Henning von Schenck

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.

Renal handling of inorganic mercury in mice. The early excretion phase following a single intravenous injection of mercuric chloride studied by the Silver Amplification method.

SummaryThe early renal excretion of mercuric mercury was studied in male BALB/c mice between 15 seconds and 30 min following a single intravenous injection of 3 mg HgCl2/kg body weight. The cytochemical Silver Amplification method applied at the light and electron microscopical levels showed mercury to be excreted by glomerular filtration and reabsorbed by proximal tubular epithelial cells by means of adsorptive endocytosis. Mercury was rapidly demonstrated in the lysosomal vacuome of proximal tubular epithelial cells. No uptake was observed from the peritubular side, and there was no evidence of tubular secretion of mercury.It is proposed that mercury is excreted in the form of mercury-protein complexes, assisted by the physiological proteinuria in mice, which is enhanced by mercury-induced damage to the glomerular structures.

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.

OMEGA-3 ETHYL ESTER CONCENTRATE DECREASES TOTAL APOLIPOPROTEIN CIII AND INCREASES ANTITHROMBIN III IN POSTMYOCARDIAL INFARCTION PATIENTS

SummaryThis study investigated whether an ethyl ester preparation of fish oil (ω-3) could normalise raised plasma concentrations of triglycerides, apolipoprotein CIII on apolipoprotein B-containing particles (LP CIII:B) found in patients with recent acute myocardial infarction. We also studied the effect of fish oil on antithrombin III levels. Out of 75 patients with a plasma triglyceride value ≥2.0 mmol/L, 22 normalised their triglycerides during diet and were therefore not randomised. The remaining patients were randomly assigned to 12 weeks’ treatment with a daily dose of 4g ω-3 or placebo. Mean plasma triglyceride concentrations were reduced by 24% from 3.10 ± 1.15 (SD) to 2.53 ± 0.94 mmol/L (p < 0.001) on ω-3 (p < 0.001 vs placebo). The reduction was due to decreases in very low density lipoprotein concentrations. Total apolipoprotein CIII decreased significantly. This was due to reductions in LP CIII:non B concentrations, but the ratio LP CIII:non B/LP CIII:B was unaffected because of a slight insignificant decrease in LP CIII:B. The plasma triglyceride decreasing effect of ω-3 could therefore not be due to redistribution of CIII between lipoproteins. Low density lipoprotein (LDL) cholesterol increased significantly with ω-3 by 7%, and anti-thrombin III increased significantly with fish oil.In conclusion, ω-3 had a moderate plasma triglyceride lowering effect and increased LDL cholesterol slightly, while antithrombin III increased in patients with hypertriglyceridaemia who had recently experienced a myocardial infarction.

Isolation and characterization of phospholipase A2 from rat lung with affinity chromatography and two-dimensional gel electrophoresis

A phospholipase A2 (PLA2, EC 3.1.1.4) from rat lung has been isolated and characterized. PLA2 was purified with ion-exchange and affinity chromatography and the purified enzyme was characterized with regard to pH optimum and calcium dependence. The isolated enzyme was also analyzed with two-dimensional gel electrophoresis and identified by Western immunoblots. The enzyme activity was found to be highest at pH 9.5-10.0, with a requirement for calcium, and the molecular mass was estimated to be 12 kDa by means of SDS-polyacrylamide gel electrophoresis. The two-dimensional gel electrophoresis analysis revealed two isoforms of PLA2 with isoelectric points of 7.8 and 9.5. On DEAE-Sepharose, PLA2 eluted as two peaks, one in the flow-through fraction and the other with increased salt concentration. Both peaks contained the same two PLA2 isoforms, as judged by two-dimensional gel electrophoresis. These results demonstrate the presence in rat lung of two isoforms of a calcium-dependent 12 kDa PLA2 with alkaline pH optimum. Using two-dimensional gel electrophoresis, this enzyme can be identified also in rat bronchoalveolar lavage fluid.

Demonstration of a phospholipase A2 inhibitor in human plasma and in plasma from the European hedgehog (Erinaceus europaeus)

1. Endogenous phospholipase A2 (PLA2) inhibitors in human plasma and in plasma from the hedgehog (Erinaceus europaeus) were demonstrated. 2. The PLA2 activity increased 45-fold in human plasma when a PLA2 binding factor was removed. Furthermore, two peaks of PLA2 inhibitory activity were found after DEAE-chromatography. 3. High levels of PLA2 inhibitory activity was found in plasma from the European hedgehog, E. europaeus. 4. The molecular weight was estimated to 140,000. 5. On DEAE-chromatography two peaks were found which were chromatographically similar to the PLA2 inhibitors in human plasma.