Efficacy and safety of micronised fenofibrate in a randomised double-blind study comparing four doses from 200 mg to 400 mg daily with placebo in patients with hypercholesterolemia.

The aim of this study was to evaluate the efficacy on LDL-cholesterol (LDL-C) of micronised fenofibrate given for three months at doses ranging from 200 to 400 mg once daily, compared with placebo. A double-blind, randomised, parallel-group, multi-centre trial was performed in four centers of France in 340 hypercholesterolemic patients (163M, 177F) aged 18-75 years. After a 2-3 month single-blind run-in period on placebo and diet, patients with LDL-C greater than or equal to 4.65 mmol/l (180 mg/dl) maintained on the same diet throughout the study were randomly allocated to placebo or to 200, 267, 340 or 400 mg micronised fenofibrate, given once daily with the evening meal for 3 months. LDL-C, total cholesterol (TC), total triglycerides (TG) and apolipoprotein B (Apo B) significantly decreased compared with placebo in all four fenofibrate groups. For all randomised patients, the decrease in the fenofibrate groups ranged from 31.6-38.8% for LDL-C, 24.5-31.9% for TC, 26.7-40.8% for TG, and 27.3-35.0% for Apo B. An increase in HDL-cholesterol of 4.1-8.2% was observed in the fenofibrate groups, but did not reach statistical significance. Lipid values in the placebo group remained unchanged. The therapeutic goal of LDL-C<3.36 mmol/l (130 mg/dl) was reached in 27% in the 200 mg group and increased to 56% in the 300 mg group. There were no major clinical or biological adverse events in the dose interval from 200 mg to 400 mg of micronised fenofibrate per day. This study showed treatment for 3 months with micronised fenofibrate at doses up to 400 mg per day is effective and can reduce LDL-cholesterol up to 30% allowing further evaluation of these doses on longer trials.

Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: possible implications in pathogenesis of atherosclerosis.

Macrophages have been shown to play a key-role in the development of atherosclerotic lesions. Monocyte attraction and activation in the arterial wall lead to foam cell formation, cholesterol accumulation and secretion of inflammation mediators. Among macrophage secretions, prostacyclin and thromboxane are prostaglandins involved in the regulation of coagulation and vascular permeability. In this study, we have evaluated the effects of human native low-density and high-density lipoproteins on macrophage prostaglandin production (P388D1 mouse cell line). Lipoprotein fractions were purified from venous blood of healthy volunteers by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and prostaglandins quantified by high-performance liquid chromatography. Our technique allows the determination of the main classes of prostaglandins. In the presence of low-density lipoproteins, time-course study showed an increase in total prostaglandin production within 10 min (50 times basal secretion level). This increase was dose-dependent. A steady-state was obtained at 20 mg protein LDL/1. Stimulation of thromboxane B2 and prostacyclin was predominant, with a main effect on the proaggregant thromboxane. Production of the proinflammatory PGF2 alpha and the immunoregulatory PGE2 was lower. In the presence of high-density lipoproteins, P388D1 cells also increased their total prostaglandin secretion at 30 min, in a dose-dependent manner. This increase was directly related to a stimulation of prostacyclin, with no significant effect on thromboxane. Our results demonstrate that normal low-density lipoproteins can stimulate macrophage prostaglandin secretions, with putative deleterious effects on the arterial wall, in particular thrombus formation. On the other hand, high-density lipoproteins, by mainly stimulating prostacyclin, could theoretically have a beneficial influence.

[The diabetic and his psychological dimension]. / Le diabète et sa dimension psychique.

PIP: Insulin-dependent diabetes is the most poorly accepted chronic illness for the following reasons: the customary suddenness and young age at onset of diabetes, the obligatory nature of insulin injections, the incurability of the disease, the need to regulate the diet, and the need for continued surveillance. Among persisting problems of diabetics are frustration at dietary constraints, ambivalence toward insulin, anxiety due to the malfunctioning pancreas, and fear of blindness, amputations, or other complications. The adjustment of a patient to diabetes depends greatly on the age at onset. The disease and its constraints may heighten the usual difficulties of adolescence. The family plays an essential role in adaptation of the diabetic to his condition. The mother of a diabetic child faces 10 principal problems: injections, diet, hypoglycemia, control of diabetic equilibrium, expense, psychological support, time requirements, the need for independence of the child, the feeling that the illness is a punishment, and fears about the future. Renal insufficiency requiring dialysis is another aspect of degraded bodily image for the diabetic. Concerning reproduction, number of pregnancies must be limited because of their potentially unfavorable effects on microangiopathy; maternal health must be monitored even prior to fertilization to avoid fetal malformations. Complications such as these accentuate in the diabetic the usual ambivalence of women toward contraception. Combined oral contraceptives with their vasular risk and IUDs with their risks of infection are not ideal contraceptive methods for diabetics. Tact is needed in couseling diabetics on contraception to avoid stressing once their differences from other women. Tubal ligation, still too frequently practiced, should be avoided so as not to add a further highly sumbolic mutilation. The emotional demands of pregnancy for a diabetic woman are greater than usual, but the desire for pregnancy sometimes increases tolerance of the constraints of the disease. The largescale introduction of portable insulin pumps has met with both positive and negative reactions. The team providing health care to the diabetic should be particularly sensitive in interacting with patient during periods of stress such as immediately after diagnosis, during adolescence, pregnancy, or the appearance of degenerative complications.^ieng