Etofibrate enhances 123I-LDL-binding in human liver.

Etofibrate, a combination of fibric and nicotinic acid, is successfully used for the treatment of type IIb and IV hyperlipidemia. While an up-regulation of specific low density lipoproteins (LDL) binding sites in human platelets has been demonstrated, action on LDL-binding to the liver in patients and kinetic studies rare. This study aimed to investigate the influence of twice 500mg etofibrate daily given for 6 weeks on the in vivo binding of autologous LDL to the liver in 11 patients, 6 males, 5 females; aged 37-57 years, suffering from mixed hyperlipidemia. Etofibrate enhanced in vivo liver uptake of (123)I-LDL by 16.1% at mean, shortened plasma decay of LDL and improved lipid profile: serum total cholesterol was lowered by 14.9%, LDL-cholesterol was lowered by 22.2% and high-density lipoprotein (HDL)- cholesterol was increased by 10.9%. These findings are documenting a beneficial effect of the drug at the LDL liver receptor level in vivo.

Iodine-125-fibrinogen kinetics in the rabbit arterial wall.

Elevated fibrinogen has been claimed as an independent risk factor for the development of atherosclerosis. Incorporation of fibrinogen into human atherosclerotic lesions has been demonstrated. We assessed in a rabbit model of experimental atherosclerosis, biodistribution as well as kinetics and vascular uptake of (125)I-fibrinogen. Rabbits aged 6 months were fed a 1% cholesterol supplemented diet. After experimental de-endothelialization of rabbit aorta using a Fogarthy catheter, (125)I-fibrinogen uptake was enhanced by more than one order of magnitude as compared to intact segments covered by endothelium. Six rabbits per group were examined. Even re-endothelialized segments showed a significantly higher uptake of the radiolabeled protein. Maximum arterial uptake varied between 12 (de- and re-endothelialized segments) and 24h (intact areas) after injection of (125)I-fibrinogen. In conclusion, these experiments for the first time suggest the increased uptake of radiolabeled fibrinogen in the aortic de-endothelized wall in rabbits.

Passive cigarette smoking increases isoprostane formation.

Passive smoking has been demonstrated to exert a variety of deleterious effects eventually resulting in vascular damage. Isoprostanes, a reliable marker of in vivo oxidation injury, have been shown to increase in active cigarette smoking. Data for passive smoking are lacking. We were examining the isoprostane 8-epi-PGF2alpha in 12 smokers and non-smokers exposed daily to passive cigarette smoke for 12 days. Plasma samples stored at liquid nitrogen from people having been examined earlier were used. Prevalues of 8-epi-PGF2alpha are higher in cigarette smokers. Exposure to passive smoking causes a significant increase in 8-epi-PGF2alpha in non-smokers, while in smokers there is only a trendwise increase. After repeated passive smoke exposure, 8-epi-PGF2alpha in non-smokers approaches the respective values of smokers. There is a significant correlation of 8-epi-PGF2alpha to the thromboxane (plasma, serum, conversion from exogenous precursor, 11-dehydro-TXB2) parameters (MDA, HHT- conversion) examined in these patients before. The findings document a significant temporary increase in in vivo oxidation injury due to passive smoke favouring development and/or progression of vascular disease.

Enhanced oxidative stress in coronary heart disease and chronic heart failure as indicated by an increased 8-epi-PGF(2alpha).

The role of oxidation injury as an important factor in the pathophysiology of cardiomyopathy (CMP) has recently gained increasing interest. Semiquantitative analysis for isoprostane, 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), and oxidised low-density lipoprotein (ox-LDL) of coronary vascular tissue samples derived from CMP patients revealed an increased extent and intensity of uptake as compared to the respective controls. To evaluate oxidative stress in vivo, we examined plasma, serum, salivary, and urinary 8-epi-PGF(2alpha) in patients with dilated CMP (n=20) and ischemic CMP (n=20) with decreased left ventricular ejection fraction (LVEF). Patients with coronary heart disease (CHD) (n=20) and 20 healthy, age-matched, and sex-matched controls were investigated in parallel. 8-Epi-PGF(2alpha) levels were correlated with the functional severity of heart failure [New York Heart Association (NYHA) classification] and LVEF. 8-Epi-PGF(2alpha) levels were matched according to risk factors (smoking and hypercholesterolemia) and were significantly higher in patients with CMP as compared to healthy controls and patients with CHD in all investigated compartments. A positive correlation between NYHA stages and 8-epi-PGF(2alpha), as well as a negative correlation to LVEF, could be demonstrated in a subgroup analysis. These findings reflect the enhanced oxidation injury in patients with CMP and, to a lesser extent, in CHD as compared to healthy controls, thus highly indicating the relevance of oxidative stress for the pathogenesis and progression of cardiovascular disease.

Antiplatelet activity of semotiadil fumarate.

Calcium antagonists are known to exert antiplatelet activity. Semotiadil fumarate (SD-3211), a new benzothiazine, was therefore examined for its antiplatelet activity. The inhibitory activity on adenosine diphosphate (ADP)-, collagen-, arachidonic acid (AA)-, and platelet activating factor (PAF)-induced platelet aggregation after the 1-, 30-, 60- and 120-min incubation at concentrations ranging from 1 x 10(-3), 1 x 10(-4), 1 x 10(-5), 1 x 10(-6) and 1 x 10(-7) was examined. The data were compared with those using diltiazem, nifedipine and amlodipine under identical conditions in blood from eight healthy volunteers (four males, four females; aged 23-36 years) and eight hypertensive patients (four males, four females; aged 31-46 years). Semotiadil showed a dose-dependent inhibition of platelet aggregation in vitro with all the agents examined. Using the various aggregation-inducing agents, the dose-dependent inhibitory action was comparable for all the compounds tested. The antiaggregatory potency was in the order diltiazem, semotiadil, amlodipine and nifedipine. The incubation period did not significantly affect the antiaggregatory effect. No difference between platelets derived from healthy volunteers and hypertensive patients was noted. These findings indicate potent antiplatelet activity of the new calcium antagonist semotiadil.

Narghile (water pipe) smoking influences platelet function and (iso-)eicosanoids.

The biological effects of smoking water pipe on haemostasis and the eicosanoid system is unknown. Water pipe smoking is familiar to approximately 1 billion people around the world. Considering this quite impressive number, we investigated the potential effect of smoking the Narghile on oxidation injury by monitoring parameters of the (iso)eicosanoid system. Patients were allowed to smoke a water pipe once daily for 14 days. Blood was drawn from 7 healthy adult non-cigarette smoking male volunteers before and immediately after the first smoking of the water pipe and additionally after 6 hours. One and 2 weeks thereafter, blood was drawn again before and after smoking. A total of 7 blood samples was drawn during the study, and parameters of in vivo oxidation injury (8-epi-PGF2alpha, malondialdehyde [MDA]) and haemostasis (11-dehydro-thromboxane B2 [11-DH-TXB2]) were investigated. A single smoking session increased oxidation injury (8-epi-PGF2alpha: p=0.03; MDA: p=0.001) and 11-DH-TXB2 (p=0.00003) significantly, and repeated daily smoking induced a persistent long-lasting oxidation injury reflected by elevated prevalues but a smaller response to the actual water pipe smoke. These findings indicate a significant increase of in vivo oxidative stress by regular water pipe smoking.

Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia.

BACKGROUND: The hypoglycemic effect of prickly pear is well known by native local Indian population since a long time. Beside the beneficial effects on lipid metabolism, oxidation injury and platelet function has been claimed in experimental animals. We recently found an upregulation of apo-B/E receptor. MATERIAL AND METHODS: We therefore examined 10 patients with isolated heterozygous familial hypercholesterolemia (FH) being enrolled in a dietary run-in phase of 6 weeks after dietary counselling and a further 6 weeks of prickly pear addition. Uptake of autologous (123)I-radiolabeled LDL was determined at entry as well as after 6 weeks of daily prickly pear ingestion. RESULTS: We found a significant (p < 0.0001) increase in LDL-uptake by the liver (24.5 +/- 4.9 vs. 31.1 +/- 5.2%) and an enhanced decay in circulating blood. Total (298.0 --> 268.0 mg/dl; p < 0.0001) and LDL-cholesterol (210.5 --> 176.4 mg/dl; p = 0.0001) were significantly affected, while HDL (p = 0.0629) and triglycerides were not. CONCLUSIONS: These findings demonstrate a significant upregulation of (123)I-LDL binding by prickly pear in FH-patients invivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation.