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Biomedical subjects

A L Pasqui

Publications and source records attributed to A L Pasqui.

At least 37 records · Page 2Linked to original sources
PubMed2002

Time-dependent effect of statins on platelet function in hypercholesterolaemia.

BACKGROUND: Reduction of platelet activity induced by statins has been described as a positive effect exerted by such molecules on vascular thrombotic events. However, the relations among cholesterol (LDL-C) reduction, the timing of the antiplatelet effect, the involved mechanisms and the doses of each statin able to reduce platelet function are not actually well known. The aim of our study was to evaluate the impact of simvastatin (20 mg day-1), atorvastatin (10 mg day-1), fluvastatin (40 mg day-1) and pravastatin (40 mg day-1) on platelet function in hypercholesterolaemic subjects with relation to (LDL-C), oxidized-LDL (ox-LDL) and antiport mechanism modifications. MATERIALS AND METHODS: Sixteen subjects were assigned to each treatment (40 males, 24 females, mean age 48.7 +/- 13.4, LDL-C 5.13 +/- 0,23 mmol L-1) and evaluated for platelet surface P-selectin (P-sel), lipid profile, ox-LDL, platelet-associated ox-LDL (Pox-LDL), platelet cholesterol content, antiport mechanisms, and intracellular and systemic NO synthase every 7 days for one month. RESULTS: Our data show a strong relation between enhanced P-sel and Pox-LDL (r = 0.68, P < 0.01). Simvastatin, atorvastatin, fluvastatin and pravastatin reduce platelet activity after 1, 2, 3 and 4 weeks of treatment, respectively (P < 0.001, P < 0.001, P < 0.01, P < 0.05). Pox-LDL are modulated early by simvastatin, atorvastatin and fluvastatin Pox-LDL (r = 0.66, 0.65 and 0.52; P < 0.001, 0.001 and 0.01, respectively) whereas LDL-C and ox-LDL reductions associated to modifications of antiport activity act later. Moreover, they are the most relevant finding in pravastatin-related subjects. CONCLUSIONS: Our data suggest a different impact of several statins on platelet function, which is initially related to interference with Pox-LDL rather than LDL-C reduction.

Adult↗
PubMed2001

Effect of diet and treatment with statins on platelet-dependent thrombin generation in hypercholesterolemic subjects.

BACKGROUND AND AIM: Platelets are strictly involved in arterial thrombosis and their hyperactivity has been shown in hypercholesterolemia. It has been reported that drugs affecting cholesterol metabolism (statins) decrease cardiovascular events by lowering lipid levels or by means of non-lipidic actions such as the direct inhibition of platelet function. The aim of this study was to detect the effect on platelet-dependent thrombin generation (PDTG) of a reduction in cholesterol obtained by means of a lipid-lowering diet or treatment with statins. METHODS AND RESULTS: We compared PDTG (T0) in 144 hypercholesterolemic subjects (94 males and 50 females of child-bearing age, mean age 48.2 +/- 13.8, plasma total cholesterol 6.93 +/- 0.64, high density lipoprotein cholesterol 1.25 +/- 0.14, triglycerides 1.15 +/- 0.19 mmol/L) and 70 normolipidemic controls (37 males and 33 females, mean age 43.1 +/- 12.6. After six weeks on an appropriate diet, the patients were randomised to receive different statin therapies if there was no reduction in their lipid profile and/or PDTG (T1). They were re-evaluated six weeks later, and the drug doses were maintained or increased on the basis of the variables (T2). A final evaluation was made after a further six weeks (T3). All of the data were evaluated using ANOVA and Spearman's correlation coefficent. The results showed increased PDTG in hypercholesterolemic subjects (418.2 +/- 29.2 mIU/mL, p < 0.001 vs controls). Diet alone did not reduce PDTG (380.2 +/- 28.5 mIU/mL, p = 0.226 vs controls). At T2, simvastatin and atorvastatin significantly decreased PDTG (P < 0.001 vs T0-1) and low-density lipoprotein cholesterol (LDL-C). No correlation was found between the two variables in the simvastatin group (r = 0.16). Cerivastatin reduced PDTG without significantly decreasing LDL-C (p < 0.001 and p = 0.476, r = 0.14). Pravastatin and fluvastatin significantly reduced thrombin generation only at T3 (40 mg/day); pravastatin was also associated with a decrease in LDL-C (p < 0.01, r = 0.66). CONCLUSIONS: Our results confirm an increased PDTG in patients with type IIa hyperlipoproteinemia, which is not reduced by diet. Statins at different doses significantly decrease PDTG but do not correlate with a reduction in LDL-C.

Adult↗
PubMed2001

Different mechanisms of fibrinolysis impairment among dyslipidemic subjects.

To determine whether there is a correlation between fibrinolytic activity and dyslipidemia, we performed a study of 72 subjects (20 patients with hypercholesterolemia, 20 with hypertriglyceridemia, 12 with isolated low high-density lipoprotein (HDL)-cholesterol (mean age 47.7 +/- 6.3, body mass index 24.7 +/- 0.4) and 20 healthy controls. Plasminogen activator inhibitor-1 (PAI-1), tissue-plasminogen activator activity and plasmin-antiplasmin complexes (PAP) were detected at baseline and after venous occlusion test. We also measured at baseline lipidic pattern, soluble E and P selectins (sE-sel, sP-sel), prothrombin factor 1+2 (F1+2), lipoprotein(a), factor VII, plasma insulin, fibrinogen, homocysteine, and thrombin activable fibrinolysis inhibitor (TAFI) activity. Fibrinolysis was significantly reduced in hypertriglyceridemic patients compared with hypercholesterolemic patients and control subjects (PAP, p < 0.01 and p < 0.001) and was associated with increased PAI-1 (at baseline and after venous occlusion test, p < 0.001). sP-sel, F1 +2 and TAFI were not significantly different compared with controls, while hypercholesterolemic subjects showed a significant increase in these parameters (p < 0.001), which were related to decreased PAP only at the upper low-density lipoprotein (LDL)-cholesterol levels (>160 mg/dl) (p < 0.001, r = -0.76). Moreover, there was no significant difference in PAI-1 activity (at baseline and after venous occlusion test) compared with controls. In conclusion, endothelial dysfunction was the main mechanism of decreased fibrinolysis in subjects with hypertriglyceridemia and low HDL-cholesterol, while enhanced thrombin generation and TAFI activity were the main determinants in hypercholesterolemia.

Adult↗
PubMed2000

Role of platelets in tissue factor expression by monocytes in normal and hypercholesterolemic subjects. In vitro effect of cerivastatin.

Thrombosis is a complication of atherosclerosis and monocytes play a determinant role either in the progression of atherosclerotic plaque or in blood coagulation by way of tissue factor expression. Platelets play a direct role in thrombosis and a hyperfunctional state has been described in hypercholesterolemic subjects. Moreover, platelets seem to be able to enhance monocyte activity. Cholesterol-lowering molecules (statins) are reported to reduce cardiovascular risk, either by decreasing the circulating level of cholesterol or by non-lipidic actions such as the reduction of monocyte and platelet activity. The aim of our study was to investigate the influence of platelets on the expression of tissue factor by monocytes and the effect induced by cerivastatin. We measured tissue factor levels by ELISA and the procoagulant activity of stimulated monocytes by a clotting assay on cellular preparations and whole blood in 40 hypercholesterolemic subjects (22 male, 18 female, mean age 52.7 +/- 12 years, total cholesterol 251.6 +/- 19.9 mg/dl) before and after cerivastatin addition. Tissue factor expression was enhanced in hypercholesterolemic subjects compared with normal subjects (31.6 +/- 7.6 vs. 23 +/- 5.8 pg/cells, P < 0.01). The presence of platelets increased the amount of tissue factor (55.3 +/- 7.3 pg/cells, P < 0.001) and cerivastatin reduced the expression of tissue factor in isolated monocytes, in the mixed cellular system, and in whole blood (19.6 +/- 4.1 pg/cells, P < 0.001). In conclusion, tissue factor expression by monocytes is enhanced in hypercholesterolemic subjects compared with normal controls. Platelets enhance monocyte production of tissue factor, and cerivastatin is able to counteract this prothrombotic mechanism.

Adult↗
PubMed2000

Complement activation in hypercholesterolemia.

BACKGROUND AND AIM: Inflammatory and lipid factors share an important role in atherosclerosis. This study evaluates their relations in dyslipidemic subjects. METHODS AND RESULTS: We compared the complement system (serum hemolytic activity CH50, C3 and C4 fractions and terminal complex sC5b-9) in 30 hypercholesterolemic patients with elevated cholesterol and decreased HDL-cholesterol levels, 30 normolipemic patients with clinical atherosclerosis and 30 matched normal subjects. In addition we evaluated the circulating immune complexes containing cholesterol (chol-CIC) on the assumption that they might be important in complement activation, and the circulating levels of the adhesion molecule ICAM-1 (sICAM-1) as a sign of endhotelial dysfunction. We found a significant increase of sC5b-9 (but not of CH50 and C3, C4) in the hypercholesterolemics compared with the other groups. The plasma sC5b-9 level was inversely and significantly related to HDL-chol (regression analysis), whereas no direct significant relation was found between sC5b-9 and cholesterol. Chol-CIC were also significantly increased in this group. The atherosclerosis patients also presented a significant increase of sC5b-9. Lastly, both patient groups displayed a significant increase of sICAM-1. CONCLUSIONS: We suggest that complement activation in dyslipidemics may be induced by their increased immune complexes. However, the decrease of complement regulatory proteins carried by HDL is another important factor, while complement changes may be related to variations of other humoral and cell systems (endothelium, coagulative/fibrinolytic system), whose involvement is suggested in our study by the changes of sICAM-1.

Adult↗
PubMed1998

POEMS syndrome with vascular lesions and renal carcinoma - possible role of cytokines.

We describe here the case of a 60 years man with POEMS syndrome associated with renal tumor and vascular lesions. The patient had osteosclerotic myeloma IgA-lambda, polyneuropathy, endocrinopathy and skin changes. In addition, he developed renal clear cell carcinoma and gangrena of lower limbs. The humoral study showed thrombocytosis, high levels of IL-1beta and IL-6 and of some coagulative/fibrinolytic and endothelial factors (von Willebrand factor, plasmin-antiplasmine complexes, plasminogen activator). We suggest the hypothesis that these factors are capable of determining some manifestations of POEMS syndrome.

Adenocarcinoma, Clear Cell↗
PubMed1998

POEMS syndrome with vascular lesions: a role for interleukin-1beta and interleukin-6 increase--a case report.

The authors describe the case of a 60-year-old man with POEMS syndrome associated with vascular lesions. The patient had osteosclerotic myeloma IgA (lambda), polyneuropathy, endocrinopathy, and skin changes. Subsequently, he developed gangrene of the lower limbs with no response to heparin therapy. The humoral study showed thrombocythemia, high levels of interleukin-1beta (IL-1beta) and IL-6 and of some coagulative/fibrinolytic and endothelial factors (von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator, and endothelial adhesion molecule ICAM-1). The authors suggest that these factors, induced by the increased levels of cytokines, could be responsible for microvascular damage, gangrene, and heparin resistance.

Fibrinolytic Agents↗
PubMed1997

Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma.

Extracorporeal photochemotherapy (ECP) has been shown to be a potent activator of peripheral blood macrophages because it causes a marked release of macrophage-dependent proinflammatory cytokines, and it is therefore currently considered to be a safe and non-toxic immunomodulatory treatment. On this basis we studied the function of peripheral blood mononuclear cells (PBMC) in eight patients with early stage (Ib) cutaneous T-cell lymphoma (CTCL), before and 1 year after ECP, together with their clinical and histological responses. In particular we evaluated in vitro phytohaemagglutinin (PHA)-stimulated proliferation and production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) as well as lipopolysaccharide (LPS)-induced production of IL-12. Before treatment we observed that PBMC of patients produced significantly higher levels of IL-4 and lower levels of IFN-gamma and IL-12 than those of healthy control subjects. After 1 year of ECP, IL-4, IFN-gamma and IL-12 production no longer differed from that of control subjects. Moreover, we observed a good clinical result matched by histological response. Our data confirm that early-stage CTCL patients show a predominantly type-2 immune response that might be responsible for several immunological abnormalities found in this disease. We have demonstrated that ECP reverses the T-helper type 1/T-helper type 2 (Th1/Th2) imbalance and may therefore be considered an efficient biological response modifier.

Aged↗
PubMed1997

The in vitro effect of Pidotimod on some immune functions in cancer patients.

There are several reports concerning an impairment of cellular immune response in patients affected by malignant disease. The aim of this study was to evaluate the in vitro effect of Pidotimod, a synthetic biological response modifier, on some immune functions in 14 cancer patients. In particular, we showed that these subjects had a significantly reduced peripheral blood mononuclear cell (PBMC) proliferation both in response to PHA and to Con A in comparison with a group of healthy subjects. Besides, they showed a significantly reduced PBMC IL2 production, which was evaluated both through an ELISA method and a biological assay. The in vitro addition of increasing concentrations of Pidotimod (10, 25 and 50 ug/ml) was able to enhance PBMC proliferation and IL2 production significantly. However, in spite of the addition of Pidotimod, both immune functions in our neoplastic patients did not reach normal values.

Adjuvants, Immunologic↗
PubMed1995

Imipenem and immune response: in vitro and in vivo studies.

Imipenem is a new beta-lactam antibiotic endowed with very high antimicrobial activity; it is used in severe infections which often occur in those conditions characterized by impairment of the immune system. The aim of this study was to evaluate the effect of imipenem on some immune functions, both in vitro and in vivo. The authors studied the effect in vitro of three different drug concentrations (15, 30 and 60 mg/l) on polymorphonuclear leucocyte (PMN) phagocytosis and superoxide anion production, as well as on lymphomonocyte proliferative response and cytokine production. Preincubation of PMN with the highest dosages (30 and 60 mg/l) was found to increase phagocytosis evaluated via both cytofluorimeter and chemiluminescence, while no effect was detected on superoxide anion production or on lymphomonocyte tests. In the in vivo study, the authors administered imipenem/cilastatin (1500 mg/day) to 15 elderly and diabetic patients, in whom both PMN functions (phagocytosis and superoxide anion production) and lymphocyte tests (CD3, CD4, CD8, CD19, IL2 and sIL2R serum levels) were studied before and on the 3rd and 7th days of treatment. The drug assimilation did not modify the lymphocyte parameters, whereas it increased PMN superoxide anion production and phagocytosis which were depressed in basal conditions. In the former case, such increase was slight and insignificant, whereas in the latter it was significant.

Aged↗
PubMed1995

Changes of some immune functions after percutaneous transluminal coronary angioplasty (PTCA).

This study aimed to evaluate some aspects of the immune response in 10 cardiopathic patients during the execution of percutaneous transluminal coronary angioplasty (PTCA) by obtaining blood samples from coronary sinus. In particular we considered some PMN functions as well as lysosomal release and oxidative metabolism evaluated as chemiluminescence and superoxide anion (O2) production. We also studied serum levels of complement C3 and C4, lymphocyte populations (CD3, CD4, CD8, CD19, CD16) and plasmatic determinations of interleukin 2 (IL2). After PTCA, we found a decrease of total count of blood lymphocytes, whereas the number of neutrophils remained unchanged. The decrease involved to a similar extent the lymphocyte subsets CD3, CD4 and CD8, whereas CD19 and CD16 were unchanged. The plasmatic levels of IL2 did not show any significant modification. Concerning PMN, their chemiluminescence was significantly increased after PTCA as compared to basal values: this response was promptly detectable in isolated PMN, both without and with stimulation with fMLP. Similarly superoxide anion production, both spontaneous and stimulated, was increased in PMN suspensions after PTCA, even if this increase did not reach statistical significance. As regards circulating levels of lysosomal enzymes, we found a significant increase of plasmatic levels of elastase, whereas the serum determinations of lysozyme and betaglucuronidase did not change. Concerning the complement system, we found a significant decrease of complement fractions C3 and C4. In conclusion, our results showed certain changes in some humoral and cellular systems; in particular the neutrophil activation through the release of proteolytic enzymes and the generation of oxygen radicals could increase the damage to vessel walls and activate other systems having a negative effect in the ischaemia-associated consequences.

Angioplasty, Balloon, Coronary↗
PubMed1994

Pharmacodynamics and pharmacokinetics of Veliten (rutine, alpha-tocopherol and ascorbic acid) in patients with chronic venous insufficiency.

The aim of this study was to evaluate the pharmacodynamics and pharmacokinetics of a single oral dose of Veliten in 12 patients affected by chronic venous insufficiency. In particular, the pharmacokinetics of two components of Veliten, namely rutine and alpha-tocopherol, were considered, while with respect to pharmacodynamics, studies were made of venous function, haemocoagulative and fibrinolytic balance, and haemorheological parameters. Correlation between such changes and plasma drug levels was also evaluated. We found a significant increase of venous tone, venous capacity and venous distension after drug intake, as well as a significant activation of fibrinolysis (globally evaluated with euglobulin lysis time), related to a slight increase of plasminogen tissue activator. These changes appeared concomitantly with maximal plasma levels of rutine. We did not find any modifications of coagulative and haemorheological parameters.

Administration, Oral↗
PubMed1992

Pharmacodynamics of salmon calcitonin in humans: new markers of pharmacological activity.

In order to define the pharmacodynamic profile of salmon calcitonin (sCT) in humans, several markers of the biological activity of the drug have been studied, namely cAMP, adenosine and pO2 in venous blood, and the cytosolic free calcium level in circulating cells. Different dosages and routes of administration (1.5 IU.kg-1 and 0.75 IU kg-1 IM, and 1.5 IU.kg-1 via nasal spray) were compared. sCT caused an increase in cAMP, adenosine and pO2, and a decrease in cytosolic free calcium in neutrophils, lymphocytes and platelets. The peak times of all these parameters ranged between 109 and 182 min, and 101 and 168 min after IM and nasal spray administration respectively. There was greater variability in the values after IM than nasal spray of administration of sCT. It is concluded that adenosine and pO2 in venous blood, and cytosolic free calcium in circulating cells are valuable markers of the activity of sCT and that sCT decreases the cytosolic free calcium level in neutrophils, lymphocytes and platelets. Pharmacodynamic analysis of the biological effects of the drug is highly reliable and valuable in predicting its pharmacological profile. sCT administration via a nasal spray is able to produce significant biological effects, although they are less marked than after IM dosing.

Adenosine↗
PubMed1991

Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin.

The biologically final active compound of nitrovasodilators is now supposed to be nitric oxide (NO), a labile substance identical to EDRF. The effects of nitroprusside on platelet functions were studied in vitro. Platelet aggregation induced by several stimuli (ADP, collagen, arachidonic acid and PAF) was inhibited by increasing concentrations of the drug (1-50 uM); interestingly, the potency of nitroprusside is higher when PAF is employed as stimulating agent in comparison with the other agonists (ED50 = 2 uM for ADP, 2.5 uM for A.A., 4.5 uM for collagen and 0.3 uM for PAF-induced aggregations). The concomitant addition of haemoglobin is able to reverse the inhibitory effect of nitroprusside, according to the view that haemoglobin possesses a high affinity for NO, thus antagonizing the effect of this compound. Nitroprusside was also able to inhibit intracellular calcium translocation, as studied with the Quin 2 technique, induced by PAF and arachidonic acid. Fron these observations the hypothesis may be suggested that nitroprusside inhibits platelet functions by mimicking the endogenous NO, and that the intracellular calcium metabolism is involved in the inhibitory activity of the drug.

Adenosine Diphosphate↗