Efficacy of Over-the-counter Nutritional Supplements.

Curr Atheroscler Rep 2003 Jan;5(1):15-21

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. mdavidson@protocare.com

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 and Tolerability of Policosanol with Atorvastatin in Elderly Patients with Type II Hypercholesterolaemia.

Drugs Aging 2003;20(2):153-63

Castano G, Mas R, Fernandez L, Illnait J, Mesa M, Alvarez E, Lezcay M. Medical Surgical Research Center, Havana City, Cuba.

BACKGROUND: Hypercholesterolaemia is a risk factor for coronary heart disease (CHD). Clinical studies have shown that lowering elevated serum total cholesterol (TC) levels, and particularly low density lipoprotein-cholesterol (LDL-C) levels, reduces the frequency of coronary morbidity and deaths, whereas high serum levels of high density lipoprotein-cholesterol (HDL-C) protect against CHD. Policosanol is a cholesterol-lowering drug purified from sugar cane wax with a therapeutic dosage range from 5-20 mg/day. Atorvastatin is an HMG-CoA reductase inhibitor which across its dosage range (10-80 mg/day) has shown significantly greater lipid-lowering effects than all previously marketed statins. OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of policosanol with atorvastatin in older patients with type II hypercholesterolaemia. PATIENTS AND METHODS: This randomised, single-blind, parallel-group study was conducted in older patients (60-80 years) with type II hypercholesterolaemia. After 4 weeks on a cholesterol-lowering diet, 75 patients were randomised to policosanol or atorvastatin 10mg tablets taken once daily with the evening meal for 8 weeks. An interim and final check-up were performed at 4 and 8 weeks, respectively, after treatment was initiated. RESULTS: At 4 (p < 0.0001) and 8 (p < 0.00001) weeks, policosanol 10 mg/day significantly lowered serum LDL-C levels by 17.5 and 23.1%, respectively compared with baseline; corresponding values for atorvastatin were 28.4 and 29.8%. At study completion, policosanol significantly (p < 0.0001) reduced serum TC (16.4%), LDL-C/HDL-C ratio (25.5%) and TC/HDL-C ratio (19.3%), as well as (p < 0.001) triglyceride levels (15.4%). Atorvastatin significantly (p < 0.0001) decreased serum TC (22.6%), LDL-C/HDL-C (26.2%) and TC/HDL-C (19.8%) ratios, as well as (p < 0.001) triglyceride levels (15.5%). Atorvastatin was significantly more effective than policosanol in reducing LDL-C and TC, but similar in reducing both atherogenic ratios and triglyceride levels. Policosanol, but not atorvastatin, significantly (p < 0.05) increased serum HDL-C levels by 5.3%. Both treatments were well tolerated. At study completion, atorvastatin mildly, but significantly (p < 0.05) increased creatine phosphokinase (CPK) and creatinine, whereas policosanol significantly reduced AST and glucose (p < 0.01) and CPK (p < 0.05) levels. All individual values, however, remained within normal limits. Three atorvastatin but no policosanol patients withdrew from the study because of adverse events: muscle cramps (1 patient), gastritis (1 patient) and uncontrolled hypertension, abdominal pain and myalgia (1 patient). Overall, no policosanol and seven atorvastatin patients (18.9%) reported a total of nine mild or moderate adverse events during the study (p < 0.01). CONCLUSIONS: This study shows that policosanol (10 mg/day) administered for 8 weeks was less effective than atorvastatin (10 mg/day) in reducing serum LDL-C and TC levels in older patients with type II hypercholesterolaemia. Policosanol, but not atorvastatin, however, significantly increased serum HDL-C levels, whereas both drugs similarly reduced atherogenic ratios and serum triglycerides. Policosanol was better tolerated than atorvastatin as revealed by patient withdrawal analysis and overall frequency of adverse events. Nevertheless, further studies must be conducted in larger sample sizes and using dose-titration methods to achieve target lipid levels in order to reach wider conclusions.

Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia.

Int J Clin Pharmacol Res 2002;22(2):55-66

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.

Policosanol: A new treatment for cardiovascular disease?

Altern Med Rev 2002 Jun;7(3):203-17

Janikula M. ND Candidate 2003 - Southwest College of Naturopathic Health Sciences student representative to Thorne Research. Correspondence address: 1320 E Lemon St, Tempe, AZ 85281

Policosanol is a mixture of alcohols isolated and purified from sugar cane. Recently, Cuban researchers found 5-20 mg daily of policosanol to be effective at improving serum lipid profiles. Policosanol is believed to decrease total cholesterol (TC), low-density lipoprotein (LDL), and increase high-density lipoprotein (HDL) by inhibiting cholesterol synthesis and increasing LDL processing. Lipid profile improvements are seen in healthy volunteers, patients with type II hypercholesterolemia, type 2 diabetics with hypercholesterolemia, postmenopausal women with hypercholesterolemia, and patients with combined hypercholesterolemia and abnormal liver function tests. Additionally, policosanol has performed equal to or better than simvastatin, pravastatin, lovastatin, probucol, or acipimox with fewer side effects in patients with type II hypercholesterolemia. Policosanol also decreases several other risk factors of cardiovascular disease by decreasing LDL oxidation, platelet aggregation, endothelial damage, and smooth muscle cell proliferation. Furthermore, policosanol decreases progression and increases regression of cardiovascular disease assessed by thallium-labeled myocardial perfusion scintigraphy (TL-MPS) and Doppler-ultrasound, and decreases symptoms of cardiovascular disease assessed by the Specific Activity Scale. In post-marketing studies, only 0.31 percent of patients have had adverse events. Furthermore, in animal toxicity studies doses up to 1500 times normal human doses (on the basis of body weight) have shown no negative effects on carcinogenesis, reproduction, growth, and development. However, despite the positive research on policosanol on Cubans, policosanol produced in Cuba is not available in the United States, and only Cuban subjects have been studied. Further research is needed to determine if the same effects will be obtained in U.S. populations with non-Cuban produced policosanol.

Effects of policosanol on older patients with hypertension and type II hypercholesterolaemia.

Drugs R D 2002;3(3):159-72.

Castano G, Mas R, Fernandez JC, Fernandez L, Illnait J, Lopez E. Surgical Medical Research Center, Havana City, Cuba.

OBJECTIVE: This study was conducted to investigate the effects of policosanol administered for 12 months on the lipid profile of older patients with hypertension and type II hypercholesterolaemia and no history of coronary heart disease (CHD) or cerebrovascular disease. PATIENTS AND PARTICIPANTS: 589 older male and female patients with hypertension and type II hypercholesterolaemia and no history of CHD or cerebrovascular disease were included. METHODS: This was a prospective, randomised, double-blind, placebo-controlled study in parallel groups treated with policosanol (5 to 10 mg/day) for 1 year. After 6 weeks on a standard step I cholesterol-lowering diet, 589 patients were randomised to policosanol (5 mg) or placebo tablets, to be taken once daily for 12 months. The dosage was doubled to 10 mg/day if total cholesterol values were > 6.1 mmol/L after 6 months of therapy. RESULTS: Policosanol significantly (p < 0.00001) lowered serum low-density lipoprotein-cholesterol (LDL-C) [20.5%], total cholesterol (TC) [15.4%], triglycerides (11.9%), LDL-C/high-density lipoprotein-cholesterol (HDL-C) ratio [22.2%] and TC/HDL-C ratio (20.1%), and increased (p < 0.0001) HDL-C (12.7%). The frequency of vascular and all-cause serious adverse events (SAEs) was lower (p < 0.05) in the policosanol recipients (two vascular SAEs, 0.7%; five all-cause SAEs, 1.7%) than in the placebo recipients (six vascular SAEs, 2.0%; 12 all-cause SAEs, 4.1%). Similarly, total adverse events (AEs) were less frequent in the policosanol-treated group (29; 9.8%) compared with the placebo group (52; 17.7%) [p < 0.01]. Three placebo recipients and no policosanol recipents died during the study as a result of myocardial infarction (two patients) and sudden cardiac arrest (one). Policosanol was well tolerated, and no drug-related disturbances in safety indicators were found. Policosanol significantly decreased systolic blood pressure (BP) compared with baseline and placebo, which could be an additional advantage in this population at high coronary risk. CONCLUSIONS: Policosanol administered long term is effective in lowering LDL-C and TC as well as increasing HDL-C levels in older patients with hypertension and type II hypercholesterolaemia without a history of CHD or cerebrovascular disease. In addition, policosanol treatment also shows benefits in the occurrence of SAEs of vascular aetiology, on the general AE profile and the reduction of BP in treated patients compared with baseline.

Validation of a gas chromatographic method for determination of fatty alcohols in 10 mg film-coated tablets of policosanol.

J AOAC Int 2002 May-Jun;85(3):563-6.

Sierra R, Gonzalez VL, Magraner J. National Center for Scientific Research, Center for Natural Products, Cubanacan, Playa, Havana City, Cuba.

A gas chromatographic method using a packed column and 1-eicosanol as an internal standard was validated for the determination of the fatty alcohols that compose policosanol in 10 mg film-coated tablets. The alcohols were determined as trimethylsilyl derivatives, prepared with N-methyl-N-trimethylsilyltrifluoroacetamide. The method can detect degradation products with high retention times, without interfering with the peaks of the active principle. Good linearity (correlation coefficient = 0.9992) and accuracy (mean recovery -100.27 ? 1.66%) were proven over a range of 25-200% of the nominal concentration. Within- and between-day precision at the nominal 100% value met the acceptance criteria (<2%). Ruggedness was examined through an intralaboratory experimental study in which 6 operational changes were made; the changes were found to have no effect on quantitation, repeatability, resolution, and relative retention time. The method is suitable for the quality control process and stability studies of these tablets.

Policosanol: Clinical pharmacology and therapeutic significance of a new lipid-lowering agent.

Am Heart J 2002 Feb;143(2):356-65.

Gouni-Berthold I, Berthold HK. Medical Policlinic, University of Bonn, Bonn, Germany, and the Institute for Clinical Research/Department of Clinical Pharmacology, Center for Cardiovascular Diseases, Rotenburg der Fulda.

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.

Inhibition of rat lipoprotein lipid peroxidation by the oral administration of D003, a mixture of very long-chain saturated fatty acids.

Can J Physiol Pharmacol 2002 Jan;80(1):13-21.

Menendez R, Mas R, Amor AM, Ledon N, Perez J, Gonzalez RM, Rodeiro I, Zayas M, Jimenez S. Laboratory of Biochemistry, Center of Natural Products, National Center for Scientific Research, Havana, Cuba. dalmer@ip.etecsa.cu

Previous results have demonstrated that policosanol, a mixture of aliphatic primary alcohols isolated and purified from sugar cane wax, whose main component is octacosanol, inhibited lipid peroxidation in experimental models and human beings. D003 is a defined mixture of very long-chain saturated fatty acids, also isolated and purified from sugar cane wax, whose main component is octacosanoic acid followed by traicontanoic, dotriacontanoic, and tetracontanoic acids. Since very long-chain fatty acids are structurally related to their corresponding alcohols, we investigated the effect of oral treatment with D003 (0.5, 5, 50, and 100 mg/kg) over 4 weeks in reducing the susceptibility of rat lipoprotein to oxidative modification. The combined rat lipoprotein fraction VLDL + LDL was subjected to several oxidation systems, including those containing metal ions (CuSO4), those having the capacity to generate free radicals 2,2-azobis-2-amidinopropane hydrochloride (AAPH), and a more physiological system (resident macrophages). D003 (5, 50, and 100 mg/kg) significantly inhibited copper-mediated conjugated-diene generation in a concentration-dependent manner. D003 increased lag phase by 53.1, 115.3, and 119.3%, respectively, and decreased the rate of conjugate-diene generation by 16.6, 21.5, and 19.6%, respectively. D003 also inhibited azo-compound initiated and macrophage-mediated lipid peroxidation as judged by the significant decrease in thiobarbituric acid reactive substance (TBARS) generation. In all the systems the maximum effect was attained at 50 mg/kg. There was also a parallel attenuation in the reduction of lysine amino groups and a significant reduction of carbonyl content after oxidation of lipoprotein samples. Taken together, the present results indicate that oral administration of D003 protects lipoprotein fractions against lipid peroxidation in the lipid as well in the protein moiety.

Physico-mechanical characterization of policosanol, a novel hypocholesterolemic drug.

Drug Dev Ind Pharm 2002 Jan;28(1):89-93.

Uribarri E, Laguna A, Sierra R, Ricardo Y. Laboratorios MedSol, Havana, Cuba.

As part of the formulation studies of policosanol, a new hypocholesterolemic drug, a physico-mechanical characterization was developed. Thermal analysis, using differential scanning calorimetry was used to evaluate the purity of policosanol from batch to batch and, also, the particle size distribution. The degree of wettability of policosanol was studied by measuring the contact angle and solubility in different solvents. The compressibility and cohesion of particles were evaluated using a profile of compression forces, ranging between 6.5 kN and 39.0 kN. Also, other properties such as flow properties, true density, and tapped and bulk density were measured. The industrial batches of policosanol that were studied show an adequate purity and a uniform distribution of the particle sizes. Policosanol shows good flow properties, compressibility, and cohesion as well as a low solubility in the majority of the solvents used in the pharmaceutical industry, and its solubility in water or in aqueous solutions was, mainly, null. The wettability of policosanol in the different solvents shows the following order: methylene chloride > ethanol > acetone >> water.

Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: a 6-month double-blind study.

Int J Clin Pharmacol Res 2001;21(1):43-57.

Castano G, Mas R, Fernandez L, Illnait J, Gamez R, Alvarez E. Medical Surgical Research Center, National Center for Scientific Research, Havana City, Cuba.

Policosanol is a well defined mixture of higher aliphatic primary alcohols isolated from sugar cane wax with cholesterol-lowering effects proven for a dose range from 5-20 mg/day in patients with type II hypercholesterolemia and dyslipidemia associated with noninsulin dependent diabetes mellitus. This randomized, double-blind study investigated the cholesterol-lowering efficacy and tolerability of policosanol 20 mg/day compared with 40 mg/day. Changes in low-density lipoprotein (LDL)-cholesterol levels were predefined as the primary efficacy endpoint. Patients with type II hypercholesterolemia were enrolled in the study and instructed to continue a step I cholesterol-lowering diet for 6 weeks and those eligible to be included (89) were randomly allocated to receive under double-blind conditions placebo (n = 30), policosanol 20 mg/day (n = 29) or 40 mg/day (n = 30). After 24 weeks, policosanol at 20 and 40 mg/day significantly (p < 0.00001) lowered LDL-cholesterol by 27.4% and 28.1%, total cholesterol (p < 0.00001) by 15.6% and 17.3%, and the LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio by 37.2% and 36.5%, respectively The ratio of total cholesterol/HDL-cholesterol was lowered by 27.1% and 27.5%, while HDL-cholesterol levels increased (p < 0.001) by 17.6% and 17.0%, respectively. Compared with baseline, policosanol 20 mg/day lowered triglycerides (p < 0.05) by 12.7%, while they were lowered (p < 0.01) by 15.6% at a dose of policosanol 40 mg/day All the above-mentioned significant differences were also different from placebo and no significant changes occurred in any lipid profile parameters in the placebo group. Based on the mean values of LDL-cholesterol levels at study completion, the mean percent reductions from baseline were 27.4% and 28.1% for the 20 and 40 mg/day groups, respectively. Thus, the effects of both policosanol doses on the main efficacy variable were practically identical. Consistent with the data obtained for LDL-cholesterol, both doses were similarly effective in changing all the other lipid profile parameters. No unexpected adverse effects were observed and there were no significant between-group differences regarding safety indicator values or reported adverse effects. In conclusion, although the tolerability profile remains excellent, according to the present results policosanol at a dose of 40 mg/day does not offer significant additional cholesterol-lowering efficacy over the 20 mg/day dose.

Efficacy and tolerability of policosanol in hypercholesterolemic postmenopausal women.

Int J Clin Pharmacol Res 2001;21(1):31-41.

Mirkin A, Mas R, Martinto M, Boccanera R, Robertis A, Poudes R, Fuster A, Lastreto E, Yanez M, Irico G, McCook B, Farre A. Eva Peron Hospital, Rosario, Argentina.

This randomized, double-blind, multicenter placebo-controlled study was conducted to investigate the efficacy and tolerability of policosanol, a cholesterol-lowering drug purified from sugar cane wax, in women who had experienced menopause and showed elevated serum total cholesterol and low density lipoprotein (LDL)-cholesterol levels despite a 6-week standard lipid-lowering diet. Thus, 56 eligible patients were randomized to receive placebo or policosanol 5 mg/day for 8 weeks and the dose was doubled to 10 mg/day during the next 8 weeks. Policosanol (5 and 10 mg/day) significantly decreased LDL-cholesterol (17.3% and 26.7%, respectively), total cholesterol (12.9% and 19.5%) as well as the ratios of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (17.2% and 26.5%) and total cholesterol to HDL-cholesterol (16.3% and 21.0%) compared with baseline and placebo. HDL-cholesterol levels were significantly raised by 7.4% at study completion. No significant changes occurred in the lipid profile of the placebo group. The drug was safe and well tolerated. No drug-related adverse effects were observed. None of the patients administered policosanol but three of those administered placebo withdrew from the trial because of adverse effects: one due to a serious hypertensive status, one because of an allergic reaction (pruritus plus skin rash) and one due to gastrointestinal disturbances (nauseas plus vomiting). Eleven placebo patients reported 24 adverse effects compared with six policosanol patients who reported seven adverse effects (p < 0.05). In addition, five placebo (17.9%) and 13 policosanol patients (46.4%) (p < 0.05) reported improvements in habitual symptoms and health perception during the study. In conclusion, policosanol was effective and well tolerated in hypercholesterolemic postmenopausal women, showing additional benefits in the health perception of the study patients.

Trace determination of 1-octacosanol in rat plasma by solid-phase extraction with Tenax GC and capillary gas chromatography.

J Chromatogr B Biomed Sci Appl 2001 Oct 5;762(1):43-9.

Marrero Delange D, Gonzalez Bravo L. Center of Natural Products, CNIC, Havana, Cuba. david_delange@yahoo.com

1-Octacosanol is the major component of policosanol, a new natural lowering-cholesterol agent. A sensitive solid-phase extraction with a Tenax GC capillary gas chromatography method for determining the proportion of this fatty alcohol in plasma after its denaturation with trichloroacetic acid was developed. The trimethylsilyl ether derivative of the target analyte obtained from the organic extract showed excellent chromatographic properties and was detectable in the low nanogram range (1 ng/ml). Adequate separation from plasma's extract was achieved with a fused-silica capillary column (30m x 0.25 mm I.D.) with SPB-5 (0.5 microm film thickness) and operated with temperature programming from 100 to 200 degrees C at 40 degrees C/min and from 200 degrees C increased at 10 degrees C/min to 320 degrees C, then held for 30 min, the carrier gas flow-rate (argon) was 1 ml/min. Quantification was performed by the internal standard method using 1-hexacosanol. The reliable relative retention parameters and the mass response factors values, and their confidence levels, ensure a proper GC sensitivity, necessary for the determination of the alcohol being analyzed. The method was evaluated to a concentration range from 6 to 47.6 ng/ml of plasma obtaining recoveries from 95 to 98%. The correlation between the theoretical concentration values and the corresponding experimental values was appropriate (gamma=0.9718 x -0.0915; r2=0.9998). The method showed a good within-day (RSD=4.3%) and between-day (RSD=6.0%) precision according to the acceptance criteria (<10%). This procedure was successfully applied to the study of 1-octacosanol in rat plasma samples after a single oral administration (40 mg/kg) of policosanol.

Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts.

Arch Med Res 2001 Jan-Feb;32(1):8-12.

Menendez R, Amor AM, Rodeiro I, Gonzalez RM, Gonzalez PC, Alfonso JL, Mas R. Laboratorio de Bioquimica, Centro de Productos Naturales, Centro Nacional de Investigacion Cientifica, Havana, Cuba. dalmer@ip.etccsa.cu

BACKGROUND: Cholesterol biosynthesis is strictly controlled by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase. METHODS: Transfer of cultured fibroblasts to a lipid-depleted medium (LDM) up-regulates the enzyme levels. This, in turn, is followed by an accelerated biosynthesis of cholesterol. RESULTS: Exposure of Vero fibroblasts to LDM and policosanol (0.5-50 microg/mL), a new cholesterol-lowering drug purified from sugarcane (Saccharum officinarum L.) wax, decreased in a dose-dependent manner cholesterol biosynthesis from [14C]-acetate and 3H-water, but not from [14C]-mevalonate. CONCLUSIONS: This suggests an effect on HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis. When enzyme activity was measured in the presence of various concentrations of policosanol (0.5-50 microg/mL), reductase was not suppressed. Therefore, there was no evidence for a competitive or noncompetitive inhibition of enzyme activity. However, after treatment of intact cells with policosanol (50 microg/mL) in the presence of LDM, a suppressive effect on enzyme activity was observed, suggesting a modulatory effect of policosanol on reductase activity. The previous inhibition of enzyme up-regulation by policosanol suggests to date a depression of de novo synthesis of HMG-CoA reductase and/or stimulation of its degradation. However, the exact mechanism by which policosanol inhibits the activity of HMG-CoA reductase still remains unclear. Further studies are needed to clarify the precise mechanism of its inhibitory action on cholesterol biosynthesis.

Effects of policosanol in older patients with type II hypercholesterolemia and high coronary risk.

J Gerontol A Biol Sci Med Sci 2001 Mar;56(3):M186-92.

Castano G, Mas R, Fernandez JC, Illnait J, Fernandez L, Alvarez E. Medical Surgical Research Center, National Center for Scientific Research, Havana City, Cuba.

BACKGROUND: The present study was undertaken to investigate the effects of policosanol in older patients with type II hypercholesterolemia and more than one concomitant atherosclerotic risk factor. METHODS: After 6 weeks on a lipid-lowering diet, 179 patients randomly received a placebo or policosanol at doses of 5 followed by 10 mg per day for successive 12-week periods of each dose. Policosanol (5 and 10 mg/d) significantly (p < .001) reduced low-density lipoprotein cholesterol (LDL-C; 16.9% and 24.4%, respectively) and total cholesterol (TC; 12.8% and 16.2%, respectively), while significantly (p < .01) increasing (p < .001) high-density lipoprotein cholesterol (HDL-C) by 14.6% and 29.1%, respectively. RESULTS: Policosanol significantly decreased (p < .01) the ratios of LDL-C to HDL-C (29.1%) and TC to HDL-C (28%) at study completion, although triglycerides remained unchanged. Policosanol, but not the placebo, significantly improved (p .01) cardiovascular capacity, which was assessed using the Specific Activity Scale. No serious adverse experiences occurred in policosanol patients (p < .01), compared with seven adverse experiences (7.9%) reported by placebo patients. CONCLUSIONS: This study shows that policosanol is effective, safe, and well tolerated in older hypercholesterolemic patients.

A long-term study of policosanol in the treatment of intermittent claudication.

Angiology 2001 Feb;52(2):115-25.

Castano G, Mas Ferreiro R, Fernandez L, Gamez R, Illnait J, Fernandez C. Medical Surgical Research Center, Havana City Cuba.

Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects. This study was undertaken to investigate the long-term effects of policosanol administered to patients with moderately severe intermittent claudication. The study consisted of a 6-week single-blind, placebo-controlled run in phase, followed by a 2-year double-blind, randomized treatment step. Fifty-six patients who met study entry criteria were randomized to receive placebo or policosanol 10 mg twice daily. Walking distances on a treadmill (constant speed 3.2 km/h, slope 10 degrees, temperature 25 degrees C) were assessed before and after 6, 12, 18, and 24 months of treatment. Both groups were similar at randomization. After 6 months of therapy, policosanol significantly increased (p < 0.01) the initial claudication distance from 125.9 ? 8.7 m to 201.1 ? 24.8 m and the absolute claudication distance from 219.5 ? 14.1 m to 380.7 ? 50.2 m. Both variables remained unchanged in the placebo group (p < 0.01). These effects did not wear off but improved after long-term therapy, so that final values were 333.5 ? 28.6 m (initial claudication distance) and 648.9 ? 54.1 m (absolute claudication distance); both significantly greater (p < 0.0001) than those obtained in the placebo group, which showed values of 137.9 ? 21.8 m (initial claudication distance) and 237.7 ? 28.1 m (absolute claudication distance), respectively. At study completion, 21 policosanol and 5 placebo patients attained increases in claudication distance values > 50% (p < 0.001). Policosanol, but not placebo, significantly increased the ankle/arm pressure index. In addition, from month 6 up to study completion, the frequency of patients reporting improvement of lower limb symptoms was greater in the policosanol group than in the placebo group. The treatment was tolerated well. There were 16 withdrawals (12 placebo, 4 policosanol) from the study. Eight patients in the placebo group experienced a total of 10 serious adverse events, 8 of which were vascular events, compared with none in the policosanol group (p < 0.01). In addition, 3 patients in the policosanol group and 3 patients in the placebo group reported mild adverse events during the study. The present results demonstrate the long-term usefulness of policosanol therapy to treat patients with intermittent claudication.

A comparative study of policosanol vs lovastatin on intimal thickening in rabbit cuffed carotid artery.

Pharmacol Res 2001 Jan;43(1):31-7.

Noa M, Mas R, Mesa R. Department of Pharmacology, Center of Natural Products, National Center for Scientific Research, Havana, Cuba. dalmer@ip.etecsa.cu

Policosanol is a cholesterol-lowering drug isolated from sugar cane wax, which acts by inhibiting cholesterol biosynthesis. Previous studies have demonstrated that policosanol inhibited smooth muscle cell (SMC) proliferation in the cuffed carotid artery of the rabbit and in arterial wall damage induced by forceps in the central artery of the ear of rabbits. The present study was undertaken to compare the effects of policosanol and lovastatin on SMC proliferation in the cuffed carotid artery of rabbits. Collars were placed around the left carotid for 7 and 15 days. The contralateral artery was sham operated. We studied eight experimental groups: two controls groups receiving vehicle for 7 and 15 days, respectively, a satellite sham operated control group, four groups treated with policosanol at 5 and 25 mg kg(-1)for 7 and 15 days and a reference group receiving lovastatin at 20 mg kg(-1)for 15 days. Samples of arteries were examined by light and electron microscopy. To evaluate intimal thickening the cross-sectional areas of intima and media were measured. Neointima was significantly reduced in treated animals compared with controls, but the reduction in lovastatin animals was significantly lower than in policosanol-treated groups. The SMC proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen and the reduction observed in policosanol-treated rabbits was significantly larger than in lovastatin-treated animals. It is concluded that the protective effect of policosanol against neointima formation in this experimental model was slightly better than that of lovastatin. Copyright 2001 Academic Press.

Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro.

Br J Clin Pharmacol 2000 Sep;50(3):255-62.

Menendez R, Mas R, Amor AM, Gonzalez RM, Fernandez JC, Rodeiro I, Zayas M, Jimenez S. Center of Natural Products, National Center for Scientific Research, PO Box 6880, Havana, Cuba.

AIMS: The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL-C to in vitro lipid peroxidation in human healthy volunteers. METHODS: The effect of policosanol (5 and 10 mg day(-1) on LDL-C oxidation was studied in a double-blind, randomized, placebo-controlled trial conducted in 69 subjects. LDL-C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL-C oxidation. We tested the susceptibility of LDL-C to lipid peroxidation in a cell-free system by the addition of copper ions as well as in a more physiological system, macrophage-mediated oxidation. RESULTS: At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose-dependent manner increased the lag phase of conjugated diene generation (mean ? s.d.) from 83.79+/-29.16 min to 94.90+/-25.50 min (5 mg day(-1)) and from 82.74+/-17.16 min to 129.89+/-35.71 min (10 mg day(-1)), while in the placebo group LDL-C oxidation did not change significantly. Policosanol (10 mg day(-1)), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated-oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day(-1)) significantly lowered malondialdehyde (MDA) generation from 8.50+/-0.91 to 5.76+/- 1.01 nmol mg(-1) protein. Comparison with placebo after 5 and 10 mg day(-1) showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day(-1)) and 12.4% (10 mg day(-1)) and LDL-C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day(-1)) increased HDL-C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug-related disturbances were found. CONCLUSIONS: The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day(-1)), decreased the susceptibility of LDL-C to lipid peroxidation in vitro.

Effects of policosanol on postmenopausal women with type II hypercholesterolemia.

Gynecol Endocrinol 2000 Jun;14(3):187-95.

Castano G, Mas R, Fernandez L, Fernandez JC, Illnait J, Lopez LE, Alvarez E. Medical Surgical Research Center (CIMEQ), Siboney, Cuba.

This randomized, double-blind, placebo-controlled study was conducted to investigate the efficacy, safety and tolerability of policosanol, a cholesterol-lowering drug purified from sugar-cane wax, in postmenopausal women with type II hypercholesterolemia. A total of 244 women who had experienced the menopause and showed elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels despite 6 weeks on a standard lipid-lowering diet were randomized to receive placebo or policosanol 5 mg/day for 12 weeks, after which the dose was doubled to 10 mg/day for the next 12 weeks. Policosanol (5 and 10 mg/day) significantly lowered LDL-C levels (17.7% and 25.2%, respectively) and total cholesterol (12.6% and 16.7%, respectively), as well as the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C) (17.0% and 29.3%, respectively) and total cholesterol to HDL-C (16.7% and 27.2%, respectively), compared to the baseline and placebo; at the same time, policosanol significantly raised HDL-C levels by 16.5% and 29.3%, respectively. The drug was safe and well tolerated. No drug-related adverse events were observed, and even the extent of adverse events was less in the policosanol group than in the placebo group. Four serious adverse events occurred in the placebo group (one myocardial infarction, two cases of hypertensive status and one surgical intervention) compared to none in the policosanol group. In conclusion, policosanol is effective, safe and well tolerated in hypercholesterolemic postmenopausal women.

Protective effect of policosanol on atherosclerotic lesions in rabbits with exogenous hypercholesterolemia.

Braz J Med Biol Res 2000 Jul;33(7):835-40.

Arruzazabala ML, Noa M, Menendez R, Mas R, Carbajal D, Valdes S, Molina V. Department of Pharmacology, Center of Natural Products, National Center of Scientific Research, Havana, Cuba.

Policosanol is a mixture of higher aliphatic alcohols purified from sugar cane wax, with cholesterol-lowering effects demonstrable in experimental models and in patients with type II hypercholesterolemia. The protective effects of policosanol on atherosclerotic lesions experimentally induced by lipofundin in rabbits and rats and spontaneously developed in stumptail monkeys have been described. The present study was conducted to determine whether policosanol administered orally to rabbits with exogenous hypercholesterolemia also protects against the development of atherosclerotic lesions. Male New Zealand rabbits weighing 1.5 to 2 kg were randomly divided into three experimental groups which received 25 or 200 mg/kg policosanol (N = 7) orally for 60 days with acacia gum as vehicle or acacia gum alone (control group, N = 9). All animals received a cholesterol-rich diet (0.5%) during the entire period. Control animals developed marked hypercholesterolemia, macroscopic lesions and arterial intimal thickening. Intima thickness was significantly less (32.5 ? 7 and 25.4 ? 4 microm) in hypercholesterolemic rabbits treated with policosanol than in controls (57.6 ? 9 microm). In most policosanol-treated animals, atherosclerotic lesions were not present, and in others, thickness of fatty streaks had less foam cell layers than in controls. We conclude that policosanol has a protective effect on the atherosclerotic lesions occurring in this experimental model.

Policosanol, reaction time and event-related potentials.

Neuropsychobiology 2000;41(3):158-65.

Fontani G, Maffei D, Lodi L. Istituto di Fisiologia Umana, Universita di Siena, Italy.

The aim of the present study was to compare the results of a 1-week, double-blind placebo-controlled trial investigating the effects of isopolicosanol and octacosanol on reactivity and related brain activity. In particular, reaction time (RT) and event-related potentials such as contingent negative variations (CNV) and P300 (P3) have been studied. Thirty sedentary healthy students were tested before and after treatment (3.6 mg/die for 7 days) with orally administered tablets of placebo (group A), isopolicosanol (B) and octacosanol (C). RT were studied according to three procedures: simple RT (SRT), go/no-go RT (GRT) and choice RT (CRT). Results show that before treatment, there were no significant differences between groups A, B and C. After treatment, the RT of group A was unchanged, while the RT of groups B and C were reduced. In group B, in the SRT test, the reduction of RT was accompanied by electrical data exhibiting increased amplitudes of CNV and shorter latencies of P3. These results show that the main effect on reactivity and event-related potentials can be ascribed to policosanol and is mainly evident in the SRT test. Copyright 2000 S. Karger AG, Basel.

Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus.

Int J Clin Pharmacol Res 1999;19(4):117-27.

Crespo N, Illnait J, Mas R, Fernandez L, Fernandez J, Castano G. Enrique Cabrera Hospital, Havana, Cuba.

This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol (10 mg/day) and lovastatin (20 mg/day) in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. After 6 weeks on a lipid lowering diet, 53 patients were randomized to receive either policosanol or lovastatin tablets that were taken o.i.d. for 12 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly (p < 0.001) lowered low-density lipoprotein (LDL)-cholesterol (20.4%), total cholesterol (14.2%) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (23.7%). Lovastatin significantly (p < 0.01) lowered LDL-cholesterol (16.8%), total cholesterol (14.0%) and the ratio (p < 0.05) of LDL-cholesterol to HDL-cholesterol (14.9%). Triglyceride levels did not significantly change after therapy. Policosanol, but not lovastatin, significantly increased (p < 0.01) levels of HDL-cholesterol (7.5%). Comparison between groups showed that changes in HDL-cholesterol induced by policosanol were significantly greater (p < 0.01) than those induced by lovastatin. Both treatments were safe and well tolerated. Lovastatin moderately but significantly (p < 0.05) increased levels of aspartate aminotransferase, creatine phosphokinase and alkaline phosphatase. Adverse reactions were more frequent in the lovastatin group (p < 0.01) than in the policosanol group. In conclusion, policosanol administered at 10 mg/day produces more advantageous changes in HDL-cholesterol and has a better safety and tolerability profile than lovastatin 20 mg/day.

Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients.

Int J Clin Pharmacol Res 1999;19(4):105-16.

Castano G, Mas R, Arruzazabala ML, Noa M, Illnait J, Fernandez JC, Molina V, Menendez A. Medical Surgical Research Center, Havana, Cuba. dalmer@ip.etecsa.cu

This randomized, double-blind study was undertaken to compare the effects of policosanol and pravastatin administered at 10 mg/day on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk. After 6 weeks on a lipid-lowering diet, patients with low-density lipoprotein (LDL) cholesterol levels > 3.4 mmol/l were randomized to receive, under double-blind conditions, policosanol or pravastatin 10 mg tablets that were taken with the evening meal for 8 weeks. Policosanol significantly (p < 0.00001) lowered LDL-cholesterol (19.3%), total cholesterol (13.9%) and the ratios of LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol (28.3%) and total cholesterol/HDL-cholesterol (24.4%). Pravastatin significantly (p < 0.00001) lowered LDL-cholesterol (15.6%), total cholesterol (11.8%) and the ratios (p < 0.0001) of LDL-cholesterol/HDL-cholesterol (18.9%) and total cholesterol/HDL-cholesterol (15.7%). Policosanol, but not pravastatin, significantly increased (p < 0.001) levels of HDL-cholesterol (18.4%) and reduced (p < 0.01) triglycerides (14.1%). Policosanol was more effective (p < 0.05) than pravastatin in inhibiting platelet aggregation induced by all agonists and it significantly reduced (p < 0.0001) platelet aggregation induced by arachidonic acid at 1.5 and 3 mmol/l by 42.2% and 69.5%, respectively, platelet aggregation induced by collagen 0.5 microgram/ml (p < 0.05) (16.6%) and that induced by adenosine diphosphate 1 mumol/l (p < 0.01) (20.3%). Pravastatin significantly reduced (p < 0.001) (27%) only platelet aggregation induced by arachidonic acid 3 mmol/l. Both drugs significantly decreased (p < 0.00001) endothelemia levels but final values were significantly lower (p < 0.001) in the policosanol than in the pravastatin group. Both treatments were safe and well tolerated. Pravastatin significantly (p < 0.01) increased serum levels of alanine amine transferase but individual values remained within normal. Two patients on pravastatin discontinued the study because of adverse experiences (myocardial infarction and jaundice, respectively). In conclusion, the effects of policosanol (10 mg/day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of pravastatin.

A comparative study of policosanol Versus acipimox in patients with type II hypercholesterolemia.

Int J Tissue React 1999;21(3):85-92.

Alcocer L, Fernandez L, Campos E, Mas R. Department of Cardiology, Mexico General Hospital, Mexico City.

An 8-week, randomized, double-blind study comparing the efficacy and tolerability of policosanol and acipimox was conducted in patients with type II hypercholesterolemia. Prior to entry into active treatment, all patients followed a standard cholesterol-lowering diet for 12 weeks. Sixty-three patients were randomized to receive either policosanol (10 mg/day) or acipimox (750 mg/day) tablets for 8 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly reduced total cholesterol (p < 0.0001) (15.8%), low-density lipoprotein (LDL)-cholesterol (21%) and the ratios of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (15.8%) and cholesterol to HDL-cholesterol (11.5%). Acipimox significantly lowered both cholesterol and LDL cholesterol by 7.5%. The percent changes of total cholesterol, LDL-cholesterol and both ratios were larger in the policosanol group than in the acipimox group. Both drugs were well tolerated. Acipimox significantly increased (p > 0.001) aspartate amino transferase levels but only four patients showed increases above the normal limit. Policosanol significantly reduced creatinine values (p > 0.05) but no patients had values out of the normal range. Four patients withdrew from the study (two from each group) but none withdrew because of adverse effects. No adverse effects were reported in the policosanol group, while five patients on acipimox reported adverse effects (hot flushes, nausea, vomiting, headache, hypochondrial pain and leg edema). These results indicate that policosanol (10 mg/day) was more effective and well tolerated than was acipimox (750 mg/day) in this study population.

Effect of policosanol on cerebral ischemia in Mongolian gerbils.

Braz J Med Biol Res 1999 Oct;32(10):1269-76.

Molina V, Arruzazabala ML, Carbajal D, Valdes S, Noa M, Mas R, Fraga V, Menendez R. Department of Pharmacology, Center of Natural Products, National Center of Scientific Research, Havana, Cuba.

Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane wax, whose main component is octacosanol. An inhibitory effect of policosanol on platelet aggregation and cerebral ischemia in animal models has been reported. Thus, the objective of the present study was to evaluate the effect of policosanol on cerebral ischemia induced by unilateral carotid ligation and bilateral clamping and recirculation in Mongolian gerbils. Policosanol (200 mg/kg) administered immediately after unilateral carotid ligation and at 12- or 24-h intervals for 48 h significantly inhibited mortality and clinical symptoms when compared with controls, whereas lower doses (100 mg/kg) were not effective. Control animals showed swelling (tissue vacuolization) and necrosis of neurons in all areas of the brain studied (frontal cortex, hippocampus, striatum and olfactory tubercle), showing a similar injury profile. In the group treated with 200 mg/kg policosanol swelling and necrosis were significantly reduced when compared with the control group. In another experimental model, comparison between groups showed that the brain water content of control gerbils (N = 15) was significantly higher after 15 min of clamping and 4 h of recirculation than in sham-operated animals (N = 13), whereas policosanol (200 mg/kg) (N = 19) significantly reduced the edema compared with the control group, with a cerebral water content identical to that of the sham-operated animals. cAMP levels in the brain of control-ligated Mongolian gerbils (N = 8) were significantly lower than those of sham-operated animals (N = 10). The policosanol-treated group (N = 10) showed significantly higher cAMP levels (2.68 pmol/g of tissue) than the positive control (1.91 pmol/g of tissue) and similar to those of non-ligated gerbils (2.97 pmol/g of tissue). In conclusion, our results show an anti-ischemic effect of policosanol administered after induction of cerebral ischemia, in two different experimental models in Mongolian gerbils, suggesting a possible therapeutic effect in cerebral vascular disorders.

Validation of a gas chromatographic method for determining fatty alcohols that compose policosanol in five-milligram film-coated tablets.

J AOAC Int 1999 Jul-Aug;82(4):834-9.

Gonzalez Canavaciolo VL, Magraner Hernandez J. National Center for Scientific Research, Center of Natural Products, Havana City, Cuba.

A gas chromatographic method using a packed column and 1-eicosanol as an internal standard was developed and validated for determination of the aliphatic fatty alcohols that compose policosanol in 5 mg film-coated tablets. The alcohols were analyzed as trimethylsilyl (TMS) derivatives, prepared with N-methyl-N-trimethylsilylfluoroacetamide. The method can detect degradation products with high retention times without interfering with the peaks of the active principle. Good linearity (correlation coefficient = 0.9996) and accuracy (recovery = 100.44%) were proven over a range of 50-150% of the nominal concentration. Within-day and between-day precisions at the nominal 100% value met the acceptance criteria (< 2%). Ruggedness was examined through an intralaboratory experimental study in which 7 operational changes were made and the observed results were quantitation, repeatability, resolution, and relative retention time. Among these results, only the relative retention time (tC28,C20) was significantly affected when the column used was 2.1 m instead of 3.1 m. Repeatability and reproducibility (r = 0.1506 and R = 0.2450, respectively) were obtained from a uniform-level interlaboratory test. The method is suitable for quality control and stability studies of these tablets.

Oral administration of policosanol inhibits in vitro copper ion-induced rat lipoprotein peroxidation.

Physiol Behav 1999 Aug 1;67(1):1-7.

Menendez R, Fraga V, Amor AM, Gonzalez RM, Mas R. Pharmacology Department, Center of Natural Products, National Center for Scientific Research, Havana, Cuba.

Policosanol, a new cholesterol-lowering agent, is a mixture of higher aliphatic primary alcohols isolated from sugar cane (Saccharum officinarum L.) wax, which prevents the onset of espontaneously and experimentally induced atherosclerotic lesions in experimental models. Because the oxidation of low-density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis, we investigate the effect of policosanol on copper oxidative susceptibility of rat lipoprotein fractions (VLDL + LDL). Rats fed normal diet were treated with policosanol (250-500 mg/kg/day) for up to 4 weeks. EDTA-free lipoprotein particles were oxidized in a cell-free system by the addition of copper ions, and conjugated dienes generation was monitored by changes of optical density at 234 nm. Thiobarbituric acid-reactive substances (TBARS) content and lysine-amino group reactivity were investigated. After administration, there was no change in cholesterol, triglycerides, and phospholipid content of lipoprotein fractions; however, policosanol significantly prolongs the lag time and reduces the propagation rate of diene generation. Also, policosanol reduces TBARS content and increases lysine reactivity in lipoprotein fractions treated with Cu2+. In conclusion, policosanol, in addition to its cholesterol-lowering effect, has other properties that enables it to reduce the potential of lipoprotein to undergo lipid peroxidation. Such effect can be considered of promissory value in the management of atherosclerosis.

Comparative effects of policosanol and two HMG-CoA reductase inhibitors on type II hypercholesterolemia.

Rev Med Chil 1999 Mar;127(3):286-94.

Prat H, Roman O, Pino E. Centro Cardiovascular Hospital Clinico Universidad de Chile.

BACKGROUND: Policosanol is a new cholesterol lowering agent derived from sugar cane. AIM: To compare the cholesterol lowering efficacy of policosanol with HMG CoA inhibitors. PATIENTS AND METHODS: Patients with a LDL cholesterol over 160 mg/dl were studied. If, after 6 weeks of diet, cholesterol persisted elevated, they were doubly blind randomized to receive policosanol 10 mg/day (55 patients), lovastatin 20 mg/day (26 patients) or simvastatin 10 mg/day (25 patients). Serum cholesterol was measured again after 8 weeks of therapy. RESULTS: Initial demographic and laboratory data were similar among treatment groups. A 24% LDL cholesterol reduction was obtained with policosanol, compared with a 22% reduction with lovastatin and a 15% reduction with simvastatin. HDL cholesterol significantly increased in patients on policosanol and did not change in the other treatment groups. Adverse effects of policosanol were mild and unspecific. No changes in hepatic enzymes were observed. CONCLUSIONS: Policosanol is a safe and effective cholesterol reducing agent.

Effects of policosanol in patients with type II hypercholesterolemia and additional coronary risk factors.

Clin Pharmacol Ther 1999 Apr;65(4):439-47.

Mas R, Castano G, Illnait J, Fernandez L, Fernandez J, Aleman C, Pontigas V, Lescay M. Center of Natural Products, National Center for Scientific Research, Havana City, Cuba.

INTRODUCTION: This study was undertaken to evaluate the efficacy, safety, and tolerability of policosanol, a new cholesterol-lowering drug, in patients with type II hypercholesterolemia and additional coronary risk factors. PATIENTS AND METHODS: After 5 weeks of a standard step-1 lipid-lowering diet, 437 patients were randomized to receive, under double-blind conditions, 5 mg policosanol or placebo once a day with the evening meal for 12 weeks and 10 mg policosanol or placebo for the next 12 weeks. RESULTS: Both groups were similar at randomization. Policosanol (5 and 10 mg/day) significantly reduced (P < .001) serum low-density lipoprotein cholesterol (18.2% and 25.6%, respectively) and cholesterol (13.0% and 17.4%), and it significantly raised (P < .01) high-density lipoprotein cholesterol (15.5% and 28.4%). Triglycerides remained unchanged after the first 12 weeks and lowered significantly (5.2%; P < .01) at study completion. Policosanol was safe and well tolerated, and no drug-related disturbances were observed. Two male patients who received placebo died during the studyone because of a myocardial infarction and the other because of a cardiac arrest that occurred during a surgical intervention. There were 11 serious adverse events (5.1%) in 10 patients who received placebo (4.6%), 7 of which were vascular, compared with no serious adverse events reported in patients receiving policosanol (P < .01). CONCLUSIONS: Subjects in the group treated with policosanol did not have serious adverse events during the 24-week study. This study shows that policosanol is effective, safe, and well tolerated in patients with hypercholesterolemia and concomitant coronary risk factors.

Effects of some natural extracts on the acetylcholine release at the mouse neuromuscular junction.

Pharmacol Res 1999 Mar;39(3):239-45.

Re L, Barocci S, Capitani C, Vivani C, Ricci M, Rinaldi L, Paolucci G, Scarpantonio A, Leon-Fernandez OS, Morales MA. Institute of Experimental and Clinical Medicine, Laboratory of Pharmacology, University of Ancona, Ancona, 60131, Italy.

Natural extracts have been proved to be useful in different human pathological conditions. The scientific consideration of the therapeutic potential of plant extracts is still inappropriate due to the lack of both pharmacological and epidemiological basic studies. Here, we started from an electrophysiological point of view, a study on the effects of two extracts on the acetylcholine (ACh) release at the neuromuscular junction. The extracts purified from Sugar cane (policosanol) and Psidium guajava (quercetin) have been submitted to this study. The wide epidemiology of these agents suggests therapeutic potentials not yet well outlined at the basic level. Our data demonstrate some interactions in the modulation of the ACh release at the mouse neuro-muscular junction, which are well correlated with the suggested molecular mechanisms. Policosanol enhances to a small extent either the spontaneous or the evoked ACh release. Furthermore, an increase of the rate of the conformational change induced at the nicotinic receptor-channel complex by ACh is also observed. Quercetin induced a reduction of the ACh evoked release. The possibility that this effect could be ascribed to some interaction with presynaptic calcium channel is noteworthy. The results are discussed in terms of a possible interference with acetylcholinesterase by policosanol and of a presynaptic molecular action of quercetin modulating the cytosolic calcium concentration. Copyright 1999 The Italian Pharmacological Society.

A double-blind, placebo-controlled study of the effects of policosanol in patients with intermittent claudication.

Angiology 1999 Feb;50(2):123-30.

Castano G, Mas R, Roca J, Fernandez L, Illnait J, Fernandez JC, Selman E. Medical Surgical Research Center, Havana City, Cuba.

This study was undertaken to evaluate the efficacy and tolerability of policosanol, a new cholesterol-lowering drug with concomitant antiplatelet effects, in patients with intermittent claudication. After a baseline period of 6 weeks, 62 patients were randomized to receive, under double-blind conditions, either placebo (31 patients) or policosanol (31), 10 mg twice daily. Walking distances in a treadmill (constant speed 3.2 km/hr, slope 10 degrees) were assessed before and after 6 months of treatment. Both groups were similar at randomization. Policosanol increased significantly (p < 0.01) the initial claudication distance from 132.5+/-13.5 m (baseline) to 205.7+/-36.3 m (after therapy) and the absolute claudication distance (p<0.0001) from 229.5+/-22.0 m to 365.4+/-46.9 m; meanwhile both variables remained unchanged in the placebo group (p<0.05). The reduction of lower limb symptoms showed a greater benefit in the policosanol group. There was no significant change in either group in the ankle/arm pressure ratio. The treatment was well tolerated. There were 10 discontinuations (seven placebo, three policosanol) from the study. Six withdrawals occurred because of adverse events (AE); all were in placebo patients. There were five serious vascular AEs in the placebo group but none in the policosanol group (p<0.05). Overall, 12/31 (38.7%) placebo patients and 3/31 (9.7%) policosanol patients experienced AEs after randomization, which showed a lesser incidence of AEs in the policosanol group (p<0.01). The present study demonstrates a beneficial effect of policosanol in patients with intermittent claudication.

Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients.

Int J Tissue React 1998;20(4):119-24.

Arruzazabala ML, Mas R, Molina V, Carbajal D, Mendoza S, Fernandez L, Valdes S. Center of Natural Products, National Center for Scientific Research, Havana, Cuba.

Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects proved in experimental models and healthy volunteers. This study reports the results of a 4-week, randomized, double-blind, placebo-controlled trial investigating the effects of policosanol on platelet aggregation in type II hypercholesterolemic patients. Patients started or continued on a step-one cholesterol-lowering therapy for 4 weeks and those with total cholesterol > 5.0 mmol/L despite dietary conditions were randomized to receive under double-blind conditions placebo or policosanol (10 mg/day) for 30 days. Both groups were similar at randomization. Effects of policosanol on platelet aggregation induced by arachidonic acid (3.2 mM), collagen (0.5-1 microgram/ml) and ADP (0.5-1 uM) were determined at baseline and after 30 days of treatment. Policosanol significantly reduced platelet aggregation induced by arachidonic acid and collagen, meanwhile it only inhibited significantly the platelet aggregation induced by the lowest doses of ADP (0.5 uM). No adverse events occurred during the trial. Only one patient (placebo) discontinued from the study because of arthralgia.

Effect of policosanol on intimal thickening in rabbit cuffed carotid artery.

Int J Cardiol 1998 Dec 1;67(2):125-32.

Noa M, Mas R, Mesa R. Laboratory of Histology, Center of Natural Products, National Center for Scientific Research, Havana, Cuba.

We studied the effect of policosanol on smooth muscle cell proliferation in the cuffed carotid artery of the rabbit. Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane wax, with cholesterol lowering effects proved in experimental models and patients with type II hypercholesterolemia. It acts by inhibiting cholesterol biosynthesis. The positioning of a nonocclusive silicone collar around the rabbit carotid artery results in the formation of a neointima. We wished to determine whether policosanol orally administered prevented intimal thickening. Collars were placed around the left carotid for 15 days. The contralateral artery was sham operated. We included three experimental groups: a control received vehicle and two others policosanol at 5 and 25 mg Kg until sacrificed. Samples of arteries were examined by light and electron microscopy. To evaluate intimal thickening the cross-sectional area of intima and media were measured. Neointima was significantly reduced in policosanol-treated animals compared with controls. The smooth muscle cell proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen and a significant reduction was observed in policosanol treated rabbits. It is concluded that policosanol has a protective effect on the neointima formation in this experimental model.

Long-term therapy with policosanol improves treadmill exercise-ECG testing performance of coronary heart disease patients.

Int J Clin Pharmacol Ther 1998 Sep;36(9):469-73.

Stusser R, Batista J, Padron R, Sosa F, Pereztol O. Clinical Research Center, Havana University, Playa, Cuba.

This study examined the effects of long-term lipid-lowering therapy with policosanol on the clinical evolution, and exercise-ECG testing responses of 45 coronary heart disease (CHD) patients with myocardial ischemia, documented by exercise 201T1-myocardial perfusion scintigraphy, in an overall randomized, double-blind, placebo-controlled trial, made for different test endpoints. Fifteen patients were treated with 5 mg of policosanol twice daily; another 15 patients were administered the same drug dose plus 125 mg aspirin; and the other 15 patients received placebo plus equal aspirin dose. They were followed for 20 months, previous baseline observations, with treadmill exercise-ECG, besides serum lipid test. Beneficial changes on proportions among the 2 policosanol groups and the placebo group, showed an increment on functional capacity class, a decrement on rest and exercise angina, and a significant decrease in cardiac events, and in ischemic ST segment response, especially in the policosanol plus aspirin group (p = 0.05, X2(2df) = 5.8; p = 0.04, p = 0.02; Fisher). After treatment, sets of mean changes revealed an increase on maximum oxygen uptake, and a decline on double product simultaneously in both policosanol groups (p < or = 0.02, p < or = 0.002; Pillais, Hotellings' T2), while the placebo group was impaired. Aerobic functional capacity percent showed an increment in policosanol groups (p < or = 0.05, paired T). Lipid levels improved as other endpoints already reported. A supposed ergogenic effect of octacosanol, policosanol's main active compound, was not detected with this design. These results show that policosanol-treated CHD patients improved clinical evolution, and exercise-ECG responses, owing to the amelioration of myocardial ischemia, even more when administered with aspirin.

Interaction policosanol-warfarin on bleeding time and thrombosis in rats.

Pharmacol Res 1998 Aug;38(2):89-91.

Carbajal D, Arruzazabala ML, Valdes S, Mas R. Center of Natural Products, CNIC, Playa, Havana, Cuba.

Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and type II hypercholesterolemic patients. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. This study investigated the effects of the concomitant administration of policosanol and warfarin on bleeding time and experimentally-induced venous thrombosis in rats. Policosanol did not change the bleeding time, meanwhile warfarin alone and the combination policosanol + warfarin induced a moderate, but significant prolongation of the bleeding time. The addition of policosanol to warfarin therapy did not enhance the prolongation of the bleeding time induced by warfarin alone. A significant reduction of thrombus weight was observed after policosanol or warfarin monotherapies. When the combination was used instead of either drug alone, no significant benefits were observed on the reduction of thrombus weight.

Evaluation of peri- and post-natal toxicity of Policosanol in rats.

Teratog Carcinog Mutagen 1998;18(1):1-7.

Rodriguez MD, Garcia H. Department of Toxicology, National Center for Scientific Research, Havana, Cuba.

The effects of Policosanol, a newly developmented hypocholesterolemic drug administered during the perinatal and postnatal periods, were studied in Sprague-Dawley rats. This compound was administered orally to female rats at dose levels of 0 (control), 5, 50, and 500 mg/kg/day, from day 15 of pregnancy to day 21 after parturition. The animals were allowed to deliver and their offspring were examined for postnatal growth and development. No signs of toxic effects related to the test material were observed in the dams F0 during pregnancy and lactation. No adverse effects were observed on the postnatal growth, behaviours, or reproductive ability of pups F1. The physical and sensorial development of pups F2 was also normal. These results confirm that Policosanol does not affect the reproductive performance or fetal/neonatal development.

Effect of policosanol on arterial blood pressure in rats. Study of the pharmacological interaction with nifedipine and propranolol.

Arch Med Res 1998 Spring;29(1):21-4: Arch Med Res 1998 Winter;29(4):361

Molina Cuevas V, Arruzazabala ML, Carbajal Quintana D, Mas Ferreiro R, Valdes Garcia S. Centro de Productos Naturales, CNIC, Havana, Cuba.

BACKGROUND: Policosanol is a natural mixture of higher aliphatic primary alcohols isolated from sugar cane wax (Saccharum officinarum, L) with cholesterol-lowering effects demonstrated in experimental models and in patients with type II hyperlipoproteinemia. The purpose of this study is to determine the effect of policosanol on arterial blood pressure and its interaction with propranolol and nifedipine. METHODS: Single doses of policosanol (25, 50 and 200 mg/kg) orally administered to spontaneously hypertensive rats (SHR) did not significantly change arterial pressure. RESULTS: The study on pharmacological interactions between policosanol (200 mg/kg) and both antihypertensive agents revealed that pretreatment with high doses of policosanol significantly increased propranolol-induced hypotensive effects, while the effects of nifedipine remained unchanged. CONCLUSIONS: Our results show that policosanol does not antagonize the hypotensive effect of beta-blockers but it can increase the hypotensive effect of beta-blockers without modifying cardiac frequency.

Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers.

Prostaglandins Leukot Essent Fatty Acids 1998 Jan;58(1):61-4.

Carbajal D, Arruzazabala ML, Valdes S, Mas R. Center of Natural Products, CNIC, Cubanacan Habana, Cuba.

Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and patients with type II hypercholesterolemia. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. This study reports the results of a 2-week, randomized, double-blind, placebo-controlled trial investigating the effects of policosanol on platelet aggregation and thromboxane B2 and prostacyclin (6 keto PGF1alpha) production after stimulation with collagen in healthy volunteers. The volunteers were on a placebo-baseline period for 7 days and thereafter they received randomly, under double-blind conditions, placebo or policosanol (10 mg/day) for 15 days. Platelet aggregation was determined at baseline and after 15 days of treatment. Significant reductions of arachidonic acid and collagen-induced platelet aggregation were observed. Thromboxane, but not prostacyclin, generation induced by collagen was also inhibited by policosanol.

Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers.

Pharmacol Res 1997 Oct;36(4):293-7.

Arruzazabala ML, Valdes S, Mas R, Carbajal D, Fernandez L. Department of Pharmacology, Centre of Natural Products, CNIC, Habana, Cuba.

A randomized, double-blind, placebo-controlled study was conducted in 43 healthy volunteers to compare the effects of policosanol (20 mg day-1), aspirin (ASA) (100 mg day-1) and combination therapy (policosanol 20 mg day-1 plus ASA 100 mg day-1) on platelet aggregation. The healthy volunteers were randomly treated for 7 days. Both, platelet aggregation and coagulation time were measured at baseline and after therapy. When policosanol was administered platelet aggregation induced by ADP (37.3%), epinephrine (32.6%) and collagen (40.5%) were significantly reduced. Meanwhile, aspirin significantly reduced platelet aggregation induced by collagen (61.4%) and epinephrine (21.9%) but not ADP-induced aggregation. Combined therapy significantly inhibited aggregation induced by all the agonists reaching the highest reductions of platelet aggregation induced by collagen (71.3%) and epinephrine (57.5%). Coagulation time did not change significantly in any group. No subject withdrew from the trial. Four volunteers reported mild adverse experiences during the study: three ASA-treated cases referred headache, epigastralgia and nose bleeding, meanwhile one patient receiving combination therapy reported gum bleeding. The present results demonstrate that policosanol (20 mg day-1) is as effective as ASA (100 mg day-1). Moreover, combination therapy shows some advantages compared with the respective monotherapies.

Effect of policosanol on circulating endothelial cells in experimental models in Sprague-Dawley rats and in rabbits.

J Pharm Pharmacol 1997 Oct;49(10):999-1002.

Noa M, Mas R, Mesa R. National Centre for Scientific Research, Havana, Cuba.

The effect of policosanol on circulating endothelial cells has been studied in different experimental models with endothelium damage. Oral administration of 25 mg kg-1 policosanol to Sprague-Dawley rats resulted in significant protection of the endothelial lining against the desquamating effect of citrate. Oral administration of 5 mg kg-1 policosanol to spontaneously hypertensive rats (SHR) resulted in a significant reduction of circulating endothelial cells compared with controls. Moreover, comparison between groups revealed a lower frequency of aortic lesions in policosanol-treated animals than in controls. On the other hand, administration of 5 mg kg-1 policosanol to rabbits with intimal hyperplasia induced by cuff placement in the carotid artery resulted in levels of circulating endothelial cells significantly lower than in controls. These results demonstrate the protective effect of policosanol in different experimental models and suggest its potential for endothelial protection.

Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation.

Arch Med Res 1997 Autumn;28(3):355-60.

Fraga V, Menendez R, Amor AM, Gonzalez RM, Jimenez S, Mas R. Centro Nacional de Investigaciones Cientificas, Centro de Productos Naturales, Havana, Cuba.

Policosanol, a defined mixture of high molecular weight aliphatic alcohol isolated and purified from sugar cane (Saccharum officinarum, L) wax is a new cholesterol-lowering agent effective in experimental models, healthy volunteers, and patients with type II hypercholesterolemia. Also, policosanol prevents the onset of spontaneously- and experimentally-induced atherosclerotic lesions and cerebral ischemia in Mongolian gerbils. Free radicals are linked to many diseases including atherosclerosis and ischemia/ reoxidation cellular injury. Therefore, in this study the authors evaluate the antioxidant activity of policosanol on rat liver microsomes. The extent of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS). When policosanol was administered orally (100 and 250 mg/kg) for up to 4 weeks, a partial prevention of rat in vitro microsomal lipid peroxidation was noted. The formation of TBARS in microsomes isolated from treated rats was significantly decreased by about 50%, when peroxidation was initiated by Fe3+/ADP/ NADPH, Fe2+/ascorbate and CCl4/NADPH-generating system. Also, oral administration of policosanol in rats provides a partial inhibition of lipid peroxidation, but the mechanism supporting such effect remains to be elucidated. This beneficial effect of policosanol on membrane lipid peroxidation may be useful in protecting to some extent against free radical-associated diseases.

Cholesterol-lowering effect of policosanol on rabbits with hypercholesterolaemia induced by a wheat starch-casein diet.

Br J Nutr 1997 Jun;77(6):923-32.

Menendez R, Arruzazabala L, Mas R, Del Rio A, Amor AM, Gonzalez RM, Carbajal D, Fraga V, Molina V, Illnait J. Department of Pharmacology, National Center for Scientific Research, Havana, Cuba.

The effect of policosanol, a mixture of high-molecular-weight aliphatic alcohols isolated from sugarcane wax, on casein-induced hypercholesterolaemia in rabbits was studied. When policosanol was administered by the oral route once daily for 30 d (50 mg/kg) the increases in plasma total cholesterol and LDL-cholesterol (LDC-C) were significantly reduced when compared with the control group. The incorporation of 3H2O into sterols in the liver was significantly depressed, suggesting inhibition of hepatic cholesterol biosynthesis. The oral administration of policosanol raised the rate of removal of 125I-labelled LDL from serum. Kinetic parameters calculated following injection of [125I]LDL showed than in casein-fed rabbits, the terminal half-life (t1/2) was significantly decreased after policosanol treatment. The hepatic LDL-binding activity was increased after policosanol administration which suggested that the enhanced clearance was due, at least in part, to increased receptor-mediated uptake of LDL by the liver. Considered together, these results suggest that policosanol can significantly reduce the increase of plasma LDL-C in rabbits fed on a wheat starch-casein diet by reducing cholesterol biosynthesis in the liver. Such an effect could account for the enhancement of LDL catabolism through the receptor-mediated pathway.

Multigeneration reproduction study of policosanol in rats.

Toxicol Lett 1997 Feb 7;90(2-3):97-106.

Rodriguez MD, Sanchez M, Garcia H. Department of Toxicology, National Center for Scientific Research, Havana, Cuba.

The hypocholesterolaemic drug policosanol was administered to Sprague-Dawley rats of both sexes throughout three successive generations at concentrations of 0, 5, 50 and 500 mg/kg bw/day by gavage. For each generation two litters were reared until they were at least 3 weeks old. No clinical signs which could be related to the administration of the test substance were observed in the F0, F1b and F2b parents. There were no differences among groups in the number of animals that conceived, the number of pups born live or dead, the rate of male to female pups, the number of pups that survived until weaning and the pups' body weights through the lactancy. The following test showed no treatment-related effects on F3b offspring: righting on a surface, air righting, corneal, pirmal and pain reflexes, auditory startle and visual placing. The results of the present study did not demonstrate any deleterious effects on the fertility, reproductive performance or development of rats administered policosanol at levels of up to 500 mg/kg bw/day over three successive generations.

Effect of policosanol successive dose increases on platelet aggregation in healthy volunteers.

Pharmacol Res 1996 Nov-Dec;34(5-6):181-5.

Arruzazabala ML, Valdes S, Mas R, Fernandez L, Carbajal D. Departamento de Farmacologia, Centro Nacional de Investigaciones Cientificas, Havana, Cuba.

Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and type II hypercholesterolemic patients. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. The effect of successively increasing doses of policosanol on platelet aggregation was investigated in a randomized, placebo-controlled, double-blind study conducted in 37 healthy volunteers. The volunteers were on a placebo-baseline period (two tablets per day) for 7 days and thereafter they received randomly, under double-blind conditions, placebo or policosanol (10 mg day-1) for 7 days. After this period dosage was doubled to 20 mg day-1 for the next 7 days and then again doubled to 40 mg day-1, while the control group received placebo tablets all the time. Platelet aggregation as well as coagulation time was measured at baseline and after each dosing step. Results showed that antiplatelet effects of policosanol were successfully enhanced throughout the study, thus suggesting a dose-dependent relationship. No significant effect was reached during the first dosing period, but significant reductions of epinephrine and ADP-induced platelet aggregation were observed after the second one. Finally, a significant inhibition of platelet aggregation induced by all the agonists was observed at the last dosing step. Coagulation time remained unchanged during the trial.

Effect of policosanol on foam-cell formation in carrageenan-induced granulomas in rats.

J Pharm Pharmacol 1996 Mar;48(3):306-9.

Noa M, de la Rosa MC, Mas R. Laboratory of Histology, National Center for Scientific Research, La Habana, Cuba.

Policosanol is a new cholesterol-lowering drug isolated and purified from sugar-cane wax, which prevents the development of lipofundin-induced lesions and foam-cell formation in New Zealand rabbits and Wistar rats. This study was conducted to examine the effects of policosanol on foam-cell formation in carrageenan-induced granulomas in rats. Eighteen Wistar rats were randomly distributed in three experimental groups which received orally for 20 days Tween 20 H2O as vehicle (control group) or policosanol at 2.5 or 25 mg kg-1. At the 11th day, lipofundin was injected intraperitoneally for 8 days to induce formation of foam cells in the granuloma. At day 13, carrageenan was injected subcutaneously for granuloma induction and seven days later animals were killed. A significant reduction of the foam-cell formation in granulomas of policosanol-treated rats was observed. It is concluded that policosanol prevents the development of foam cells in carrageenan-induced granulomas (extravascular medium) in rats.

Effect of policosanol on hyperlipidemia and coronary heart disease in middle-aged patients. A 14-month pilot study.

Int J Clin Pharmacol Ther 1996 Mar;34(3):134-7.

Batista J, Stusser R, Saez F, Perez B. Cardiovascular Laboratory, Havana University, Cuba.

To find out the long-term lipid-lowering efficacy of policosanol in low dose and its influence in the evolution of coronary heart disease (CHD), a pilot clinical randomized single-blind, placebo-controlled trial was conducted on 23 middle-aged outpatients, with well documented diagnosis of chronic CHD and primary or marginal hyperlipidemia. Twelve patients received policosanol tablets of 1 mg twice daily, and 11 patients placebo in the same fashion, followed with rest and stress electrocardiogram (ECG), and serum lipid blood samples by 14 months. The treated group showed significant reduction of total cholesterol in 14.8% (p < or = 0.001) and of low density lipoprotein (LDL) in 15.6% (p < or = 0.05), against non significant increase of 3% and 5.5%, respectively, in the placebo group. No patient had new coronary events in both groups, but 5 of 12 treated patients exhibited a clinical tendency to improve their CHD, in comparison with no one in the placebo group (p < or = 0.05). These findings show the effectiveness of low dose of policosanol lowering total cholesterol and LDL levels and suggest a CHD improvement in middle-aged patients with primary or marginal hyperlipidemia.

Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolemic rats.

Biol Res 1996;29(2):253-7.

Menendez R, Amor AM, Gonzalez RM, Fraga V, Mas R. Centro de Productos Naturales, Centro Nacional de Investigaciones Cientificas, La Habana, Cuba.

We have suggested previously, measuring 14C-acetate incorporation into free cholesterol, that oral administration of policosanol inhibits hepatic cholesterol biosynthesis in rats. Nevertheless, since acetate has limitations to study cholesterol synthesis in vivo, we now investigate rates of incorporation of labeled water into hepatic sterol after policosanol treatment. Absolute rates of incorporation of 3H-water in sterols were depressed by policosanol by about 20%, giving a more accurate degree of cholesterol biosynthesis inhibition in this species. Since policosanol did not inhibit labeled mevalonate incorporation into cholesterol in rat liver, we also studied the effect of policosanol on hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase. Reductase activity assayed in microsomes treated with policosanol remained unchanged, suggesting that cholesterol synthesis is not inhibited by a direct action of policosanol on this enzyme.

Effect of policosanol on platelet aggregation in healthy volunteers.

Int J Clin Pharmacol Res 1996;16(2-3):67-72.

Valdes S, Arruzazabala ML, Fernandez L, Mas R, Carbajal D, Aleman C, Molina V. Center of Natural Products, National Center for Scientific Research, Cubanacan, Havana, Cuba.

Policosanol is a new drug whose cholesterol-lowering effects have been demonstrated in experimental models, healthy volunteers, and patients with type II hypercholesterolaemia. The effect of policosanol on platelet aggregation was investigated in a randomized, placebo-controlled, double-blind study conducted on healthy volunteers. This included a trial of the effects of single doses (5 to 50 mg) and a study of the effects of repeated doses administered for 7 days. In the single-dose study, the percentage of platelet aggregation in response to the threshold concentration of ADP and epinephrine measured from 8:00 to 10:00 increased significantly in the placebo group, while policosanol (5, 10, 25 and 50 mg), administered orally, inhibited the increase of platelet aggregation induced by ADP and epinephrine determined at the same time. Policosanol administered at 20 mg/day for 7 days significantly inhibited platelet aggregation induced by ADP and epinephrine, although the inhibition reached by the 10 mg/day dose tended to be less significant (p = 0.06). A modest effect (p = 0.068) on collagen-induced platelet aggregation was only observed at the highest dose (50 mg/day). The low dose (5 mg/day) was ineffective. Policosanol did not affect the coagulation time when administered at single or repeated doses. No side-effects were reported in treated or placebo groups.

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