Treatment of hypercholesterolaemia in children.
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Child↗
Biomedical subjects
I Virgolini
Publications and source records attributed to I Virgolini.
13,14-Dihydro-prostaglandin E1 decreases low-density lipoprotein influx into rabbit aorta.
The effect of 4-week daily administration of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1; 2 micrograms/kg) on LDL influx into the rabbit aortic wall was examined versus the effect of the same dose of PGE1 and sham-treatment in 108 male animals fed an 1% cholesterol supplemented diet. Treatment was started after de-endothelialization of the abdominal aorta with a Fogarty catheter. After the 1-month treatment period the animals were injected with 10 microCi 125I-low-density lipoprotein (LDL; 0.5 mg protein/ml). Uptake of the radiolabelled LDL was measured in morphologically verified endothelialized, re-endothelialized and de-endothelialized abdominal aortic segments. The LDL influx into the aorta was significantly (P less than 0.001) lower in 13,14-DH-PGE1- and PGE1-treated rabbits than in the controls. This reduction was most pronounced in re- and de-endothelialized segments. No significant difference between effect of PGE1 and of its biologically active derivative, 13,14-DH-PGE1, on arterial LDL entry was found. These data demonstrate a comparable beneficial effect of 13,14-DH-PGE1 and PGE1 on vascular wall lipid metabolism by decreasing LDL entry into the aortic wall in vivo.
Alprostadil↗
Characterization of prostaglandin (PG)-binding sites expressed on human basophils. Evidence for a prostaglandin E1, I2, and a D2 receptor.
Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2.
Alprostadil↗
Ticlopidine and platelet function in healthy volunteers.
The influence of a 4-weeks therapy with 500 mg ticlopidine daily on platelet function parameters was examined in 10 male healthy volunteers aged 20-33 years in order to extend the knowledge on the antiplatelet activity of this substance. Ticlopidine significantly (p less than 0.01) affected ex-vivo platelet aggregation induced by ADP and increased platelet sensitivity to the antiaggregatory action of PGI2. Generation of TXB2 from endogenous substrate during spontaneous clotting of blood (serum-TXB2), conversion of exogenous radiolabelled arachidonic acid into TXB2 and MDA-formation in isolated platelets were unaffected by the treatment. The TXB2-level in plasma of volunteers, however, was decreased, after administration of the drug. The diminished alpha-granule content liberation (beta-thromboglobulin: p less than 0.01; PDGF: p less than 0.01; PF4 not significant) indicates that ticlopidine induces a decrease in platelet activity. The beneficial effect on release reaction is not associated with a decrease in TXA2-formation. Our results demonstrate that ticlopidine inhibits platelet activity, especially the PDGF-release. These results confirm the value of this drug in the prevention of atherosclerosis and its thromboembolic complications.
Adult↗
Modification of platelet function by isosorbide dinitrate in patients with coronary artery disease.
The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.
Adenosine Diphosphate↗
Liver function in acute viral hepatitis as determined by a hepatocyte-specific ligand: 99mTc-galactosyl-neoglycoalbumin.
Twelve patients with recently diagnosed acute viral hepatitis underwent serial 99mTc-galactosyl neoglycoalbumin scanning of the liver (for up to 8 mo). Injection of 99mTc-galactosyl neoglycoalbumin (150 mBq) at a rate of 3.5 mg (50 nmol; 1 ml) revealed that the liver is the exclusive site of tracer uptake. Simulation of 99mTc-galactosyl neoglycoalbumin kinetics allowed quantification of galactosyl neoglycoalbumin binding to human hepatic binding protein. Return of liver function test scores to normal values was associated in two patients with hepatitis A, in four patients with hepatitis B and in two patients with non-A, non-B hepatitis virus infection, with increases in hepatic binding protein concentration (up to three times the initial concentration), binding rate constant and hepatic blood flow. In the other four patients (three patients with hepatitis B and one patient with cytomegalovirus infection) a prolonged course of disease was monitored. In the mean, hepatic binding protein increased from 0.41 +/- 0.11 mumol/L after onset of acute hepatitis (n = 12) to 0.78 +/- 0.21 mumol/L after 6 mo of follow-up (n = 10) (p less than 0.001). During this period, binding rate constant (72.4 +/- 12.6 vs. 82 +/- 11.5 mumol/L/sec; p less than 0.05) and hepatic blood flow (0.027 +/- 0.0051 vs. 0.031 +/- 0.0083 L/sec; p less than 0.05) increased. Hepatic binding protein concentration correlated highly with actual laboratory test results for liver function (r = 0.98; p = 0.0001). We conclude that scintigraphic evaluation of functional liver cell mass using the new receptor-tracer 99mTc-galactosyl neoglycoalbumin could provide an in vivo diagnostic means of quantifying liver function and assessing liver morphology. In addition, our findings suggest that changes in hepatic binding protein-receptor concentration are likely to occur in vivo.
Acute Disease↗
Platelet PGI2-receptor behaviour change after treatment with acetylsalicylic acid in healthy volunteers.
After treatment of human platelet membrane fractions with different concentrations of acetylsalicylic acid (ASA) the Iloprost binding capacity (Bmax) and also the dissociation constant (Kd) of the high-affinity PGI2-receptor increased significantly (p less than 0.01, low-affinity receptor only an increase of Bmax, p less than 0.01), whereas only a significant (p less than 0.05) increase of the Kd of the high-affinity receptor was observed for intact platelets.
Adolescent↗
Concomitant aspirin treatment abolishes the antiatherosclerotic effects of the calcium channel blocker isradipine mediated by PGI2.
108 male rabbits, aged 6 months, with experimental hypercholesterolemia and experimental abdominal aortic lesioning received different regimen of antiatherosclerotic treatment; 36 of them were treated with isradipine, a dihydropyridine calcium antagonist (0.3 mg/kg/daily), 36 with isradipine in combination with aspirin whereas 36 animals received placebo. The entry of 125I-radiolabelled LDL into the aorta was demonstrated to be significantly diminished in isradipine-treated rabbits as well as positive Sudan-III-staining and aortic cholesterol content were in comparison to placebo. This benefit was almost completely abolished by concomitant aspirin-treatment. The notable increase in vascular prostacyclin (PGI2) is supposed to mediate the strong antiatherosclerotic effect of isradipine resulting in an inhibition of LDL-entry and vascular cholesterol accumulation. Aspirin almost totally blocked the raise in PGI2-synthesis by the inhibition of cyclooxygenase detected in isradipine-treated animals. It can be concluded, that aspirin-treatment may minimize the antiatherosclerotic actions of calcium antagonists which are mediated by the PG-system.
Animals↗
Effect of irradiation on the prostaglandin system of human hypernephroma cells.
Specific PGE1-, PGE2-, PGI2-binding sites and the eicosanoid production were investigated in cultured human hypernephroma cells. Low numbers of PGE1-, PGE2- as well as PGI2-high-affinity binding sites and high levels of PG-production were found as compared to normal kidney. Treatment with acetylsalicyclic acid (ASA) significantly (p less than 0.01) increased PGE1-, PGE2- and PGI2-binding sites and inhibited PG-formation. Following irradiation, PG-receptors and eicosanoid generation were significantly (p less than 0.01) diminished, however, were insignificantly lowered in the ASA-treated group. These findings suggest that ASA may modify the radioresponse of cultured hypernephroma cells by preventing the decrease of PG-receptors induced by irradiation.
Aged↗
Prostaglandin (PG) E1 and 13,14-dihydro (DH) PGE1 are diminishing radiation-induced arterial damage.
Rabbit abdominal aorta was irradiated with single or repeated doses up to 10 Gy. The rabbits were killed at different time intervals after irradiation. 5 micrograms/kg x 6/hr PGE1 or its biologically active metabolite 13,14-DH-PGE1 were administered either 6 hours before or 6 hours after irradiation. The administration of both PGEs reduced radiation-induced mitotic activity (3H-thymidine incorporation) and extracellular matrix [collagen-(14C-proline) and glycosaminoglycan (35-S-sulphate)]-formation as determined by means of autoradiography. The initial peak increase in vascular PGI2-synthesis was partly abolished, while the long lasting depression was less pronounced. 13,14-DH-PGE1 was only slightly less active as compared to the parent compound. Pre-radiation treatment was more effective than post-irradiation therapy. These findings suggest that both the PGs exert significant radiation-protective actions on the arterial wall.
Alprostadil↗
Isradipine improves platelet function in hypertensives.
The effect of treatment for eight weeks with isradipine 1.25 mg twice daily for 4 weeks and thereafter 2.5 mg twice daily for 4 weeks on ex vivo platelet function was investigated in 10 male hypertensive patients, aged 51 (6.1) y. Systolic and diastolic blood pressure, platelet aggregation in response to ADP, serum thromboxane B2 and beta-thromboglobulin levels were significantly decreased at rest before exercise ergometry, during exercise and at rest after exercise. The platelet count, platelet sensitivity and the plasma levels of 6-oxo-prostaglandin F1 alpha were not affected by isradipine. It is concluded that a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit in the routine treatment of hypertension.
Analysis of Variance↗
In vivo quantification of cholesterol content in human carotid arteries by quantitative gamma-camera imaging after injection of autologous low density lipoproteins (LDL).
Low density lipoproteins (LDL) were isolated by immunoaffinity chromatography from 18 patients (31-70 years) suffering from primary hypercholesterolemia with angiographically proven atherosclerosis of either one or both carotid arteries. LDL were labeled with 123I (1 mCi/mg LDL) by the iodine monochloride method followed by purification with dialysis and immediately reinjected thereafter. Gamma-camera serial controls over carotid regions allowed visual detection of uptake of the radiocompound uptake in 12 out of the 18 patients. The lipid entry ratio (LER; counts over the vascular region/pixel as compared to the contralateral side after background subtraction) confirmed the visual findings. Whole body images performed until 20 h after reinjection showed 3 different kinetic types of LDL-influx into the vessel wall: decreasing (type I), increasing and then decreasing (type II) and continuously increasing (type III) with time. Four patients underwent endarterectomy within 2-7 weeks after gamma-camera imaging. Histological control revealed an extensive amount of "foam cells" in tissue samples derived during surgery and an absence of endothelial lining in samples belonging to patients with type II kinetics.
Adult↗
Binding of 111In-labeled HDL to platelets from normolipemic volunteers and patients with heterozygous familial hypercholesterolemia.
High density lipoproteins (HDLs; d = 1.063 - 1.21 g/ml) were isolated by ultracentrifugation and radiolabeled with 111In. The in vitro binding onto platelets from healthy volunteers (n = 15) and patients (n = 36) with heterozygous familial hypercholesterolemia (FH) was investigated. Binding was saturable and indicated high-affinity binding sites, which bound 1,882 +/- 361 ng protein of 111In-HDL/10(9) platelets (dissociation constant [Kd] = 7 +/- 3 micrograms protein/ml) in healthy volunteers and significantly (p less than 0.01) lower amounts in the FH patients (1,012 +/- 439 ng protein of 111In-HDL/10(9) platelets [Kd = 12 +/- 4 micrograms protein/ml]; p less than 0.01). The capacity to displace one half of the bound ligand (IC50) amounted to 14 +/- 3 micrograms protein/ml in healthy volunteers and 22 +/- 9 micrograms protein/ml in FH patients (p less than 0.001). Treatment with lipid-lowering drugs (gemfibrozil, alone or in combination with cholestyramine) in 10 patients resulted in an increased HDL binding capacity: before treatment, 1,280 +/- 883; after 2 months of treatment, 2,052 +/- 873 (p less than 0.05); and after 6 months of treatment, 2,127 +/- 812 ng protein/10(9) platelets (p less than 0.01). There was a significant (p less than 0.001) correlation between 111In-HDL binding data and plasmatic lipid and lipoprotein values. Furthermore, those FH patients with the additional risk factors of smoking (p less than 0.05) and hypertension (p less than 0.01) showed significantly lower 111In-HDL binding onto platelets. The findings indicate specific 111In-HDL binding sites for human platelets, which may be decreased in patients with heterozygous FH. Upregulation of HDL binding sites during lipid-lowering medication therapy supports the hypothesis that high-affinity HDL binding is involved in hyperlipemic disorders and is possibly related to the reactivity of platelets.
Adult↗
Aspirin abolishes the decreased low-density lipoprotein (LDL) entry into the rabbit arterial wall induced by the calcium channel blocker isradipine.
After deendothelialization and experimentally induced hypercholesterolemia in rabbits, an increased LDL entry into the vascular wall can be monitored using radiolabelled LDL. In male rabbits aged 6 months the abdominal aortic endothelium was removed by a Fogarty catheter. The animals fed a 1% cholesterol supplemented diet were treated either with isradipine (0.3 mg/kg/daily) (n = 36) alone or in combination with aspirin (5 mg/kg/daily) (n = 36) for four weeks. Thirty-six animals served as controls. 1, 3, 6, 12, 24 and 48 hours prior to sacrificing, 10 microCi 125I-LDL was administered intravenously to six rabbits in each group. The LDL entry was quantified in the abdominal aorta according to morphologically assessed type of surface lining. Aortic cholesterol content was assessed by Sudan-III staining and quantitative determination. Endothelialized segments exhibited a significantly (p less than 0.05 - p less than 0.001) lower LDL uptake as compared to re- or deendothelialized segments. The LDL entry was significantly lower with isradipine treatment than in controls. In parallel the cholesterol content decreased and the Sudan-III-positive areas were smaller in size. This beneficial effect as well as that on aortic lipid content was abolished by a pretreatment with aspirin. While in the isradipine-treated animals PGI2 synthesis was significantly (p less than 0.01) enhanced, it was almost completely blocked by aspirin. These findings indicate that the benefit of reduced LDL entry caused by isradipine may be mediated by an increased endogenous PGI2 synthesis.
Animals↗
Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage.
The entry of autologous iodine-125 low density lipoprotein (125I-LDL) into the aortic wall in rabbits was measured. After abdominal endothelium abrasion with a Fogarthy catheter the animals were fed a 1% cholesterol-supplemented diet for 4 weeks. The animals were killed 1-48 h after administration of 25 muCi 125I-LDL. Local entry of radiolabelled LDL was estimated and correlated to endothelial surface lining and foam cell content, both controlled morphologically. Endothelialized segments showed the lowest entry of 125I-LDL, the maximum uptake was reached at around 8 h. In de-endothelialized segments the entry was higher and the peak later (12 h), while in re-endothelialized segments a continuous increase in 125I-LDL entry up to 48 h was measured. Number and extent of foam cells correlated with the entry of LDL. The data indicate the usefulness of LDL radiolabelling for qualitative in vivo information on surface lining and foam cell content.
Animals↗
Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage.
The monitoring of local vascular kinetics after injection of autologous radiolabelled low-density lipoprotein (LDL) allows characterization of human atherosclerotic lesions as to the presence of foam cells and the quality of endothelial coverage. The following evidence exists: (1) dynamic imaging reveals two types of visual LDL accumulation in the vascular bed, one increasing, becoming visible sometimes only as late as after 24 h, and the other one appearing very early on, but decreasing with time; (2) the accumulation of iodine-123 LDL or iodine-131 LDL in the vascular bed shows three major types of local kinetic curves, which correlate with scintigraphic findings; (3) the accumulation of radiolabelled LDL in the vascular bed of humans in vivo is similar to its uptake in de- and re-endothelialized vessels of experimental animals using 125I-LDL; (4) morphological control in endarteriectomy samples confirms the hypothesis that this promising new approach may for the first time allow the in vivo monitoring of preclinical lesions in humans.
Adult↗
Intravenous prostacyclin (PGI2) infusion to 108 patients with ischaemic peripheral vascular disease: phase II-open study.
We recently reported the results of a double-blind trial of PGI2 in 108 patients with ischaemic peripheral vascular disease Stage II according to Fontaine. They were randomly allocated to receive an intravenous infusion of either PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days) or placebo and classified as treatment responders or non-responders on the basis of changes in absolute and relative walking times. Patients treated with placebo and those who did not improve in this double blind trial entered an open trial in which they all received infusion of PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days). The results of this open trial are reported here. Patients who had been allocated to PGI2 in the blind trial had significantly (p less than 0.01) longer walking times as compared to placebo-treated patients prior to receiving the second (PGI2) infusion. PGI2-infusion caused significant (p less than 0.01) prolongation of walking times in both groups up to the 2nd follow-up month. One month after infusion 52% (23 patients) of the initially placebo-treated patients and 31% (14 patients) of the initially PGI2-treated patients were scored as positive treatment responders (p less than 0.01).
Aged↗
Effect of prostaglandin E1 on low density lipoprotein apo-B-receptor binding in human, rat and swine liver in vitro.
The effect of PGE1 on low density lipoprotein (LDL) apo-B-receptor binding was examined in human, rat and swine liver. Autologous LDL (for humans and swines) and homologous LDL (for rats) were isolated by ultracentrifugation and labelled with 123I using Iodogen followed by purification with dialysis. LDL-concentrations of 0.1-6 micrograms protein/ml were used for direct binding assays investigating the specific binding of labelled LDL in presence of increasing PGE1-concentrations (100 pM to 100 microM). In separate experiments the effect of PGE1 on displacement of specifically bound 123I-LDL by unlabelled ones was studied. The binding capacities estimated by Scatchard analysis were similar for human and rat liver LDL-apo-B-receptor binding, however, swine liver exhibited a significantly (p less than 0.001) lower binding capacity for 123I-LDL. PGE1 significantly (p less than 0.01-0.001) increased the amount of 123I-LDL specifically bound to the liver apo-B-receptors and the binding affinity in all liver preparations of the 3 species in a dose-dependent manner. PGE1 also significantly increased competition of unlabelled LDL for 123I-LDL bound to its specific apo-B-receptors in a dose-dependent manner (p less than 0.01-0.001) with an ED50 of 123 +/- 64 nM for human liver, 901 +/- 102 nM for rat liver obtained during anaesthesia, 74 +/- 23 nM for rat liver obtained after decapitation and 941 +/- 121 nM for swine liver. In human liver iloprost (ED50 = 876 +/- 53 nM) and PGI2 (ED50 = 52 +/- 12 microM) were less effective than PGE1, PGE2 had no effect on LDL-induced competition. It is concluded that PGE1 renders LDL more sensitive for apo-B-receptor binding suggesting a potential hypolipidemic action of PGE1.
Adult↗