Effects of D-003, a mixture of long-chain aliphatic primary acids, fluvastatin and the combined therapy of D-003 plus fluvastatin on the lipid profile of normocholesterolemic rabbits.
D-003 is a mixture of long-chain aliphatic primary acids isolated from sugar cane wax with cholesterol-lowering effects proven in animals and healthy human volunteers. D-003 reduced serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in rabbits, while it increased high-density lipoprotein cholesterol (HDL-C) and did not affect triglycerides. D-003 inhibits cholesterol synthesis by regulating, instead of directly inhibiting, hydroxamethylglutaryl-CoA (HMGCoA) reductase activity. Although the ways in which D-003 and statins inhibit cholesterol biosynthesis are not identical, the strong competitive inhibition of cholesterol biosynthesis induced by statins suggests that an enhanced decrease of LDL-C and TC caused by the combined therapy D-003 plus statins is not expected. Nevertheless, taking into account the differential effects of D-003 and statins in HDL-C and triglycerides in rabbits, potential benefits of such combined therapy on other lipid variables cannot been discarded. Fluvastatin is a statin that inhibits competitively HMGCoA reductase, like other members of this class. This study was undertaken to compare the cholesterol-lowering effects of D-003, fluvastatin and the combined therapy of D-003 plus fluvastatin in normocholesterolemic rabbits. Animals were randomly distributed into four groups of eight. One control group received the vehicle, two groups were treated with D-003 or fluvastatin at 5 mg/kg/day each, and the fourth group received the combined therapy of both drugs at 5 mg/kg/day each. Treatments were orally administered for 30 days. Body weight, food consumption and overall animal behavior were recorded to detect any warning sign resulting from combined therapy. After treatment, it was found that both D-003 and fluvastatin had significantly lowered LDL-C - D-003 by 81.5% (p < 0.01) and fluvastatin by 61.4% (p < 0.05). Combined therapy reduced LDL-C values (75.9%). Final values and percent changes reached in all groups were different from the control (p < 0.01). The reductions of TC were consistent with LDL-C decreases, so that D-003, fluvastatin and combined therapy significantly lowered TC by 48.4% (p < 0.01), 39.7% (p < 0.05) and 45.3%, respectively, values being different from those of the control (p < 0.01). The responses of LDL-C and TC to combined therapy were statistically similar, but less pronounced than those reached by D-003 alone. D-003 and combined therapy, but not fluvastatin alone, increased HDL-C (+21.5% and + 19.0%, respectively), these changes being significant versus the control (p < 0.05). In turn, fluvastatin and combined therapy, but not D-003 alone, lowered triglycerides (13.6% and 13.0%, respectively, p < 0.05 versus control). The effects of combined therapy on HDL-C were similar to those of D-003 alone, and the effects of combined therapy on triglycerides were similar to those of fluvastatin alone. The only advantage of combined therapy appears to be that it shows better effects on HDL-C than those of fluvastatin alone and better effects on triglycerides than D-003 alone. No significant changes in lipid profile were observed in the control group. All groups showed similar food consumption and body weight gain, health status being unaffected by the treatments. It is concluded that D-003 and fluvastatin at 5 mg/kg/day administered orally for 30 days to normocholesterolemic rabbits lowered LDL-C and TC, D-003 being more effective in increasing HDL-C and fluvastatin in lowering triglycerides. Combined therapy did not improve the response of LDL-C and TC with respect to monotherapies, but induced better responses of HDL-C and triglycerides than fluvastatin alone had on HDL-C or D-003 alone had on triglycerides.
Mendoza
S
S
Center of Natural Products, National Center of Scientific Research, Havana City, Cuba.
Gamez
R
R
Mas
R
R
Goicochea
E
E
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005227:Fatty Acids / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000627:therapeutic use*; D000077340:Fluvastatin; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008077:Lipoproteins, LDL / Q000187:drug effects*; D008297:Male; D011817:Rabbits; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D008055:Lipids; D008077:Lipoproteins, LDL; D014280:Triglycerides; D000077340:Fluvastatin; D002784:Cholesterol