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Biomedical subjects

L Calabresi

Publications and source records attributed to L Calabresi.

At least 19 recordsLinked to original sources
PubMed2004

Development of a model based on body composition to predict drug kinetics-1 evaluation in healthy volunteers.

A kinetic model for widely used drugs, based on body composition analysis, was developed and evaluated in young and elderly healthy individuals. Body composition was studied by body impedance analysis (BIA). Antipyrine, amlodipine, digoxin and tobramycin kinetics, liver microsomal activity enzyme (lidocaine/MEGX test), and appropriate clinical and laboratory tests were carried out. Major variables (V(d), AUC, t(1/2), C(max), Cl) for these drugs were calculated, and the possible relationships with the other clinical and biochemical data were analyzed by the Pearson's moment correlation, forecasting models being then obtained by a multiple linear regression method. Major kinetic parameters, particularly for the mixed elimination drugs (liver/renal), i.e. digoxin and amlodipine, proved to be well correlated to data collected during the study, in particular with body structure parameters. Results were less satisfactory in the case of the mainly renally handled tobramycin. Mathematical models to forecast the kinetic behaviors of the three chosen drugs, using readily accessible data, showed both in the young and the elder, as well as in the whole examined population, very satisfactory correlations in the case of digoxin (R(2) ranging from 0.89 to 0.85) and amlodipine (R(2) between 0.81 and 0.91), less satisfactory (with a wide range of R(2), from 0.65 to 0.94), in the case of tobramycin.

Adult↗
PubMed2004

Development of a model based on body composition to predict drug kinetics; II. Application of the model to the use of digoxin in elderlies.

The applicability of a kinetic model for the prediction of steady-state blood levels, based on body composition as assessed by bioelectric impedance analysis (BIA), was applied to a population of elderly patients, candidates for digoxin therapy. Elderlies, all >70 years of age, underwent standard laboratory and clinical evaluation but no further characterization of liver or renal function. These 72 patients were given 0.125 mg digoxin for 5 days, in order to reach steady-state levels. Treatment was then interrupted and samples were collected 2 and 48 h after the last administration. Plasma digoxin levels were determined both by the immunochemical method with TDX and according to the BIA method described in the accompanying paper. Plasma levels calculated and measured in 2 h samples did not differ statistically, but levels were about 15% higher in the directly measured samples. There was a similar underestimation, i.e. about 15%, for the 48 h calculated levels. However, only approximately 5% of the levels were outside of the 95% confidence intervals as determined from the directly measured levels. These findings indicate that digoxin levels, calculated based on a BIA evaluation, may be sufficiently reliable, in the majority of patients, to allow direct determination of the more appropriate doses of digoxin.

Aged↗
PubMed2001

Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.

BACKGROUND: Carriers of the apolipoprotein A-I(Milano) (apoA-I(M)) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. METHODS AND RESULTS: Twenty-one A-I(M) carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86+/-0.25 and 0.88+/-0.29 mm, respectively) compared with control subjects (average IMT, 0.64+/-0.12 mm); the apoA-I(M) carriers instead showed normal arterial thickness (average IMT, 0.63+/-0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I(M) carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I(M) carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. CONCLUSIONS: Despite severe HA, carriers of the apoA-I(M) mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

Adult↗
PubMed2001

A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease.

The proband is a 50 year-old woman born from a consanguineous marriage. She has been suffering from angina pectoris since the age of 38 and underwent coronary bypass surgery for three-vessel disease at 48. The presence of low plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol (2.4 and 0.1 mmol/l) and apo AI (<15 mg/dl), associated with corneal lesions and a mild splenomegaly suggested the diagnosis of Tangier disease. However, none of the other features of Tangier disease, including hepatomegaly, anemia and peripheral neuropathy, were present. The analysis of the dinucleotide microsatellites located in chromosome 9q31 region demonstrated that the proband was homozygous for the alleles of D9S53, D9S1784 and D9S1832. The mother and son of the proband, both with low levels of HDL cholesterol, shared one of the proband's haplotypes, whereas neither of these haplotypes was present in the normolipidemic proband's sister. The sequence of ATP-binding cassette transporter 1 (ABC1-1) cDNA obtained by reverse transcription-PCR (RT-PCR) of total RNA isolated from cultured fibroblasts showed that the proband was homozygous for a C>T transition in exon 13, which caused a tryptophane for arginine substitution (R527W). This mutation was confirmed by direct sequencing of exon 13 amplified from genomic DNA. It can be easily screened, as the nucleotide change introduces a restriction site for the enzyme Afl III. R527W substitution occurs in a highly conserved region of the NH2 cytoplasmic domain of ABC1 protein. R527W co-segregates with the low HDL phenotype in the family and was not found in 200 chromosomes from normolipidemic individuals.

ATP Binding Cassette Transporter 1↗
PubMed2001

Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.

Patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unknown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease.

Adult↗
PubMed2001

Limited proteolysis of a disulfide-linked apoA-I dimer in reconstituted HDL.

The apolipoprotein A-I(Milano) (apoA-I(M)) is a molecular variant of apoA-I characterized by the Arg(173)-->Cys substitution, leading to the formation of homodimers A-I(M)/A-I(M). Upon interaction with palmitoyloleoylphosphatidylcholine, A-I(M)/A-I(M) forms only two species of reconstituted HDL (rHDL) particles, with diameters of 7.8 and 12.5 nm. We used limited proteolysis to analyze the conformation of A-I(M)/A-I(M) in the two rHDL particles, in comparison with that of apoA-I in rHDL of similar size. ApoA-I in the small, 7.8-nm rHDL is degraded to a greater extent (50% after 6 h) than in the large rHDL (<10% degraded after 6 h). The protease susceptibility of A-I(M)/A-I(M) in small and large rHDL is instead remarkably the same, with A-I(M)/A-I(M) being much more sensitive to proteolytic digestion (50% degraded after 10 min) than apoA-I. The identification of the proteolytic fragments by immunoblotting, N-terminal sequencing, and molecular mass determination, shows that the N-terminus of both proteins is resistant to proteolysis, with six cleavage sites located in the central and carboxy-terminal portions of the molecules. Cleavage in the middle of apoA-I occurs at distinct sites in 7.8-nm (Lys(118)) and 12.7-nm (Arg(123)) rHDL, indicating a different conformation in small and large rHDL particles. The A-I(M)/A-I(M) instead adopts a unique and identical conformation in small and large rHDL, with the carboxy-terminal portion of the molecule being remarkably more accessible to the proteases than in apoA-I. This suggests the presence of a novel carboxy-terminal domain in A-I(M)/A-I(M), not organized in a compact structure and not shared by wild-type apoA-I, which may account for the unique functional properties of A-I(M)/A-I(M).

Antibodies, Monoclonal↗
PubMed2000

Cardiovascular risk changes after lipid lowering medications: are they predictable?

Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34-37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs' effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a 'one drug' approach.

Anticholesteremic Agents↗
PubMed2000

Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses.

Elevations of plasma cholesterol and/or triglycerides, and the prevalence of small, dense LDL particles remarkably increase coronary risk in patients with familial combined hyperlipidemia (FCHL). A total of 14 FCHL patients were studied, to investigate the ability of Omacor, a drug containing the n-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA and DHA), to favorably correct plasma lipid/lipoprotein levels and LDL particle distribution. The patients received four capsules daily of Omacor (providing 3.4 g EPA+DHA per day) or placebo for 8 weeks in a randomized, double-blind, cross-over study. Omacor significantly lowered plasma triglycerides and VLDL-cholesterol levels, by 27 and 18%, respectively. Total cholesterol did not change but LDL-cholesterol and apolipoprotein B (apoB) concentrations increased by 21 and 6%. As expected, LDL particles were small (diameter=24.9+/-0.3 nm) and apoB-rich (LDL-cholesterol/apoB ratio=1.27+/-0.26) in the selected subjects. After Omacor treatment LDL became enriched in cholesterol (LDL-cholesterol/apoB ratio=1.40+/-0.17), mainly cholesteryl esters, indicating accumulation in plasma of more buoyant and core enriched LDL particles. Indeed, the separation of LDL subclasses by rate zonal ultracentrifugation showed an increase of the plasma concentration of IDL and of the more buoyant, fast floating LDL-1 and LDL-2 subclasses after Omacor, with a parallel decrease in the concentration of the denser, slow floating LDL-3 subclass. However, the average LDL size did not change after Omacor (25.0+/-0.3 nm). The resistance of the small LDL pattern to drug-induced modifications implies that a maximal lipid-lowering effect must be achieved to reduce coronary risk in FCHL patients.

Adult↗
PubMed2000

L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a).

BACKGROUND AND AIMS: Elevated Lp(a) levels are a significant cardiovascular risk factor, particularly for young individuals and for subjects with concomitant high LDL cholesterol. Increased Lp(a) is believed to be linked to an enhanced production of the lipoprotein, controlled by genetic factors; it can be reduced by agents such as nicotinic acid, lowering free fatty acid inflow to the liver. METHODS AND RESULTS: L-carnitine, a natural compound stimulating fatty acid oxidation at the mitochondrial level, was tested in a double blind study in 36 subjects with Lp(a) levels ranging between 40-80 mg/dL, in most with concomitant LDL cholesterol and triglyceride elevations. L-carnitine (2 g/day) significantly reduced Lp(a) levels (-7.7% vs baseline and -11.7% vs placebo treatment), the reduction being more dramatic in the subjects with the more marked elevations. In particular, in the L-carnitine group, 14 out of 18 subjects (77.8%) had a significant reduction of Lp(a) vs only 7 out of 18 (38.9%) in the placebo group (chi 2 = 4.11, p = 0.0452). In a significant number of subjects the reduction of Lp(a) resulted in a return of this major cardiovascular risk parameter to the normal range. CONCLUSIONS: L-carnitine offers a potentially useful therapeutic agent for atherogenic conditions characterized by high Lp(a) levels, also in view of the excellent tolerability and essential lack of major side effects.

Aged↗
PubMed1999

Cell cholesterol efflux to reconstituted high-density lipoproteins containing the apolipoprotein A-IMilano dimer.

The apolipoprotein A-IMilano (apoA-IM) is a molecular variant of apoA-I characterized by the Arg(173)-->Cys substitution, resulting in the formation of homodimers A-IM/A-IM. The introduction of the interchain disulfide bridge in the A-IM dimer limits the apolipoprotein conformational flexibility and restricts HDL particle size heterogeneity, thus possibly affecting HDL function in lipid metabolism and atherosclerosis protection. To investigate whether the structural changes in A-IM/A-IM affect apoA-I capacity for cell cholesterol uptake, we tested the ability of four reconstituted HDL (rHDL), that contained either apoA-I or A-IM/A-IM, to remove cholesterol from Fu5AH hepatoma cells and cholesterol-loaded murine primary macrophages (MPM). As the HDL particle size is known to affect the rHDL capacity for cell cholesterol uptake, the reconstitution conditions were carefully selected to produce two sets of rHDL particles of small and large size (7.8 and 12.5 nm in diameter). The small A-IM/A-IM rHDL were more efficient than the corresponding apoA-I particles as acceptors of membrane cholesterol from Fu5AH cells and MPM, and as inhibitors of cholesterol esterification in MPM. The large rHDL and the lipid-free apolipoproteins displayed instead similar capacities for cell cholesterol efflux. These results suggest that cell cholesterol efflux to rHDL particles of different size occurs through different mechanisms. Large HDL accommodate and retain the cholesterol molecules that have desorbed from the cell membrane into the extracellular fluid, in a process that is less sensitive to protein conformation. Small HDL accelerate the desorption of cholesterol from the cell membrane, in a process that is influenced by the conformation of the proteins on the surface of the acceptor particle. The enhanced efficiency of small A-IM/A-IM rHDL seems related to the peculiar structure of the protein on the rHDL surface, with a hydrophobic C-terminal domain extending out of the rHDL particle, available for anchoring the acceptor to the plasma membrane.

Animals↗
PubMed1999

Recombinant apolipoproteins for the treatment of vascular diseases.

The protein components of human lipoproteins, apolipoproteins, allow the redistribution of cholesterol from the arterial wall to other tissues and exert beneficial effects on systems involved in the development of arterial lesions, like inflammation and hemostasis. Because of these properties, the antiatherogenic apolipoproteins, particularly apo A-I and apo E, may provide an innovative approach to the management of vascular diseases. The recent availability of extractive or biosynthetic molecules is allowing a detailed overview of their therapeutic potential in a number of animal models of arterial disease. Infusions of apo E, or more dramatically, of apo A-I, both recombinant or extractive, cause a direct reduction of the atherosclerotic burden in experimental animals. Naturally, as the apo A-I(Milano) (apo A-I(M)) dimer, or engineered recombinant apolipoproteins with prolonged permanence in plasma and improved function may offer an even better approach to the therapeutic handling of arterial disease. This progress will go on in parallel with innovations in the technologies for direct, non invasive assessments of human atherosclerosis, thus allowing closer monitoring of this potential new approach to therapy.

Animals↗
PubMed1999

Increased cholesterol efflux potential of sera from ApoA-IMilano carriers and transgenic mice.

The ability of HDL to remove cholesterol from peripheral cells and drive it to the liver for excretion is believed to explain most of the strong inverse correlation between plasma HDL cholesterol levels and coronary heart disease. Carriers of the ApoA-IMilano (A-IM) mutant have a severe hypoalphalipoproteinemia but are not at increased risk for premature of coronary heart disease. To explain this apparent paradox, we compared the capacity of serum from A-IM and control subjects to extract cholesterol from Fu5AH cells. Because the A-IM carriers are all heterozygotes for the mutation, we also compared the cholesterol efflux capacity of serum from transgenic mice expressing A-IM or wild-type ApoA-I (A-IWT), in the absence of murine ApoA-I. In the whole series of human or mouse sera, cholesterol efflux was significantly correlated with several HDL-related parameters; after adjustment for concomitant variables, the only parameter that remained significantly correlated with cholesterol efflux was the serum ApoA-I concentration (r2=0.85 in humans and 0.84 in mice). The same was true when samples from control subjects, A-IM carriers, A-IWT or A-IM mice were analyzed separately. Cholesterol efflux to sera from the A-IM carriers was only reduced slightly compared with control sera (25.0+/-4.2% versus 30.4+/-3.3%), although there was a large reduction (-45%) in the serum ApoA-I concentration in the former. Cholesterol efflux was also lower to sera from A-IM than A-IWT mice (15.6+/-3.8% versus 30. 1+/-7.1%), but less than expected from the 70% reduction in serum ApoA-I concentration. A relative efflux potential of serum was calculated in each group as the slope of the regression line fitting cholesterol efflux to ApoA-I concentrations. Therefore, the relative efflux potential reflects the relative efficiency of ApoA-I in determining cell cholesterol efflux. The relative efflux potential of mouse and human sera was in the following order: A-IM mice>A-IM carriers>A-IWT mice=control subjects, suggesting a gene-dosage effect of the A-IM mutation on the efficiency of serum to extract cholesterol from cells. The high efficiency of A-IM-containing HDL for cell cholesterol uptake would result in an improved reverse cholesterol transport in the A-IM carriers, possibly explaining the low susceptibility to atherosclerosis development.

Adult↗
PubMed1998

Modulated serum activities and concentrations of paraoxonase in high density lipoprotein deficiency states.

Paraoxonase is a high density lipoprotein (HDL) associated enzyme with a hypothesised role in the protection of low density lipoproteins (LDL) from oxidative stress. The present study examined paraoxonase in several genetically distinct HDL deficiency states. Despite reduction or even absence of detectable HDL, enzyme activity was present in sera from A-I-Pisa, A-I-Helsinki, A-I-Milano and Tangier patients. Both enzyme activities and peptide concentrations were modulated (reduced) but specific activities were broadly similar to controls, suggesting an impact on peptide concentration rather than an inhibition of enzyme activity. Despite the absence of HDL in A-I-Pisa and Tangier subjects, there was no association of paraoxonase with very low density lipoproteins or LDL. Paraoxonase function is maintained in HDL deficient states. It implies that certain HDL-associated anti-atherogenic processes may not be entirely compromised by HDL deficiency. This has important implications for the cardiovascular risk associated with modulated HDL concentrations.

Adult↗
PubMed1997

Reconstituted high-density lipoproteins with a disulfide-linked apolipoprotein A-I dimer: evidence for restricted particle size heterogeneity.

The apolipoprotein A-IMilano (apoA-IM) is a molecular variant of apoA-I characterized by the Arg173-->Cys substitution, resulting in the formation of homodimers (A-IM/A-IM) and heterodimers with apoA-II. In order to examine the effects of the introduction of an interchain disulfide bridge on the lipid-binding properties of apoA-I, the present studies compare the kinetics of association of A-IM/A-IM and apoA-I with dimyristoylphosphatidylcholine (DMPC), and the structure and properties of reconstituted HDL containing palmitoyloleoylphosphatidylcholine (POPC) and either A-IM/A-IM or apoA-I. The results show that apoA-I dimerization does not affect the rate of association with DMPC. Apolipoprotein-POPC complexes instead, when analyzed by nondenaturing gradient gel electrophoresis, demonstrate that, differently from apoA-I, A-IM/A-IM forms only two species of rHDL particles despite a wide range of initial lipid to protein ratios. These two rHDL species contain one or two A-IM/A-IM molecules and have a diameter of 7.8 nm and 12.5 nm. Investigations of the A-IM/A-IM structure in these two rHDL, by circular dichroism, fluorescence, and second-derivative UV spectroscopy, suggest that the secondary and tertiary structures of A-IM/A-IM are remarkably similar in both small and large particles. These results suggest that the introduction of an interchain disulfide bridge does not affect the association of apoA-I with lipids but restricts HDL particle size heterogeneity, thus possibly affecting HDL function in lipid metabolism and atherosclerosis protection.

Apolipoprotein A-I↗