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Background/aims: Increased osteoclast activity is a pivotal finding in osteoporosis. This increase is mediated via the mevalonate-to-cholesterol pathway, which is involved in producing the intermediates required for osteoclast activity. D-003, a mixture of high molecular weight sugarcane wax acids, has been shown to inhibit cholesterol synthesis prior to mevalonate production, resulting in a reduction of bone loss and resorption in ovariectomized rats. Moreover, previous studies have demonstrated that short-term D-003 treatment reduces urinary excretion of deoxypyridinoline/creatinine in postmenopausal women., Methods: We performed a double-blinded, placebo-controlled study to investigate the effects of D-003 (10 mg/day) treatment for 3 years on bone mineral density (BMD) in 83 postmenopausal women with low BMD., Results: Over 3 years, D-003 treatment increased lumbar spine BMD (5.1%, p < 0.01) and improved osteoporosis-related quality of life scores as compared with placebo-treated controls. D-003 was also well tolerated; the frequency of adverse events in the bone, joints, or muscle with D-003 treatment (p < 0.05) was lower than in the placebo group., Conclusions: D-003 treatment (10 mg/day) for 3 years increased lumbar spine BMD and produced clinical improvements in postmenopausal women with low BMD. Further studies, however, will be required to confirm these results.

Increased platelet aggregation contributes to vascular risk. D-003, a mixture of high molecular weight sugarcane wax acids, has shown antiplatelet effects in experimental models and healthy volunteers. This randomised, double-blinded, placebo-controlled study investigated the effects of titrated doses of D-003 (5-20 mg/d) on platelet aggregation in hypercholesterolemic patients. After a 4-week baseline phase, 56 patients were randomised to D-003 5 mg/d or placebo. The doses were doubled every 15 days if arachidonic acid (AA)-induced platelet aggregation was not inhibited at least by 15%. AA (0.75 and 1.5 mmol/L) and collagen (1 microg/mL)-induced platelet aggregation, laboratory and physical safety indicators were assessed at baseline and every 15 days thereafter, when adverse events (AE) were also reported. No significant change of platelet aggregation was found in the placebo group. After 15, 30 and 45 on therapy, D-003 reduced platelet aggregation induced with both AA 0.75 mmol/L (18.1%, 19.0% and 30.3%, respectively) and AA 1.5 mmol/L (17.0%, 16.3% and 22.5%, respectively), and also collagen-induced platelet aggregation (26.6%, 20.8% and 29.4%) (p < 0.01 at days 15 and 30 versus placebo, p < 0.0001 at study completion). The mean inhibition of platelet aggregation with D-003 at day 15, at which all patients had received the lowest dose, was over 15%. Nineteen out of 28 D-003 randomised patients (67.9%) required dose titration to achieve such goal. At trial completion, the mean estimated dose was 11.6 mg/d. D-003 lowered low-density lipoprotein (22.0 %), total cholesterol (14.7%) and raised high-density lipoprotein-cholesterol (10.9%) (p < 0.0001 versus placebo). Six patients (2 placebo, 4 D-003) withdrew from the trial, none due to AE. D-003 did not modify the safety indicators with respect to placebo. Four patients (2 placebo, 2 D-003-treated) reported AE: pruritus and increased blood pressure (2 placebo) and rash and polyphagla (2 D-003). In conclusion, D-003 (5-20 mg/d) given as doses titrated every 15 days (5-20 mg/d) inhibited AA- and collagen-induced platelet aggregation in hypercholesterolemic patients and was well tolerated.

The main goal of hypercholesterolemia management for coronary prevention is to reduce serum low-density lipoprotein cholesterol (LDL-C) levels. D-003 is a mixture of high molecular weight aliphatic acids purified from sugarcane wax, while policosanol is a cholesterol-lowering drug purified from the same source, consisting in a mixture of higher aliphatic alcohols. No previous comparative study of both drugs in humans has been reported. This randomized, double-blind study compares the efficacy and tolerability of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia. After a baseline period, 100 patients were randomized to D-003 or policosanol both at 5 mg/day and 10 mg/day, for 8 weeks. D-003 and policosanol 5 mg/day reduced (p < 0.0001) LDL-C by 26.9% and 20.9%, respectively. These reductions increased with 10 mg/day (35.1% for D-003, 25.1% for policosanol. The reductions of LDL-C achieved with D-003 5 mg/day and 10 mg/day were greater (p < 0.05 and p < 0.001, respectively) than with policosanol. The frequency of patients treated with D-003 (5 mg/day) reaching LDL-C reductions > or = 15% (22/25, 88%) was greater (p < 0.01) than with policosanol (5 mg/day) (19/25, 76%), and the same was true for D-003 10 mg/day (25/25, 100%) and policosanol (22/25, 88%; p < 0.01). D-003 and policosanol (5 mg/day) also lowered (p < 0.001) total cholesterol (TC) (16.2% and 13.5%, respectively), and increased high-density lipoprotein cholesterol (HDL-C) by 15.3% (D-003) and 6.7% (policosanol). At 10 mg/day, D-003 and policosanol reduced (p < 0.001) TC (21.3% and 16.0%, respectively), while HDL-C was increased by 17.3% and 9.8%, respectively, D-003 being more effective than policosanol. Treatments did not affect triglycerides. Both drugs were well tolerated, with D-003 tolerated as well as policosanol. Three patients discontinued the study, none due to adverse events (AEs). Seven patients (three from the D-003 group and four from the policosanol group) experienced mild AEs. In conclusion, D-003 (5 and 10 mg/day) administered to patients with type II hypercholesterolemia was more effective than policosanol in lowering LDL-C and TC, and in increasing HDL-C. D-003 could be useful for treating type II hypercholesterolemia, but this subject deserves further clinical research.

D-003 is a mixture of high molecular weight aliphatic primary acids purified from sugar cane wax with antiplatelet and cholesterol-lowering effects. Previous studies showed that D-003 (10-20 mg/day) administered for a short time inhibits platelet aggregation, 14 days being the longest duration investigated. This study was conducted to investigate the effects of D-003 (5 and 10 mg/day) for 30 days on platelet aggregation in normocholesterolemic subjects. This report shows the effects of D-003 on platelet aggregation to arachidonic acid (AA) (1.5 mM), collagen (2 microg/ml) and adenosine 5'-diphosphate ADP (2 microM) assessed at baseline and at treatment completion. Fifty-four subjects were randomized to placebo or D-003 (5 or 10 mg/day) for 30 days. Platelet aggregation to AA, collagen and ADP were assessed. D-003 at the lowest dose (5 mg/day) significantly but modestly inhibited (p < 0.01) platelet aggregation to AA (5.0%) and (p < 0.01) to collagen (7.5%). D-003 at 10 mg/day inhibited (p < 0.001) platelet aggregation to AA and collagen (p < 0.01) by 20.3% and 14.7%, respectively. ADP-induced aggregation, however, was unchanged. D-003 at 10 mg/day, but not at 5 mg/day, lowered (p < 0.01) plasma fibrinogen. D-003 (5 and 10 mg/day) reduced low-density lipoprotein cholesterol (LDL-C) by 17.7% and 26.4%, respectively, and total cholesterol (TC) by 14.5% and 18.5%, while at 10 mg/day, but not at 5 mg/day, it increased high-density lipoprotein cholesterol (HDL-C) by 9.6%. Triglycerides, however, were unchanged with D-003. No disturbances in safety indicators were induced with D-003. One subject (D-003 5 mg/day) discontinued the study and four patients (three taking D-003 and one taking placebo) reported adverse effects (AE) (headache in two patients taking D-003 and one patient taking placebo, and polyphagia in one patient taking D-003). In conclusion, D-003 (5-10 mg/day) for 30 days inhibited platelet aggregation to AA and collagen but not to ADP Therefore, the antiplatelet effect was present with the longer treatment, even at a dose of 5 mg/day. The cholesterol-lowering effects of D-003 were consistent with those expected for such a short treatment. In addition, D-003 at 10 mg/day significantly lowered plasma fibrinogen. The treatment was well tolerated.

Biphosphonates, which are antiresorptive agents used to treat osteoporosis, inhibit the mevalonate pathway, preventing protein prenylation and inhibiting osteoclast activity. Statins decrease cholesterol biosynthesis by blocking the mevalonate pathway and have been reported to have beneficial effects on bone. D-003 is a mixture of high molecular weight acids purified from sugarcane wax that inhibits cholesterol biosynthesis before mevalonate production. D-003 prevents bone loss and resorption in rats with osteoporosis induced with ovariectomy or corticoids. Biochemical markers of bone turnover are used to monitor the short-term efficacy of antiosteoporotic therapy. This randomized, double-blind, placebo-controlled study was undertaken to investigate the short-term effects of D-003 (10 mg/day) on biochemical markers of bone turnover in postmenopausal women with low bone mineral density (BMD). After 4 weeks on a low-fat diet, 34 women were randomized to D-003 (10 mg/day) or placebo for 6 months. Pre- and post-treatment samples were analyzed for urinary excretion of deoxypyridinoline (DPD)/creatinine (Cr), a marker of bone resorption, and serum bone specific alkaline phosphatase (BSAP), a marker of bone formation. The effects on lipid profile and safety indicators, as well as adverse events (AE), were investigated. D-003 (10 mg/day) lowered urinary excretion of tDPD/Cr versus baseline (20.6%) (p < 0.001) and placebo (33.7%) (p < 0.01), but did not modify serum BSAP. D-003 decreased low-density lipoprotein-cholesterol (LDL-C) (32.8%), total cholesterol (TC) (16.4%) and the TC/high-density lipoprotein-cholesterol (HDL-C) ratio (34.7%), increased HDL-C (30.3%) (p < 0.001) and did not modify triglycerides. The effects on these variables were significant as early as 3 months after treatment initiation. D-003 was well tolerated. Three patients (one in the placebo group and two in the D-003 group) withdrew from the study. Two of these withdrawals were due to AE: abdominal pain (placebo) and heartburn (D-003). Five patients (four in the placebo group [22.2%] and one in the D-003 group [6.3%]) reported mild AE. In conclusion, D-003 (10 mg/day) reduced urinary excretion of tDPD/Cr, a bone resorption marker and did not change serum BSAP, a bone formation marker, while it lowered cholesterol in study patients. These preliminary results suggest that D-003 could be useful in treating postmenopausal women with low BMD. However, the potential value of D-003 in treating or preventing osteoporosis deserves further clinical investigation.

D-003 is a mixture of very high molecular weight aliphatic acids purified from sugar cane wax showing cholesterol-lowering and antiplatelet effects proven in experimental and clinical studies. Experimental evidence indicates that inhibition of platelet aggregation induced by D-003 is associated with a reduction of thromboxane B2 (TxB2) and an increase of prostacyclin (Pgl2) serum levels. This double-blinded, randomized, placebo-controlled study was undertaken to investigate whether D-003 (20 mg/day) modifies serum levels of TxB2 and Pgl2 and inhibits platelet aggregation in human healthy volunteers. Thirty-one subjects were randomized to placebo or D-003 at 20 mg/day for 14 days. Serum levels of TxB2 and Pgl2 and platelet aggregation to arachidonic acid (AA) (1.75 mM) and collagen (1 microg/ml) were assessed. D-003 (20 mg/day) significantly reduced (p < 0.001) TxB2by 36.4% and increased Pgl2 serum levels by 31% compared with baseline, and these changes were different from placebo. As expected, D-003 significantly inhibited (p < 0.001) platelet aggregation to AA (81.9-65.6%) and to collagen (75.3-62.3%). No subject withdrew from the study. No drug-related disturbances were observed. We conclude that D-003 at 20 mg/day for 14 days significantly inhibited platelet aggregation to AA and collagen and reduced TxB2 and increased Pgl2 serum levels. These results are consistent with those observed in experimental models, indicating that the antiplatelet effect of D-003 is associated with the observed changes on the levels of AA metabolites. Further studies, however, should explore the mechanism involved in this action in greater depth.

Background: D-003 is a mixture of long-chain aliphatic primary acids isolated from sugar-cane wax and having cholesterol-lowering effects and a safety profile that have been proven in animals and in previous clinical studies in healthy volunteers. Lovastatin, the first member of the statin class, is an effective and well tolerated cholesterol-lowering drug. Some lovastatin-related adverse effects have been reported, and preclinical assessment has shown that the rabbit is the most sensitive species to lovastatin toxicity., Objective: To compare the cholesterol-lowering effects and toxicity pattern of D-003 and lovastatin in normocholesterolaemic rabbits., Methods: In order to study cholesterol-lowering effects, rabbits were randomly distributed into three groups (eight animals/group): one control group, only receiving the vehicle, and two groups treated with D-003 or lovastatin at 5 and 10 mg/kg/day, respectively. All treatments were orally administered for 30 days. To study toxicity, rabbits were distributed into four groups (six animals/group): one control group and three groups treated with D-003 200 and 400 mg/kg, respectively, or lovastatin 100 mg/kg., Results: After 30 days, D-003 5 mg/kg and lovastatin 10 mg/kg significantly (p < 0.05) and similarly lowered serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels versus baseline. D-003, but not lovastatin, increased high-density lipoprotein-cholesterol (HDL-C) significantly (p < 0.05), whereas only lovastatin decreased (p < 0.05) triglycerides. Low doses of both drugs did not change safety indicators. D-003 (200 and 400 mg/kg) and lovastatin (100 mg/kg) administered for 10 days reduced TC and LDL-C levels significantly (p < 0.05). HDL-C values increased significantly (p < 0.05) with D-003, but were unchanged with lovastatin. Neither treatment affected triglycerides. No significant changes in lipid profile were observed in the control groups of the two series. Lovastatin 100 mg/kg impaired bodyweight gain and food consumption versus the controls, while D-003 did not. Lovastatin 100 mg/kg increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values (p < 0.05 versus baseline and controls) and liver weight (p < 0.05 versus controls). D-003 200 or 400 mg/kg did not affect AST, ALT or liver weight. Lovastatin 100 mg/kg, but not D-003 200 or 400 mg/kg, induced typical hepatocellular and renal tubular necrosis in the rabbits., Conclusions: D-003 5 mg/kg/day administered orally for 30 days to normocholesterolaemic rabbits lowered LDL-C and TC, as did lovastatin 10 mg/kg. D-003 was more effective in increasing HDL-C, while lovastatin was more effective in lowering triglycerides. Administration of higher doses for 10 days did not show D-003-related toxicity, but did demonstrate the typical pattern of lovastatin-induced toxicity in rabbits.

Objective: To investigate the effects of D-003 on the bleeding time (BT) and lipid profile of healthy human volunteers., Methods: This single-blind, randomised, placebo-controlled, parallel-group study was conducted in healthy volunteers. Step 1 investigated the effects of single doses of D-003 5, 25 or 50 mg on BT in comparison with placebo. Step 2 investigated the effects of 30 days of D-003 5, 25 or 50 mg/day compared with placebo on lipid profile with an interim assessment at 14 days. BT, lipid profile, physical and haematological safety indicators were measured and adverse events (AEs) recorded. Both steps were followed by a 14- or 30-day washout period., Results: Step 1: D-003 25 and 50 mg significantly increased mean BT 2 hours after administration compared with baseline, but a significant difference versus placebo occurred only with the 50 mg dose. Individual values from participants taking this dose, however, remained within normal limits. This effect was reversible. BT values obtained 2 hours after drug administration showed a moderate dose-dependent relationship. No drug-related changes in safety indicators were found with D-003. Step 2: After 7 days on D-003 50 mg/day, BT was significantly increased compared with baseline and placebo up to the end of the active treatment period. However, all individual values for participants taking this dosage remained within the normal range. This effect was reversible by the end of the washout period. After 30 days, D-003 (5, 25 and 50 mg/day) significantly reduced serum TC (by 13.3 to 17.4%) and LDL-C (by 11.6 to 22.6%) levels, and raised HDL-C levels (by 14.6 to 29.7%), but did not affect triglyceride levels. The significant increase in HDL-C was observed after 14 days on treatment. The effects on the lipid profile were reversible by the end of the 30-day washout period, although after 14 days of washout the effects on HDL-C and LDL-C still remained significant, revealing a certain persistence of effect. Eight participants (four receiving placebo and four receiving D-003 5, 25 or 50 mg/day) reported a total of nine AEs, none of which were drug-related. Of these patients, only two treated with D-003 25 and 50 mg/day discontinued treatment., Conclusions: D-003 in single or repeated doses (50 mg) induced significant and reversible increases in BT. In addition, repeated doses (5, 25 and 50 mg/day) significantly and reversibly lowered serum LDL-C and TC levels and significantly raised serum HDL-C levels. These effects were reversible by 30 days after the end of treatment.