Treatment of Diet-Resistant Polygenic Hypercholesterolaemic Patients with a New Nicotinate Derivative; In Vivo and In Vitro Low Density Lipoprotein Metabolic Studies

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Abstract
Six patients (four women and two men) with mild to moderate hypercholesterolemia, but with no clinical evidence of the disease being monogenic familial hypercholesterolaemia and who, over the previous 3 months on a rigidly controlled hypolipidaemic diet therapy, showed no reduction in plasma cholesterol levels, were recruited into a study to assess the metabolic effects of Pirozadil, a new nicotinic acid derivative. After a 3 month treatment period, a significant reduction in plasma cholesterol from 299.8 ± 31.2 mg/dl (mean ± SD) to 256.8 ± 18.1 mg/dl (P < 0.02) and Low Density Lipoprotein (LDL) cholesterol from 211.7 ± 44.9 mg/dl to 168.8 ± 19.0 mg/dl (P < 0.05) was observed. Although there was a trend toward decreased plasma and Very Low Density Lipoprotein (VLDL) triglyceride, the differences did not reach statistical significance. High Density Lipoprotein (HDL) cholesterol was unchanged. The drug was well tolerated with no side effects noted. To assess the mode of action, autologous125I‐labelled LDL was injected and apoprotein B (apo B) kinetic parameters were measured; production rate (PR) and fractional catabolic rate (FCR). An in vitro measurement of the in vivo catabolism (LDL‐apo B receptor activity in freshly isolated lymphocytes) was also measured pre‐ and post‐treatment. The pharmacological intervention resulted in a significant decrease of 19.9% in PR from 10.5 ± 1.81 mg/kg/d to 8.41 ± 1.13 mg/kg/d (P < 0.05) while the FCR remained relatively unchanged (0.260 ± 0.042 vs 0.248 ± 0.040 pools/d) as did the LDL receptor activity (78.2 ± 20.9 vs 69.3 ± 21.4 ng LDL/mg cell protein/hr). Our data suggest that in polygenic hypercholesterolaemia, a condition in which the LDL receptor and hence catabolism is normal, the alternative therapy to facilitating enhanced catabolism is one that decreases the synthesis of the lipoprotein and, as such, nicotinic acid and its derivatives may be effective hypolipidaemic agents.