Fernando Labarrios

Synthesis and hypolipidaemic evaluation of a series of α-asarone analogues related to clofibrate in mice

A series of α‐asarone analogues related to clofibrate, containing an acetic acid group at C‐2 of the aromatic ring, has been prepared as the acids or as the ethyl and methyl esters. The corresponding alcohols were also synthesized by reduction of the ethyl esters. The compounds were examined in hyperlipidaemic male mice to evaluate their ability to modify serum lipoprotein cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and triglycerides after oral administration of 40 and 80 mg kg−1 for 6 days.

Hypolipidaemic activity of dimethoxy unconjugated propenyl side‐chain analogs of α‐asarone in mice

The hypolipidaemic activity of several dimethoxy unconjugated propenyl side‐chain analogs of α‐asarone were investigated in hyperlipidaemic mice after six days of treatment. Eugenol and the α‐asarone analog with amino groups on the C‐4 position of the aromatic ring were observed to be the most effective hypolipidaemic agents at the dose of 80 mg/kg/day p.o. These compounds significantly lowered total serum cholesterol, low density lipoprotein (LDL‐cholesterol), and triglycerides content. On the other hand, high density lipoprotein (HDL‐cholesterol) was increased by administration of these hypolipidaemic agents. The ability to modulate the levels of these lipids suggests that these agents could be effective in the treatment of hyperlipidaemic states. These compounds appeared to be safe when administered at an oral dose of 80 mg/kg/day, which is within the therapeutic range in mice. Drug Dev. Res. 43:105–108, 1998.

Hypolipidaemic and antiplatelet activity of phenoxyacetic acid derivatives related to α-asarone

The phenoxyacetic acid derivatives 1–6 [2‐methoxy‐4‐(2‐propenyl)phenoxyacetic acid (1); 2‐methoxy‐5‐nitro‐4‐(2‐propenyl)phenoxyacetic acid (2); methyl 2‐methoxy‐4‐(2‐propenyl)phenoxyacetate (3); ethyl 2‐methoxy‐4‐(2‐propenyl)phenoxyacetate (4); methyl 2‐methoxy‐5‐nitro‐4‐(2‐propenyl)phenoxyacetate (5); ethyl 2‐methoxy‐5‐nitro‐4‐(2‐propenyl)phenoxyacetate (6)] related to α‐asarone have been reported previously as hypolipidaemic agents in diet‐induced hyperlipidaemic mice. We have aimed to expand the pharmacological profile of these derivatives by investigating their hypolipidaemic activity in rats and mice under different experimental conditions. The antiplatelet activity was tested also in‐vitro from blood derived from consenting healthy volunteers. In normolipidaemic rats, compounds 2, 3 and 5 at oral doses of 40 and 80 mg kg−1 significantly decreased total cholesterol and LDL‐cholesterol levels. Moreover, analogues 3 and 5 administered to hypercholesterolaemic rats at the same doses for seven days also produced a reduction in the content of these same lipoproteins. In neither case were the high‐density lipoprotein cholesterol and triglyceride concentrations affected. However, practically all tested compounds were found to be hypocholesterolaemic agents, and were shown to effectively lower low‐density lipoprotein cholesterol and triglyceride levels in Triton‐induced hyperlipidaemic mice at oral doses of 50 and 100 mg kg−1. In all tests, all animals appeared to be healthy throughout the experimental period in their therapeutic ranges. Triton‐induced hypercholesterolaemic mice appeared to be a desirable model for this class of hypolipidaemic drugs. On the other hand, compounds 1, 2, 4 and 5 significantly inhibited ADP‐induced aggregation in‐vitro. These findings indicated that all of these compounds appeared to be promising for the treatment of human hyperlipidaemia and thrombotic diseases.

Dominant lethal study of α-asarone in male and female mice after sub-chronic treatment

Dominant lethal studies were conducted in male and female mice with α‐asarone, the active hypolipidaemic component of Guatteria gaumeri Greenman, by per os sub‐chronic treatment (10 and 20 mg/kg, 5 days/week, for 8 weeks) and subsequent mating. α‐Asarone did not produce germinal mutations in either males or females. Epididymal sperm examination of male mice immediately after treatment failed toreveal any alteration in sperm count on shape. No significant alterations were observed in testicular or epididymal weights or testicular histology. Copyright

Effect of α‐asarone and a derivative on lipids, bile flow and Na+/K+‐ATPase in ethinyl estradiol‐induced cholestasis in the rat

Administration of ethinyl estradiol (EE), a widely used component of oral contraceptives, has been associated with impairment of bile flow and the capacity to excrete organic anions in man and experimental animals. α‐Asarone (2,4,5‐trimethoxypropenylbenzene) and 2‐methoxy‐4‐(2‐propenyl) phenoxyacetic acid (MPPA) have shown hypolipidemic effects. In addition to these effects, we decided to evaluate the properties of these compounds on EE‐induced cholestasis. Wistar male rats were injected subcutaneously with 10 mg/kg of EE for 5 days; simultaneously, α‐asarone or MPPA were also administered and appropriate controls were performed. α‐asarone and MPPA decreased plasma and bile cholesterol. EE diminished triglycerides total, low‐density lipoprotein, high‐density lipoprotein and bile cholesterol. MPPA further decreased these lipid parameters. Alkaline phosphatase (an enzyme marker of cholestasis) was increased after administration of EE, but this effect was prevented significantly by α‐asarone or MPPA administration. Bile flow was importantly decreased by EE and increased by α‐asarone alone. Furthermore, α‐asarone or MPPA preserved the normal bile flow in EE‐treated rats. EE inhibited the activity of the Na+/K+‐ATPase, while both α‐asarone and MPPA preserved this enzyme activity. Na+/K+‐ATPase is involved in Na+‐coupled uptake of bile acids into hepatocytes and, therefore, ultimately is the driving force for the generation of bile flow. Therefore, the anticholestatic effects of α‐asarone and MPPA, described herein by the first time, may be due to its ability to preserve ATPase activity. This enzyme is negatively regulated by membrane cholesterol, thus the hypolipidemic effects of the compounds tested may be responsible for Na+/K+‐ATPase activity and bile flow maintenance.