. What our industry needs are effective products backed by unambiguous science. Policosanols are on the right track to meeting this need. However, product fragmentation, "borrowed" science, commoditization, and worst of all, the possibility of completely ineffective products bearing the name policosanol will hinder the availability of this potentially effective new treatment. Perhaps we should all learn a lesson from the pharmaceutical industry and realize that it is better to over name your product (e.g., Lipitor®, with projected sales of $8 billion in 2002), than under name your product (e.g., policosanols).NW
About the author:
Michael Yatcilla is senior chemist with Technica Consumer Health, Hayward, CA, which provides scientific and engineering expertise to the nutraceticals, pharmaceuticals and functional foods industries. He can be reached at yatcilla@hotmail.com.
