Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs

Objective: To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. Methods: Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. Results: Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-α-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. Conclusions: Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowerin

Regulation of healthcare ethics committees in Europe

In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECs’ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification, steps should be taken to develop consistent policies for both Eastern and Western European countries

Thromboxane synthase inhibitors and receptor antagonists

Platelet activation plays a major role in myocardial infarction and in reocclusion following successful thrombolysis, as corroborated by several clinical studies using aspirin. However, the overall reduction of new vascular complications in patients with symptomatic arterial disease by aspirin was only around 25%. Therefore, there is great interest in finding new means to inhibit platelet activation more efficiently. One line of research has focused on ways to interfere with the action of thromboxane A2 in a more selective way than aspirin does. As such, the development of thromboxane synthase inhibitors, followed by thromboxane receptor antagonists, raised hopes for a better treatment. However, both classes of drugs have some drawbacks, which could be overcome by combining them. This aim has led to the development of compounds that intrinsically possess both activities. Ongoing research indicates that such a dual inhibitor may indeed be more powerful than either aspirin or drugs with the single actions.status: publishe

Continuous inhibition of serotonin-induced platelet-aggregation during chronic ketanserin administration to man can be detected after plasma-ph control

Ketanserin is a well-known serotonin S2 receptor antagonist but its capacity to inhibit serotonin-induced aggregation ex vivo during chronic administration has been a matter of debate. In vitro evidence is presented that the inhibitory capacity of ketanserin is lowered by increasing plasma pH. Since the pH of plasma kept at the open air increases with time, we studied the effect of chronic administered ketanserin on serotonin-induced platelet aggregation in plasma kept at a lowered pH of 7.70, by replacing the air with 95% O2-5% CO2. Using this slightly modified technique, we could, in contrast to our previous studies, observe a complete inhibition of the serotonin-induced aggregation throughout the ketanserin treatment period.status: publishe

Platelet inhibitory activity of prostacyclin in the presence of erythrocytes as studied with the impedance aggregometer

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A thromboxane synthetase inhibitor reorients endoperoxide metabolism in whole blood towards prostacyclin and prostaglandin E2

During incubation of citrated blood at 37 degrees C the levels of 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and prostaglandin E2 (PGE2) remain constant, but rise markedly within one minute after the addition of collagen, particularly when thromboxane synthetase is blocked. The amount of 6-keto PGF1 alpha formed is dose-dependent for both collagen and the thromboxane synthetase inhibitor (UK-37,248). Moreover, the number of platelets will determine the extent of the 6-keto PGF1 alpha jump, that does not occur when blood is drawn after aspirin ingestion. The production of 6-keto PGF1 alpha in function of time is composed of a fast platelet-related (intercept) and a slower probably leukocyte-dependent contribution (slope). In the absence of UK-37,248 the intercept is 115 +/- 85 pg/ml, the slope is 12.9 +/- 7.7 pg/min/ml whereas in the presence of the thromboxane synthetase inhibitor they are 411 +/- 177 pg/ml and 56.2 +/- 25 pg/min/ml respectively. The present findings indicate that a thromboxane synthetase inhibitor, by not only reducing thromboxane A2 production but also enhancing prostacyclin generation with blood is exposed to thrombogenic stimuli such as collagen, should be superior to aspirin as an antithrombotic agent, although possible interference by enhanced PGE2 production should be taken into account.status: publishe

Lack of synergism between dazoxiben and dipyridamole following administration to man

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Prolonging prostacyclin production by nafazatrom or dipyridamole

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The effect of sulphinpyrazone on whole blood thromboxane and prostacyclin generation in man

A new method, based on the observation that leukocytes contain PGI2-synthetase activity, was used to measure the effect of pharmacological levels of sulphinpyrazone on the TXA2 and PGI2 production in whole blood. Four human volunteers took 400 mg sulphinpyrazone twice daily for 5 1/2 days. Blood was drawn before the study started, 3-4 h after the initial dosage, 12 h after the 10th dosage on the 5th day, and 3-4 h after the 11th (final) dosage on the 6th day. Collagen was added to the citrated blood samples to stimulate prostaglandin production. Aliquots were removed at regular intervals and TXB2 and 6-keto-PGF1 alpha measured by radioimmunoassay. The production of PGI2 was significantly inhibited in all the samples collected after sulphinpyrazone intake (p less than 0.01). The production of TXA2 was significantly inhibited only in the samples collected 3-4 h after sulphinpyrazone intake on the 6th day (p less than 0.01). These results confirmed the cyclooxygenase inhibitory action of sulphinpyrazone and also showed that in the whole blood system, PGI2 production was more effectively inhibited than TXA2 production.status: publishe

Thrombosis in injured small vessels

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