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Biomedical subjects

C R Sirtori

Publications and source records attributed to C R Sirtori.

At least 19 recordsLinked to original sources
PubMed2004

Evaluation of a soft atherosclerotic lesion in the rabbit aorta by an invasive IVUS method versus a non-invasive MRI technology.

The intravascular ultrasound (IVUS) modality has rapidly gained acceptance for the measurement of arterial plaque thickness and for anatomical characterization. In view, however, of the growing interest in the direct assessment of plaque size after therapeutic modalities directly reducing plaque burden, a non-invasive method such as magnetic resonance imaging (MRI) may be of help for repeated evaluations. The two methods were compared directly on a focal plaque developed at the abdominal aortic level by a combination of local electric lesion followed by a hypercholesterolemic diet. The plaque was fully characterized histopathologically at intervals up to 120 days from lesion induction, and maximal plaque formation was detected at 90 days from electrical injury. Plaques could be well assessed by IVUS at each time point analyzed and data correlated very well to histopathologic findings (r = 0.969, P = 0.0014). The MRI technology provided reliable determinations only at 90 days after lesion induction, i.e. at maximal plaque formation, with excellent correspondence to IVUS determinations (r = 0.989, P = 0.0111). Altogether these findings indicate that the non-invasive MRI technology, when applied to the analysis of arterial plaques of adequate size, can be used successfully for plaque determination, with results comparable to the invasive IVUS technique.

Analysis of Variance↗
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↗
PubMed2002

N-3 fatty acids and diabetes.

Fatty acids of the omega-3 series (n-3 fatty acids) are a well established dietary component affecting plasma lipids (mainly triglycerides) and also major cardiovascular parameters, such as arrhythmogenesis. In view of their peculiar metabolic handling, it has been suggested that they may reduce glucose tolerance in patients predisposed to diabetes. On the other hand, insulin is required for the endogenous synthesis of the long chain n-3 fatty acids from precursors; the heart may thus be particularly susceptible to their depletion in diabetes. This review examines large population studies, carried out particularly by this research group, evaluating the risk of developing glucose intolerance/clearcut diabetes in large series of patients with predisposing conditions. While diabetes development was in no way accelerated in any of these studies, there was, instead, clear evidence of a significant hypotriglyceridemic activity of the supplements. In long-term treatments, there was also a tendency toward a significant reduction of low density lipoprotein (LDL) cholesterolemia, with positive effects on high density lipoprotein (HDL). These findings fit well with cellular changes indicative of improved glucose handling. Finally, recent data suggest an improvement of heart rate variability by fish intake in coronary patients, that is also exerted by the n-3 fatty acids given as ethyl esters, thus providing further indication for the potential benefit of such treatments in diabetic patients.

Animals↗
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

Aescin: pharmacology, pharmacokinetics and therapeutic profile.

Aescin, the major active principle from Aesculus hippocastanum (Hippocastanaceae) the horse chestnut tree, has shown satisfactory evidence for a clinically significant activity in chronic venous insufficiency (CVI), haemorrhoids and post-operative oedema. In one controlled trial aescin was shown to be as effective as compression therapy as an alternative to medical treatment for CVI. The therapeutic benefit is well supported by a number of experimental investigations in different animal models, indicative of clearcut anti-oedematous, anti-inflammatory and venotonic properties, mainly related to the molecular mechanism of the agent, allowing improved entry of ions into channels, thus raising venous tension in both in vitro and in vivo conditions. Other mechanisms, i.e. release of PGF(2) from veins, antagonism to 5-HT and histamine, reduced catabolism of tissue mucopolysaccharides, further underline the wide ranging mechanisms of the therapeutic activity of aescin. The excellent tolerability of aescin in the clinic indicates this treatment is of definite clinical benefit in patients with clinical conditions resulting in CVI, haemorrhoids or peripheral oedema formation.

Animals↗
PubMed2001

Soy proteins and cardiovascular disease.

The soybean diet is the most potent dietary tool for hypercholesterolemia. The United States Food and Drug Administration recently approved the health claim for its role in reducing the risk of coronary disease. The hypocholesterolemic effect is directly correlated to the patient's cholesterolemia, with minimal or no reductions occurring at cholesterol of 6 mmol/L or less, and the most benefit occurring in patients with cholesterol of greater than 7 mmol/L. Hypotheses on the mechanism of action include soy fiber, isoflavones (phytoestrogens), and the protein itself. Although there is no evidence for the effect of fiber, studies with ethanol-extracted soy (devoid of isoflavones) indicated a loss of effect, but the extract itself (isoflavone rich) has no hypocholesterolemic activity. In humans, soy protein activates the low-density lipoprotein (LDL) receptor pathway. Recent data suggest that soy protein subunits, particularly 7S, directly activiate LDL receptors in the human liver, thus providing a novel mechanism of plasma cholesterol reduction different from currently available diets and hypolipidemic drugs.

Cardiovascular Diseases↗
PubMed2001

Development of a lipid-rich, soft plaque in rabbits, monitored by histology and intravascular ultrasound.

Lipid rich, soft plaques in the clinic are a common forerunner to occlusive thrombus formation, even with modest arterial stenosis. Animal models of atherosclerosis, obtained by various methods, do not generally allow direct in vivo evaluation of the lesion and, furthermore, cannot be examined more than once. The aim of the study was the generation of a rabbit model of atherosclerosis, with morphological characteristics similar to human lipid-rich, soft atheromatous plaques, and the evaluation of the reliability of intravascular ultrasound (IVUS) technology in the study of the development of atherosclerotic lesions in this model. Briefly, New Zealand white rabbits undergo perivascular electrical injury at both common carotid arteries, together with a 1.5% cholesterol diet for up to 90 days. The lesioned arterial segments show progressive changes, from diffuse cellular mortality, to macrophage infiltration in the media, up to the final migration of macrophages to the neointima, resulting in bulky, eccentric, macrophage and lipid-rich lesions. At IVUS, the produced lesions clearly resemble those described as 'soft plaques' in the clinical setting, with minimal calcification and reduced echo-reflectivity versus the adventitial layer. Quantitative and morphometric analysis of plaques shows a significant correlation between histological and IVUS measurements at each time point. In conclusion, vascular injury in the common carotids of rabbits generates atherosclerotic lipid-rich, soft plaques, that can be properly assessed by the IVUS methodology. The easy accessibility of the arterial lesion allows serial IVUS investigations and the direct evaluation of a number of locally or generally delivered therapeutic agents.

Analysis of Variance↗
PubMed2001

Time course of forearm arterial compliance changes during reactive hyperemia.

Ultrasonic studies have shown that arterial compliance increases after prolonged ischemia. The objective of the present study was to develop an alternative plethysmographic method to investigate compliance, exploring validity and clinical applicability. Forearm pulse volume (FPV) and blood pressure (BP) were used to establish the FPV-BP relationship. Forearm arterial compliance (FAC) was measured, and the area under the FAC-BP curve (FAC(AUC)) was determined. The time course curve of compliance changes during reactive hyperemia was obtained by continuous measurements of FAC(AUC) for 20 s before and for 300 s after arterial occlusion. This technique allows us to effectively assess compliance changes during reactive hyperemia. Furthermore, the selected measurement protocol indicated the necessity for continuous measurements to detect "true" maximal FAC(AUC) changes. On multivariate analysis, preischemic FAC(AUC) was mainly affected by sex, peak FAC(AUC) was affected by sex and systolic BP, percent changes were affected by plasma high-density and low-density lipoprotein cholesterol, peak time was affected by age and body mass index, and descent time was affected by plasma triglyceride levels. The proposed technique is highly sensitive and well comparable with the generally accepted echotracking system. It may thus be considered as an alternative tool to detect and monitor compliance changes induced by arterial occlusion.

Adolescent↗
PubMed2001

Risks and benefits of soy phytoestrogens in cardiovascular diseases, cancer, climacteric symptoms and osteoporosis.

Phytoestrogens, plant chemicals classified as isoflavones, coumestans and lignans, display estrogen-like activity because of their structural similarity to human estrogens and exhibit high affinity binding for the estrogen receptor beta. They are common components of food items such as grains, beans, fruits and nuts. Isoflavones are primarily found in soybeans and foods made from soy. In particular, significant therapeutic properties have been generally attributed to soy isoflavones, but most of the claims have been poorly, or not at all, confirmed by well designed clinical trials. Such is the case of the purported role of soy isoflavones in reducing plasma cholesterol levels. This link is now not supported by many authors or by appropriately designed clinical studies. The role of isoflavones in cancer prevention, particularly of tumours under endocrine control (breast, prostate and others) is again only supported by weak to nonexisting clinical evidence. A similarcase is that of the prevention/treatment of postmenopausal symptoms and osteoporosis. Disturbing data have been reported on potential negative effects of soy isoflavones on cognitive function in the aged, particularly relating to tofu intake. Recent studies have finally indicated a potential role for soy isoflavones in inducing chromosomal changes in cells exposed in vitro and potentiating chemical carcinogens. These findings may not, however, be extrapolated to clinical conditions. Available data do not appear to unequivocally support beneficial effects of soy isoflavones, and warn against their wide use, in the absence of satisfactory clinical findings.

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↗
PubMed2001

Statins enhance arachidonic acid synthesis in hypercholesterolemic patients.

BACKGROUND AND AIM: It has been shown that statins enhance arachidonic acid biosynthesis from linoleic acid in vitro, and there is also evidence that statin-treated patients have high plasma and cellular arachidonic acid levels. The aim of this study was to investigate the possible effects of statins on the desaturating steps of arachidonic acid biosynthesis in patients. METHODS AND RESULTS: Plasma polyunsaturated fatty acids (percentages and concentrations), total cholesterol, LDL-cholesterol and triglycerides were measured in three groups of hypercholesterolemic patients before and after treatment with statins or fibrates for about three years, or before and after four months on a low-fat diet. As expected, there was a significant reduction in plasma total cholesterol (-23%) and LDL-cholesterol (-27%) levels in the statin group, and a significant reduction in triglycerides (-29%) and some decrease in total cholesterol (-12%) in the fibrate group; no change was observed in the control group. The selective increase in plasma arachidonic acid levels (in terms of absolute concentration and as a percentage of total fatty acids) was of the same order as the reduction in cholesterol, and the selective increase in the product/precursor ratios for delta 5 desaturation in the statin group indicated that this key step in arachidonic acid synthesis is affected. CONCLUSIONS: Our data show that an increase in arachidonic acid synthesis due to enhanced delta 5 desaturation is a major effect of statin treatment, and has the same order of magnitude as the reduction in plasma cholesterol levels.

Anticholesteremic Agents↗
PubMed2000

Interactions between carbonic anhydrase and its inhibitors revealed by gel electrophoresis and circular dichroism.

Structural properties, and especially the differential stability, of complexes between carbonic anhydrase (CA) and three sulfonamide inhibitors, acetazolamide, dorzolamide and methazolamide, were investigated by spectroscopic and electrophoretic techniques. These included denaturant gradient gel electrophoresis either across a urea or a steady-state transverse sodium dodecyl sulfate (SDS) gradient. Acetazolamide, the smallest and most hydrophilic of the sulfonamides, forms the most stable complex in the presence of urea, whereas dorzolamide, with a bulky and hydrophobic structure, is most stable against the effects of SDS. At pH 7.4, complexes with dorzolamide show minimal changes in mobility across the SDS gradient, as if unaffected by the detergent, both in the presence and in the absence of excess ligand in the gel. When bound to both acetazolamide and methazolamide, on the other hand, CA displays an increase in mobility above 0.05% SDS, lower in the presence than in the absence of excess ligand. The finding of a distinct pattern for the unliganded enzyme, however, suggests the complexes can still retain the ligand, although binding of the surfactant changes their charge density. Under saturating conditions and in the presence of SDS, the surface charge of all complexes is much lower than for unliganded, denatured CA. Circular dichroism (CD) spectra clearly indicate that the increase in secondary structure and the decrease in tertiary structure brought about in CA by the presence of low concentrations of SDS are largely prevented by complexing with the inhibitors. These observations point out peculiar properties of each CA inhibitor, of potential value in the definition of their biological activities and also in the potential development of novel antagonist molecules.

Acetazolamide↗
PubMed2000

Very low intakes of N-3 fatty acids incorporated into bovine milk reduce plasma triacylglycerol and increase HDL-cholesterol concentrations in healthy subjects.

Eight normolipidaemic volunteers, habitual partial skim milk drinkers and non-eaters of fish during the study, were given 500 ml day(-1) of partial skim milk for 1 month; they were then switched to 500 ml day(-1) of a novel commercially available milk preparation, supplying 400 mg of N-3 fatty acids-of which 300 mg were EPA+DHA-and 15 mg vitamin E, for 6 weeks. No changes in plasma lipid parameters were observed after the first run-in month; at 3 and 6 weeks on the N-3-rich milk, marked increments of plasma EPA (44 and 31%, respectively) and DHA (13 and 31%, respectively) were observed. Triacylglycerol (TG) concentrations decreased by 19% and high-density lipoprotein (HDL) concentrations increased by 19% at 6 weeks; plasma vitamin E rose by 21% while the susceptibility of plasma to oxidation was unaffected. Correlations were found between plasma EPA or DHA and TG, cholesterol, and HDL. In conclusion, the intake of a milk preparation providing low amounts of EPA+DHA to healthy individuals led to marked increases of N-3 fatty acids and vitamin E in plasma and in associated favourable changes in HDL and TG.

Adult↗
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

Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study.

The Carotid Atherosclerosis Italian Ultrasound study (CAIUS), a multicenter, double-blind clinical trial, performed in 305 asymptomatic, moderately hypercholesterolemic patients, clearly demonstrated beneficial effects of pravastatin on the carotid intima-media thickness (IMT) progression. The database of the CAIUS study was examined in order to investigate the presence of a relationship, if any, between the activity of pravastatin on IMT progression rate and its hypocholesterolemic effect. Quantitative B-mode ultrasound imaging was used to quantify the individual mean maximum IMT progression rate in 3 years. In the overall group of patients (placebo and pravastatin) covariance analysis showed that while the variable 'treatment' (0 = placebo, 1 = pravastatin) was significantly related to the reduction of IMT progression (F= 6.6, P = 0.01), the IMT progression did not correlate with the extent of LDL-C lowering (F= 0.00, P = 0.98). To further investigate this issue. the pravastatin treated group was stratified into quartiles of LDL-C reduction. In contrast to what was observed in the placebo group, in which a positive mean IMT progression rate was observed, independent of the extent of LDL-C reduction, no IMT progressionwas observed in any subgroup treated with pravastatin. No significant difference was found among quartiles and no trend could be identified. In conclusion, the effect of pravastatin treatment on carotid IMT progression rate is beneficial; however the CAIUS study demonstrated that lowering LDL-C by itself, does not explain the variability of beneficial changes in IMT.

Anticholesteremic Agents↗