Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma lipid and lipoprotein responses to clofibrate were assessed in fifteen hypertriglyceridemic patients for the purpose of ascertaining low-density lipoprotein (LDL) changes. Subjects were grouped into either Type IV (11) or IIB (4) subgroups according to initial LDL level. Clofibrate was without effect on LDL in the IIB group, but consistent, often large, elevations were noted in Type IV cases (mean increase, 37.6%, P less than 0.001). In the IIB subgroup, addition of the bile-acid sequestrant, colestipol, lowered LDL (27.8%, P less 0.02) and total cholesterol (21.3%, P less 0.01) below pre-treatment values. In the Type IV subgroup, LDL fell to 19.5% above baseline (P great than 0.05). Significant LDL elevations induced by clofibrate in three of six subjects were restored to initial levels. In both groups, triglycerides and very-low density lipoproteins (VLDL) were not affected. The efficacy of colestipol in reducing LDL levels, expressed as either absolute or percentage reductions, increased as a function of increasing post-clofibrate LDL concentration (r = 0.84, P less than 0.001). In these subjects the level of LDL after treatment with clofibrate depended upon their LDL level prior to drug therapy, the effect of clofibrate on this level, and lipoprotein phenotype. Thus colestipol was most effective in IIB subjects, Type IV subjects with the lowest baseline VLDL and hence reciprocally highest LDL, and Type IV individuals who exhibited the largest LDL induction by clofibrate. The reported ineffectiveness of clofibrate on mortality and morbidity in patients with established coronary heart disease might be related to elevations and infrequent reductions of LDL. From the perspective of lipoprotein lowering, the combination with colestipol appears more favorable.
Atherosclerosis
PMID:Clofibrate-induced low density liporotein elevation. Therapeutic implications and treatment by colestipol resin. 17 25

The binding of chlorophenoxyisobutyric (CPIB), tibric (TA) and nicotinic (NA) acids and CPIB ethyl ester (Clofibrate), TA and NA isopropyl esters (TAPE and NAPE) to human lipoproteins of low density of different classes (LDL2, LDL1 and VLDL) and high density (HDL) were studied by equilibrium dialysis and Sephadex gel filtration. Clofibrate and TAPE bound strongly to lipoproteins, but their acids, CPIB and TA and also NA and NAPE, did not bind. In the same experimental conditions, Clofibrate and TAPE bound only weakly to human serum albumin (HSA) and CPIB bound to HSA with a Ka of 3.3 X 10(5) M(-1) for 1 site of high affinity. The Clofibrate and TAPE bound to lipoproteins did not dissociate either during dialysis or during filtration on Sephadex G 25. The binding percentage remained constant for all drug concentrations studied, and the molar ratio of bound drug rose linearly with increasing concentrations. This suggests that the interaction may be irreversible, and there is some evidence that binding may induce irreversible changes in the lipoprotein molecules. These results, and those already found in experiments made with three other drugs related to Clofibrate, lead to the proposal that in their interaction with lipoproteins, the phenyl groups are necessary and the esterification is contributory. The possible role of this interaction in the lipid-lowering effect of the drugs is discussed with special reference to their possible implication in lipoprotein synthesis within the intestinal and hepatic cells.
Atherosclerosis
PMID:Binding to plasma lipoproteins of chlorophenoxyisobutyric, tibric and nicotinic acids and their esters: its significance for the mechanism of lipid lowering by clofibrate and related drugs. 18 31

Some patients with familial hypercholesterolemia (FHC, type II) are highly responsive to the cholesterol-lowering effect of clofibrate, while others are not only resistant to this effect but may even show an increase in plasma beta-lipoproteins. In an attempt to find an explanation for these striking differences, we have studied the pharmacokinetics of clofibrate in FHC patients at both extremes of responsiveness. The results disclosed several major differences between the two groups. Plasma clofibric acid (CPIB) measured during the chronic administration of the drug was significantly higher in the responders than in the non-responders, whether all patients in each group or only those with tendon xanthomas were considered. Plasma CPIB concentrations were negatively correlated with body weight in the responders but not in CPIB-resistant patients. They were also inversely proportional to decreases in plasma beta-lipoprotein cholesterol after chronic clofibrate administration in the responsive group, but directly proportional to increases in the non-responders. Increasing the dose of clofibrate from 2 to 3 g/day in CPIB-resistant patients always resulted in an increase in plasma CPIB levels, but this was followed in some patients by a decrease and in others by an increase in plasma beta-lipoprotein cholesterol concentrations, so that the overall effect was not statistically significant. The half-life of plasma CPIB was measured over 48 h after a single 1-g dose of clofibrate in patients who had not received this drug for at least 3 weeks. Half-life was significantly longer in the responsive patients. In addition, the bioavailability and the rate of absorption of clofibrate tended to be higher in this group than in the resistant patients. We suspect that both groups differ not only in the metabolic handling of clofibrate but also in some aspect of their beta-lipoprotein cholesterol metabolism.
Atherosclerosis 1977 Apr
PMID:Pharmacokinetics of clofibrate in familial hypercholesterolemia. 19 24

Groups of male rats were fed various doses of clofibrate and diosgenin, both alone and in combination for 1 week. Clofibrate suppressed the diosgenin-induced increase in hepatic cholesterol synthesis but did not alter the effectiveness of diosgenin in reducing cholesterol absorption. Diosgenin did not affect the bioavailability of CPIB. Clofibrate reduced the diosgenin induced increase in biliary levels of cholesterol; none of the regimens altered biliary bile acids. The combination produced greater decreases in LDL cholesterol than did either compound alone; the diosgenin-induced elevation in HDL cholesterol was partially reversed by clofibrate. The data provide a basis for the combined use of clofibrate and diosgenin in the control of hyperlipoproteinemia.
Atherosclerosis 1978 Mar
PMID:Combined effects of clofibrate and diosgenin on cholesterol metabolism in rats. 20 86

BR-931 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl)-acetamide], a new hypolipidemic agent of low toxicity, was evaluated in several tests of lipolysis and hyperlipidemia in rats, and in the cholesterol-induced atherosclerosis in rabbits. Significant hypolipidemic activity was observed in rats with doses of the agent at 12.5--50 mg/kg. In the Triton-induced hyperlipidemia, 50 mg BR-931 per kg was equieffective as 200 mg of clofibrate (CPIB) per kg. In contrast with CPIB, BR-931 exerted a powerful antilipolytic activity against epinephrine, ACTH, nicotine and cold exposure. BR-931 was particularly effective in diet-induced hyperlipidemias. Ethanol lipemia was totally prevented by the agent at 100 mg/kg. With Nath's diet, doses as low as 25 mg/kg significantly reduced hypercholesterolemia and hypertriglyceridemia. In these last two tests, the distribution of lipoprotein cholesterol was also determined. CPIB did not affect HDL cholesterol levels that had been decreased by the diets; in contrast, BR-931, already at doses of 50 mg/kg, brought the HDL/total cholesterol ratio back toward normal. A significant HDL cholesterol increase, together with some reduction of atheromatosis, was also observed in cholesterol-fed rabbits. BR-931, a potent inducer of liver peroxisones and of mitochondrial carmitine acetyltransferase, appears to be a hypolipidemic agent of high efficacy and low toxicity for the clinical treatment of hyperlipidemias and atherosclerosis.
Atherosclerosis 1978 May
PMID:Pharmacological profile of BR-931, a new hypolipidemic agent that increases high-density lipoproteins. 20 96

The feasibility of reducing serum lipoprotein levels in patients with atherosclerotic disease by combining diet, clofibrate and nicotinic acid (niceritrol) has been investigated. An additive lipid-lowering effect of diet and the two drugs was demonstrated. It was possible to reduce the serum triglycerides (TG) in hypertriglyceridaemic patients by 50-60%. This corresponded to a reduction of very low density lipoprotein (VLDL) TG by 73 and 66% in patients with hyperlipoproteinaemia (HLP) type IIB and IV, respectively. In normotriglyceridaemic patients the serum TG concentration decreased by 30-40%. The serum cholesterol (Chol) concentration was reduced by 33% and the low density lipoprotein (LDL) Chol by 37% in HLP type IIA and IIB. The LDL Chol decreased by 32% in normolipoproteinaemic patients and by 21% in HLP type IV. The mean value for serum cholesterol after therapy was in all groups close to 200 mg/100 ml. In hypertriglyceridaemic patients high density lipoprotein (HDL) Chol increased by 18%. Clofibrate and niceritrol differed with regard to the effect on serum lipoprotein concentrations as well as on other metabolic parameters. Niceritrol was significantly more effective than clofibrate in lowering LDL Chol and in increasing HDL Chol. Niceritrol treatment significantly reduced the Chol/TG ratio in VLDL while no such effect was seen during clofibrate administration. The two drugs also showed significantly different effects on the fractional removal rate (K2) of triglyceride-rich lipoproteins as measured by the intravenous fat tolerance test (IVFTT). The K2 was significantly increased by clofibrate but was not affected by niceritrol treatment. The two drugs differed also with regard to the effects on serum uric acid concentration and the liver function tests. The plasma fibrinogen levels and the erythrocyte sedimentation rates were reduced during treatment with both niceritrol and clofibrate. The present study demonstrates that it is possible to obtain substantial reductions of serum lipoprotein concentrations by combining lipid-lowering diet, clofibrate and niceritrol treatment. There was an additive lipid-lowering effect of this treatment and the combination of the two drugs seemed beneficial in regard to certain possible side effects. The impact of a lipid reduction within this range on cardiovascular morbidity and mortality remains to be evaluated.
Atherosclerosis 1979 Aug
PMID:Pronounced lipoprotein lipid reduction obtained by combined lipid-lowering treatment in patients with atherosclerotic disease. 22 84

The MtT-F4 tumor, a transplantable pituitary tumor of rats, induces significant hyperlipidemia in male Fisher 344 rats. The increasive hypercholesterolemia was accompanied by hypertriglyceridemia only in the first month of tumor implantation. Clofibrate feeding inhibited the development of hypercholesterolemia and maintained normal serum triglyceride levels. In contrast to the changes in lipoprotein cholesterol distribution and profile found in experimental hyperlipidemia induced by high fat and cholesterol feeding, the hypercholesterolemic tumor-bearing rats showed no accumulation of cholesterol in the very low density and intermediate density lipoproteins, and no appearance of a new class of lipoprotein, B-VLDL. An HDLc-like lipoprotein appeared as hypercholesterolemia developed. Increased amounts of cholesterol were deposited in the aorta. The effects are attributed to the lipolytic hormones secreted by the tumor and antagonism to their action by clofibrate.
Atherosclerosis 1979 Jan
PMID:Hyperlipoproteinemia induced by a transplantable pituitary tumor in the rat. 46 11

The effects of different doses of clofibrate and gemfibrozil on liver size, serum triglyceride concentration and the activities of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and carnitine acyltransferases were studied in male rats. Both clofibrate and gemfibrozil treatment effectively decreased the fructose-induced hypertriglyceridaemia and increased the liver to body weight ratio. Clofibrate treatment also induced an increase of many times in the activities of mitochondrial alpha-GPD and carnitine acyltransferases, the effect increasing with the dose used. The effect of gemfibrozil on the activities of the enzymes was significantly smaller. There was no correlation between the decrease in serum triglyceride concentration and the changes in the activities of the enzymes. Only clofibrate increased the rate of fatty acylcarnitine oxidation in isolated mitochondria. It is concluded that both drugs increased the size of the rat liver, but that only clofibrate influenced the mitochondrial enzyme activities of mitochondrial carnitine acyltransferases and the accelerated mitochondrial oxidation of fatty acids are not the mechanisms by which these drugs lower serum lipid levels.
Atherosclerosis 1979 Jan
PMID:Effect of clofibrate and gemfibrozil on the activities of mitochondrial carnitine acyltransferases in rat liver. Dose--response relations. 46 13

Individuals with familial hyperbetalipoproteinemia are at increased risk of premature atherosclerosis and thrombosis. Although there is controversy whether platelet survival is shortened or normal in this disease, several in vitro tests of platelet function are abnormal including a decreased threshold concentration for stimulation of aggregation by ADP, epinephrine and collagen and increased release of nucleotides to the same agents. These functional changes are accompanied by an increase of cholesterol to phospholipid ratio in the platelet membrane and in low density lipoprotein in individuals with type IIa hyperlipoproteinemia. Clofibrate and halofenate reverse some of the abnormalities in vitro and the former drug, when administered for 6 weeks to patients with type IIa hyperlipoproteinemia decreases platelet sensitivity to ADP and epinephrine. The platelet hypersensitivity to aggregating agents can be reproduced in vitro by increasing the cholesterol to phospholipid rather in normal platelets. These artificially hypersensitive platelets can be returned to normal by halofenate in vitro. Incorporation of cholesterol into platelet membranes increases the basal level of the membrane associated enzyme adenylate cyclase. However, the enzyme no longer responds to stimulation by prostaglandin E1, and this is associated with relative resistance of the platelet to inhibition by this pharmacologic agent. These functional alterations produced by cholesterol enrichment of platelet membranes occur is parallel with an increase in platelet membrane microviscosity suggesting that the more rigid membrane can alter the behavior of membrane associated enzymes and receptors. A correlation appears to exist between the ability of certain drugs to induce phase separation in model membranes and the potency in inhibitory platelet aggregation.
 ...
PMID:Platelet function in hyperbetalipoproteinemia. 58 Sep 82

Repeatedly-bred, male and female Sprague-Dawley rats which develop hyperglycemia, hyperlipidemia, hypertension, and arteriosclerosis spontaneously were killed at sequential time intervals, i.e., when the females had completed 1, 2, 3 and 4 pregnancies. The control breeders received no treatment; the experimental animals were given 113 mg of clofibrate/100 g of b.w., subcutaneously, daily, 5 times per week. Clofibrate-treated breeders manifested reduction in blood pressure and in the incidence and severity of arterial disease characteristic of repeatedly-bred rats. The aortic lesions of the clofibrate-treated breeders showed attenuation of the usual severe ground substance alterations, the degenerative changes in connective tissue elements, e.g., fibrosis and elastosis, and absence of calcification and cartilaginous metaplasia. Clofibrate-treated breeders did not show any unusual elevation in serum enzymes, e.g., CPK, SGOT, SGPT and LDH, or significant reduction of their hyperlipidemia. They manifested a definite reduction in adrenocortical and medullary histopathology and their circulating corticosterone levels were subnormal compared to non-treated breeders. It is suggested that the protective effect of clofibrate was mediated through its ability to block normal adrenal steroidogenic pathways rather than through its antilipemic action.
Atherosclerosis 1978 Mar
PMID:Clofibrate retardation of naturally-occurring arteriosclerosis in repeatedly-bred male and female rats. 66 83


1 2 3 4 Next >>