Jörgen Mölgaard

The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST).

The Probucol Quantitative Regression Swedish Trial tested whether treatment of hypercholesterolemic persons with probucol for 3 years affected femoral atherosclerosis. The primary end point was the change in atheroma volume estimated as change in lumen volume of the femoral artery assessed by quantitative arteriography. Three hundred three patients with visible atherosclerosis were randomized to probucol 0.5 g, twice daily, or to placebo. All patients were given diet and cholestyramine, 8 to 16 g/day. Twenty-nine patients were excluded because of inadequate primary end point measurements. The mean age of the remaining 274 subjects (158 were men) was 55 years. Seventeen percent had intermittent claudication and 24% had angina pectoris. After 3 years, the probucol-treated patients had 17% lower serum cholesterol, 12% lower low-density lipoprotein cholesterol, 24% lower total high-density lipoprotein cholesterol, and 34% lower high-density lipoprotein2 cholesterol levels than control subjects. All lipoprotein differences between the treatment groups remained highly significant during the trial. There was no statistically significant change in lumen volume between the probucol and the control group. Furthermore, there was no difference between the treatment groups with regard to change in arterial edge roughness or amount of aorto-femoral atherosclerosis; neither were there any differences between the treatment groups with regard to change in ST-segment depressions on exercise tests or ankle/arm blood pressure (secondary end points). In the control group, lumen volume increased (p < 0.001) and roughness of the femoral artery decreased (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Lowering of HDL2b by Probucol Partly Explains the Failure of the Drug to Affect Femoral Atherosclerosis in Subjects With Hypercholesterolemia : A Probucol Quantitative Regression Swedish Trial (PQRST) Report

The aim of the Probucol Quantitative Regression Swedish Trial (PQRST) (n = 303) was to investigate whether probucol (0.5 g BID) added to diet and cholestyramine (8 g BID) could retard progression or induce regression of femoral atherosclerosis in hypercholesterolemic (> 6.86 mmol/L) subjects. Probucol did not induce regression over the 3-year trial period as estimated by change in lumen volume on quantitative arteriography of a 20-cm segment of the femoral artery. In this report we studied in a representative subgroup (n = 72) whether the reduction in HDL concentrations induced by probucol could explain the failure of the drug to be effective. We analyzed the effects of treatment on HDL particle size subclasses. Probucol lowered the relative level of HDL2b, comprising the largest HDL particles, by 53% and the protein concentration of HDL2b by 67%. The protein reduction in HDL was mainly confined to the apolipoprotein A-I moiety. The change in lumen volume correlated significantly with change in HDL, ie, HDL cholesterol (r = .34, P < .01), HDL2 cholesterol (r = .37, P < .01), HDL2b protein (r = .44, P < .001), and the relative HDL2b value (r = .51, P < .001). The corresponding values for relative HDL2b, distribution calculated on the active (n = 35) and placebo (n = 37) groups separately were also significant (r = .39 and .32, respectively; both P < .05). The correlation between drug-induced change in the relative HDL2b concentration and change in atherosclerosis was independent of the alteration in triglyceride concentration and could not be explained by treatment interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication.

The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of femoral atherosclerosis in hypercholesterolemic patients during treatment with cholestyramine and probucol/placebo: Probucol quantitative regression Swedish trial (PQRST): A status report

The Probucol Quantitative Regression Swedish Trial is being performed to investigate the effects of probucol on atherosclerosis in the femoral artery. Probucol is combined with cholestyramine and dietary management in hypercholesterolemic patients, and the effects of atheroma developing in the femoral artery will be followed by a quantitative angiographic technique. A randomly selected control group is also being managed by dietary therapy and cholestyramine, but receives placebo instead of probucol. The treatment time in this double-blind trial is 3 years, and femoral angiography is performed yearly. Detailed lipoprotein and apolipoprotein analysis are performed at monthly intervals. The basic study design is described here, and some results from the open prerandomization phase of the study are presented.

Probucol Treatment Decreases Serum Concentrations of Diet-Derived Antioxidants

The effect of probucol, which is both a cholesterol-lowering drug and an antioxidant, on the serum concentrations of diet-derived antioxidants vitamin E, beta-carotene, lycopene, and vitamin A was studied in 303 hypercholesterolemic subjects. In a 3-year, double-blind, randomized trial we investigated to determine whether combined treatment with diet, cholestyramine, and probucol could reduce the progression of femoral atherosclerosis. Serum and lipoprotein antioxidant levels were measured by reverse-phase high-performance liquid chromatography. Cholestyramine significantly lowered serum concentrations of vitamin E by 7%, beta-carotene by 40%, and lycopene by 30% (all P < .001) due to impairment of gastrointestinal absorption and to serum cholesterol lowering. Probucol reduced serum vitamin E by 14% (P < .001) secondary to cholesterol and triglyceride lowering. The carotenoids were reduced by probucol by 30% to 40% (P < .001) most probably due to reductions in lipoprotein particle size and to competition with these substances for incorporation into VLDL during its assembly in the liver. This study shows that the use of a lipid-soluble antioxidant and cholesterol-lowering drug may have unfavorable effects on blood levels of diet-derived antioxidants.

Long-term efficacy and safety of simvastatin alone and in combination therapy in treatment of hypercholesterolaemia

The 3-years efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (S) (previously called synvinolin or MK-733) has been studied in single and combined therapy with cholestyramine (C) in 48 hypercholesterolaemic patients. Plasma lipids, lipoproteins and apolipoproteins A-I and B, and blood safety tests (haematology, liver function, creatine phosphokinase (CPK), creatinine, blood glucose and thyroid function) were determined regularly throughout the study. Extensive ophthalmological examinations with particular focus on the lens were done before initiation of therapy and at every 6 months during drug treatment. Maximal reductions of mean plasma total cholesterol concentration (34% with S; 47% with S + C) and low-density lipoprotein (LDL)-cholesterol concentration (42% with S; 56% with S + C) were achieved after 4 weeks on full-dose therapy. During continued treatment, years 1 through 3, the reduction of mean plasma total cholesterol was 26-29% with S alone, and 31-41% with S + C. Significant reductions of plasma triglycerides (15-27%) and very low density lipoprotein (VLDL) triglycerides (10-27%) were achieved in the group treated with S as single therapy. In this group there was also a significant increase (10-14%) of high-density lipoprotein (HDL)-cholesterol. In liver aspartate (AST) and alanine (ALT) aminotransferases, as well as alkaline phosphatase (ALP), minor and variable, but usually transient, increases were seen. Repeated ophthalmological examinations did not demonstrate any drug-related side effects. It is concluded that simvastatin is a safe and efficient cholesterol-lowering drug for long-term therapy, both as a single drug and in combination with cholestyramine.

Comparative effects of simvastatin and cholestyramine in treatment of patients with hypercholesterolaemia.

SummaryThe efficacy and safety of 20 mg simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) and of 16 g cholestyramine daily in the treatment of 34 hypercholesterolaemic patients have been compared after dietary treatment and stratified randomization. The effect of combined treatment with the two drugs was studied in 5 patients with severe hypercholesterolaemia.After 6 weeks of treatment the simvastatin group showed a significantly greater (p<0.05) decrease in the mean total plasma cholesterol concentration from 7.88 to 5.48 mmol/l than in the cholestyramine group in whom there was a fall from 7.82 to 6.73 mmol/l. Simvastatin decreased the mean plasma LDL cholesterol concentration from 6.07 to 3.76 mml/l and cholestyramine decreased it from 6.16 to 4.46 mmol/l. Simvastatin also reduced the mean plasma total triglycerides by 24%, VLDL triglycerides by 20% and VLDL cholesterol by 36%, while cholestyramine led to increases in these parameters by 64%, 85% and 63%, respectively. Mean plasma HDL cholesterol concentration and the subfractions HDL2 and HDL3 cholesterol were significantly increased by simvastatin. Simvastatin and cholestyramine reduced the mean plasma apolipoprotein B concentration by 28% and 13%, respectively.The mean plasma apolipoprotein A–I concentration was significantly higher only on simvastatin treatment.Simvastatin did not cause any subjective or objective side effects, while cholestyramine caused gastrointestinal problems in 31% of patients. Small increases in serum alanine aminotransferase (S-ALT) activity were seen with both drugs. Cholestyramine significantly raised the serum alkaline phosphatase (S-ALP) although to a level still within the normal range.It is concluded that 20 mg simvastatin was more effective than 16 g cholestyramine in the treatment of hypercholesterolaemia. Simvastatin was also better tolerated and it is more convenient for patients to take.

The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis.

The Probucol Quantitative Regression Swedish Trial (PQRST) investigated the effect of the lipid lowering and antioxidant drug probucol on the development of atherosclerosis in humans. 303 hypercholesterolemic patients were randomized to receive either probucol or placebo, in combination with dietary advice and cholestyramine for a three-year period. Probucol was not found to effect progression regression of femoral atherosclerosis significantly as assessed by quantitative arteriography. To evaluate the effectiveness of probucol as an antioxidant during the study period, detailed analyses were performed on 42 of the randomized patients. During the trial, probucol-treated patients (n = 26) had 15% lower total cholesterol (P < 0.01) and 35% lower high density lipoprotein (HDL) cholesterol (P < 0.0001) compared with controls (n = 16). Low density lipoprotein (LDL) from probucol treated individuals was more resistant to oxidation by Cu2+ as determined by the lag phase for the formation of conjugated dienes (220 +/- 8 vs. 82 +/- 7 min (mean +/- S.E)), showed a 13 times lower formation of lipid peroxides, a 97% reduction in macrophage degradation and close to 90% less decrease in LDL receptor binding following oxidation as compared with controls (P < 0.001 for all differences). The results demonstrate that although probucol provided a significant protection against Cu(2+)-induced oxidative modification of LDL, it lacked effect on the development of femoral atherosclerosis. The relevance of these observations for the proposed role of lipid oxidation in atherosclerosis is discussed.

Alfalfa seeds lower low density lipoprotein cholesterol and apolipoprotein B concentrations in patients with type II hyperlipoproteinemia

Fifteen patients with hyperlipoproteinemia (HLP), types IIA (n = 8), IIB (n = 3) and IV (n = 4) were given 40 g of heat prepared alfalfa seeds 3 times daily at mealtimes for 8 weeks with otherwise unchanged diet. In patients with type II HLP alfalfa treatment caused after 8 weeks a maximal lowering of pretreatment median values of total plasma cholesterol from 9.58 to 8.00 mmol/l (P less than 0.001) and low density lipoprotein (LDL) cholesterol from 7.69 to 6.33 mmol/l (P less than 0.01), which corresponds to decreases of 17% and 18%, respectively. Maximal decrease was 26% in total cholesterol and 30% in LDL cholesterol. In two patients with hypercholesterolemia the LDL cholesterol decreased less than 5%. Apolipoprotein B decreased in the same period from 2.17 to 1.43 g/l (P less than 0.05) in type II HLP, corresponding to 34% decrease, whereas apolipoprotein A-I did not change. Body weight increased slightly during the first 4 weeks of alfalfa treatment (P less than 0.001) probably because of the caloric content in the alfalfa seeds. After cessation of treatment, all lipoprotein concentrations returned to pretreatment levels. We conclude that alfalfa seeds can be added to the diet to help normalize serum cholesterol concentrations in patients with type II HLP.

Effect of fish oil treatment on plasma lipoproteins in type III hyperlipoproteinaemia.

Nine patients with type III hyperlipoproteinaemia and homozygosity for the apolipoprotein E2 isoform were treated with 15 g daily of MaxEPA, a fish oil preparation rich in eicosapentaenoic acid (2.7 g daily) and docosahexaenoic acid (1.8 g daily) for 16 weeks. Plasma lipoprotein and apolipoprotein concentrations were compared with those obtained during treatment with an olive oil preparation. MaxEPA treatment decreased plasma median total cholesterol, triglyceride and apolipoprotein B concentrations by 16, 53 and 19%, respectively. Plasma median very low density lipoprotein (VLDL)-cholesterol, triglyceride and apolipoprotein B concentrations were reduced by 45, 62 and 75% respectively, while the abnormal VLDL-cholesterol/triglyceride ratio remained unchanged. Individual reductions of VLDL concentrations varied considerably, for VLDL-cholesterol between 10 and 75%. In the majority of cases the abnormal late pre beta-bands on agarose electrophoresis, typical for type III hyperlipoproteinaemia normalized to pre beta-mobility on MaxEPA treatment. LDL-cholesterol and apolipoprotein B tended to increase after 8 weeks on MaxEPA but decreased again after 16 weeks. Median plasma high density lipoprotein cholesterol and apolipoprotein A-I did not change during MaxEPA treatment. It is concluded that MaxEPA have decreasing effects on plasma VLDL lipid and apolipoprotein concentrations in apolipoprotein E2 homozygous type III hyperlipoproteinaemia but that this effect is variable and unpredictable.