Ann M. Lees

Lovastatin (Mevinolin) in the Treatment of Heterozygous Familial Hypercholesterolemia: A Multicenter Study

STUDY OBJECTIVE To evaluate the efficacy and tolerability of lovastatin under controlled conditions in heterozygous familial hypercholesterolemia. DESIGN Randomized, double-blind, placebo-controlled, multicenter trial. SETTING Five lipid clinics with a central laboratory and coordinating center. PATIENTS 101 adult patients with heterozygous familial hypercholesterolemia. INTERVENTIONS Patients were on a lipid-lowering diet throughout the study. After a 4-week placebo baseline period, patients were randomized to five equal treatment groups. Each group received a different sequence of placebo or lovastatin 5 to 40 mg twice daily or 20 to 40 mg once daily in the evening, during three consecutive 6-week periods. MEASUREMENTS AND MAIN RESULTS The mean reductions in total plasma cholesterol and low-density lipoprotein cholesterol across the dosage ranges were 14% to 34% and 17% to 39%, respectively (p compared with zero and placebo less than 0.01). High-density lipoprotein cholesterol and apolipoproteins AI and AII rose slightly. Apolipoprotein B fell substantially at the higher dosage levels (-23% at 40 mg twice daily, p less than 0.01), indicating a reduction in the concentration of circulating low-density lipoprotein particles. Maximum response was achieved in 4 to 6 weeks. Twice-daily dosing was slightly more efficient than once-daily dosing. Of those patients receiving 40 mg twice a day, 89% had a fall in low-density lipoprotein cholesterol of at least 20%, and 61% had a fall of at least 40%. Adverse effects attributable to lovastatin were minimal, and no patient was withdrawn from the study. CONCLUSION Lovastatin was well tolerated and effective in the treatment of familial hypercholesterolemia.

Rhabdomyolysis from the Coadministration of Lovastatin and the Antifungal Agent Itraconazole

To the Editor: Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, widely prescribed to treat hypercholesterolemia, are clearly effective and are associated with reductions in ...

Low density lipoprotein binding to human platelets: Role of charge and of specific amino acids

Abstract Many human and animal cells possess cell surface binding sites, specific for low density lipoproteins. Human platelets are similarly endowed with specific low density lipoprotein receptors. Using chemical modofications of amino acid residues on the low density lipoprotein molecule, we have studied the role of charge and specific amino acids on the binding process. The interaction of the modified low density lipoprotein preparations with gel-filtered platelets and with glass beads was compared. Both cyclohexanedione treated and aceto-acetylated low density lipoprotein did not bind to the platelet surface. However, azo-arsanilated low density lipoprotein bound to the platelets in a manner similar to the binding of native lipoprotein. Cyclohexanedione treated lipoprotein was the only preparation which did not bind to glass beads. The importance of both the presence of the positive charge on the lipoprotein molecule and the availability of specific amino acid residues (arginine and lysine but not tyrosine and histidine) for low density lipoprotein-platelet interaction was thus demonstrated.

Adrenal cortical function in homozygous familial hypercholesterolemia.

The biosynthesis of adrenal corticosteroids requires a supply of cholesterol that can be derived from both local synthesis and uptake of plasma lipoproteins. Recent studies have provided evidence that receptor-mediated uptake of low density lipoproteins provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells that are grown in tissue culture. In the present study we have examined parameters of adrenocortical function in three patients with homozygous familial hypercholesterolemia (two receptor negative, one receptor defective) to assess whether a decreased number of LDL receptors, measured in vitro, influences in vivo corticosteroid production under basal conditions and in response to prolonged stimulation with ACTH. Basal adrenocortical function (assessed by the serum concentrations of cortisol and ACTH plus urinary excretion of 17 OHCS, 17 KS, and urine-free cortisol) was normal in all three patients. Stimulation with intravenous ACTH resulted in rapid increases in the serum concentrations of cortisol in all patients. Plateau concentrations of cortisol during prolonged ACTH stimulation were lower in the two receptor-negative patients (36 to 41 micrograms/dl) but all subjects had at least a threefold increase over basal values. Excretion of urine-free cortisol was reduced in both receptor-negative patients (33% to 36% of controls); this was paralleled by decreased excretion of 17 KS in both patients and of 17 OHCS in one patient. Urine-free cortisol excretion was reduced in the receptor-defective patient (57% of controls), but excretion of 17 OHCS and 17 KS was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Accumulation of native and methylated low density lipoproteins by healing rabbit arterial wall.

To determine whether healing arterial wall accumulation of low density lipoproteins (LDL) Is mediated by the high affinity LDL receptor, normocholesterolemlc rabbits were Injected with 125I-LDL, 99mTc-LDL, or the reductlvely methylated analogs of these compounds (125I-MeLDL, 99mTc-MeLDL), 1 month after balloon catheter deendothellallzatlon of the abdominal aorta, if the mechanism of accumulation requires Interaction with the LDL receptor, reductlvely methylated lipoproteins which do not bind to the receptor should not accumulate In healing arterial wall. Twenty-four hours after Injection of labelled lipoproteins, each animal was Injected with Evans blue dye, In order to distinguish reendothellalized from deendothellallzed aorta. One hour after dye injection, the aorta was fixed, removed, divided Into abdominal (ballooned) and thoracic (unballooned) regions and counted. For all llpoproteln preparations, there were three to four times as many counts In the abdominal as in the thoracic aorta. En face autoradlographs were made of the aortas that had been exposed to 125I-labelled llpoprotelns. In the autoradlographs, the areas of the lowest activity corresponded to the centers of healing endothelial Islands. The most Intense radioactivity for both lipoproteins occurred In the region of the leading edge of the endothelial islands where active endothelial regeneration was In progress. The overall distribution of native and MeLDL accumulation was the same. The results suggest that low density lipoproteins are accumulated In areas of active endothelial regeneration by a mechanism that does not Involve the high affinity LDL receptor.

High-Density Lipoproteins and the Risk of Atherosclerosis

Atherosclerosis, the most common lethal disease in our population, has no obvious single cause. Although hypertension, cigarette smoking, and hyperlipidemia are all prominent risk factors for ather...

Adrenal imaging with technetium-99m-labelled low density lipoproteins☆

Evaluation of adrenal cortical function by external imaging is currently accomplished by injection of radiolabelled analogs of cholesterol. Although the adrenals do utilized exogenous cholesterol for steroid hormone synthesis, the cholesterol is delivered to the glands not as free cholesterol but through the uptake of low density lipoproteins (LDL), which are subsequently degraded within the adrenal cortical cells to provide cholesterol. Thus, we sought to assess the use of 99mTc-labelled LDL injected into rabbits to obtain external images of the adrenal glands. Adrenal images of all nine rabbits tested were obtained within 18 to 21 hours after injection of 99mTc-LDL. Seven of the rabbits were subjected to adrenal cortical suppression with dexamethasone and then all nine rabbits were imaged a second time. In the untreated animals, visualization of the adrenal glands was accompanied by normal serum cortisol concentrations and accumulation of radiolabel in the adrenals, whereas in the dexamethasone-treated animals, lack of visualization of the adrenal glands was correlated with low serum cortisols, and greatly decreased accumulation of the radionuclide in the adrenals. These findings demonstrate for the first time that LDL, when labelled with 99mTc, can be used to evaluate adrenal cortical function by external imaging.

Time course of 125I-labeled LDL accumulation in the healing, balloon-deendothelialized rabbit aorta.

We previously showed by qualitative en face autoradiography that after 24 hours of circulation, 125I-labeled low density lipoprotein (LDL) injected in tracer amounts accumulated focally at the edges of regenerating endothelial islands in the balloon catheter-deendothelialized aorta of the normocholesterolemic rabbit. In the present study with the same animal model, we have used quantitative autoradiography to examine 125I-LDL accumulation in the healing aorta as a function of LDL circulation time from 2.5 to 40 hours. The results demonstrated that 125I-LDL accumulation in the healing aorta occurred in two kinetically and biochemically distinct compartments, one of which was in equilibrium with plasma and one of which sequestered LDL. LDL accumulation in the still-deendothelialized aorta (DEA) was diffuse and only moderately intense on autoradiography. It peaked 4 hours after injection; over the following 36 hours the disappearance of 125I-LDL from DEA paralleled the disappearance of 125I-LDL from plasma. In contrast, accumulation of 125I-LDL at the edges of regenerating endothelial islands was focal and intense. LDL accumulation in this compartment also peaked 4 hours after injection but remained elevated even at 40 hours, despite falling plasma levels of LDL. At 24 hours, edge LDL accumulation per unit area was more than five times greater than DEA accumulation. The data indicate that LDL accumulation in specific compartments of the functionally modified arterial wall occurs independently of either acute or chronic hypercholesterolemia. The contrast between labile LDL accumulation in DEA and persistent accumulation at the edges of healing aortic islands indicates that LDL accumulation in the two areas must involve different processes within the arterial wall itself.

Results of colestipol therapy in type II hyperlipoproteinemia

Twenty-five patinets with well defined Type ii hyperlipoproteinemia were treated with a divided 15 g daily dose of colestipol, a bile acid sequestrant, for periods of up to 20 months. The patients were divided into 3 groups: Those with no obvious sequelae, those with arcus corneae, xanthomas, and/or xanthelasmas only, and those with atherosclerotic complications. Colestipol lowered plasma cholesterol in all 3 groups, but reduced it to normal or near-normal levels in only 9 of the 25 patients (36%). The response of plasma triglycerides was highly varible; the mean for each group was elevated by the drug. Colestipol was well-tolerated and its effect did not diminish with time. It is a useful drug in the treatment of hypercholesterolemia.

Biodistribution and autoradiographic localization of I-125--labeled synthetic Peptide in aortic atherosclerosis in cholesterol-fed rabbits.

I-125-labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipoprotein that has been shown to localize in atherosclerotic plaques in experimental animals. However, its biodistribution and mechanism of localization need to be further elucidated. Twenty-four cholesterol-fed (CF) and 20 normal (NL) New Zealand White rabbits were injected with I-125-SP4 and killed 15 to 30 min (6 NL; 6 CF) or 2 h (14 NL; 18 CF) later. We obtained aortic autoradiograms and activity concentrations (% injected dose/gin) in aortic segments and other tissues. The uptake of I-125-SP4 was higher in CF than in NL rabbits in all aortic segments (p < 0.05). I-125-SP4 was cleared rapidly in both CF and NL rabbits with 60 to 70% of the injected dose cleared from the blood by 1 h. No statistically significant differences in radiotracer biodistribution were observed between NL and CF rabbits although activity tended to be higher in the liver, gallbladder, and intestine in NL rabbits and in the kidney and spleen in CF rabbits. Silver grains were distributed mainly on foam cells of the fatty streaks in aortic microautoradiograms from two additional rabbits that had been injected with I-125-SP4. There were 23,518 ± 15,878 (SD) grains/mm2 in fatty plaques but only 14,669 ± 11,035 grains/mm2 in media muscle (p< 0.0001 [9 sections, 17 areas evaluated] in an atherosclerotic animal) in injected animals and 13,439 ± 5,565 grains/mm2 in media muscle (two sections, four areas) in the normal control animals (NS versus media of atherosclerotic animal). I-125-SP4 specifically localizes in aortic atherosclerotic plaques in CF rabbits. There is no significant difference in tissue distribution between normal and CF rabbits except in the aorta. Preliminarily, it appears that the site of tracer uptake is on foam cells and this suggests the possibility of relative specificity for fatty plaque.