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Biomedical subjects

D Giannessi

Publications and source records attributed to D Giannessi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Platelet-vessel wall interactions with third-generation oral contraceptives: no evidence of detrimental effects.

Because of the association of oral contraceptives (OC) and cigarette smoking with an increased thrombotic risk, we evaluated thromboxane (TX) and prostacyclin urinary (u) metabolites, as in vivo indices of platelet-vessel wall interactions, in women assigned to third generation OC. Twenty-eight women (15 smokers) underwent a 6-month trial of 30 microg ethinylestradiol plus 0.150 mg desogestrel. Cotinine plasma levels were elevated only in persons classified as smokers and serum TXB2 determination confirmed the absence of cyclooxygenase inhibition throughout the study. u-TXB2 and 11-dehydro-TXB2 were higher in smokers than in non-smokers. OC decreased u-11-dehydro-TXB2 both in smokers (from (pg/micromol creatinine) 35.1+/-6.9 to 15.8+/-2.8; P<0.025) and non-smokers (from 31.7+/-9.8 to 20.6+/-4.8, P = N.S.). u-6-keto-prostaglandin(PG)F1alpha excretion, also higher in smokers compared to non-smokers, was also reduced after OC in smokers (from (pg/micromol creatinine) 24.3+/-5.2 to 14.8+/-2.3; P<0.05). Smokers also had a trend to higher u-2,3-dinor-6-keto-PGF1alpha, marginally reduced by OC. Thus, the OC regimen used here improves - if anything - platelet vessel wall interactions as assessed by prostanoid production in vivo. The prothrombotic tendency associated with the use of OC in smokers does not appear to be mediated by changes in platelet-vessel wall interactions.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

[Physiological significance and clinical utility of analytical methods for cardiac natriuretic peptides].

It was well-established that the heart has an endocrine function because it is able to synthesize and secrete a family of related peptide hormones (known as cardiac peptide hormones) with potent diuretic, natriuretic and with complex interactions with the hormonal and nervous systems. Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP1-98) are differently regulated in their production/secretion patterns and clearance rates; consequently, the assay for these peptides may provide complementary (or even different) pathophysiological and/or clinical information. The assay for cardiac natriuretic peptides has been utilized in clinical conditions associated with expanded fluid volume. In particular, this assay can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered as a prognostic indicator of long-term survival in patients with heart failure and/or after acute myocardial infarction. Non-competitive immunometric assays (such as two-site IRMAs), even if more expensive, seem to be preferable to RIAs for routinary assay of cardiac peptide hormones because they generally have a better degree of sensitivity, accuracy, and precision. The technical characteristics and the potential clinical usefulness of some of the methods for measuring these peptides are reviewed.

Animals↗
PubMed1998

Anti-D treatment for chronic immune thrombocytopenic purpura: clinical and laboratory aspects.

We used low-dose anti-D immunoglobulins for home treatment of Rh+ adult patients with chronic immune thrombocytopenic purpura (ITP). After informed consent, 15 unselected outpatients (ten males and five females, aged 22 to 72), affected by chronic ITP with negative HIV test, were given intramuscular injection of 900-1500 micrograms of anti-Rh0 (D) IgG over 3 days every month for 2 or 3 consecutive months. Platelet count (mean +/- SD) significantly increased from basal value of 17,000 +/- 9,000/microL to 72,000 +/- 55,000/microL at the end of treatment. Eight patients achieved a rise in platelet count above 50,000/microL (five above 100,000/microL) and two of them maintained the increase longer than 6 months without further anti-D administration. Three patients responsive to the first cycle responded to further treatment with substantially identical results. Seven patients had no response. Four of them had not responded to previous glucocorticoid and intravenous IgG therapy. Direct antiglobulin test became strongly positive in all patients and mean serum haptoglobin decreased from a basal value of 118 +/- 59 to 61 +/- 43 mg/dL; nevertheless no clinically overt hemolysis was observed in any patient, there was no rise of serum indirect bilirubin and hemoglobin level was unchanged (mean +/- SD basal level 13.6 +/- 2.2 g/dL; after anti-D 13.9 +/- 1.2 g/dL). No hematoma developed at the injection site, and no other side effects occurred. Our results show that anti-D therapy is effective in the majority of patients well tolerated, and feasible as home treatment: thus it can be recommended as a cheap and safe alternative treatment in ITP Rh+ patients.

Adult↗
PubMed1996

A prostacyclin-sparing effect of indobufen vs. aspirin.

Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.

Adult↗
PubMed1995

Preparation of mono-radioiodinated tracers for study of the in vivo metabolism of atrial natriuretic peptide in humans.

In the present paper we evaluate the optimum chemical conditions for labelling atrial natriuretic peptide (ANP) and its metabolites and for preparing highly purified radiotracers which can be used for in vivo kinetic studies of ANP in humans. Synthetic alpha h1-28ANP and some hormone metabolites were iodinated with Na125I or Na131I by means of the lactoperoxidase (ANP) or the chloramine-T (ANP metabolites) technique. The biological activity of labelled ANP was tested by means of a binding study using mouse cardiac membranes. A high-performance liquid chromatography (HPLC) procedure was used to purify the labelled hormone and the principal labelled metabolites in venous plasma samples collected up to 50 min after the injection of 125I-labelled ANP from nine healthy men. The main ANP kinetic parameters were derived from the disappearance curves of the [125I]ANP, which were satisfactorily fitted by a biexponential function in all subjects. The main advantages of this tracer technique are: (1) high accuracy, allowing the identification of the metabolites produced in vivo under steady-state conditions after injection of the precursor (labelled hormone); (2) high sensitivity, allowing the detection of minimal quantities of metabolites (that cannot be identified on the basis of the integrated areas from the ultraviolet-absorbing peaks on HPLC); (3) high specificity, allowing the detection of possible in vitro artefactual generation of cleavage products of ANP using an internal labelled standard. Utilizing this tracer method, it was possible to estimate the principal parameters of ANP kinetics and also to plot the appearance curves of the labelled metabolites produced in vivo after the injection of the labelled precursor.

Adult↗
PubMed1995

Platelet radiolabelling with 111 Indium for in vivo studies: a methodological reappraisal.

Two ligands widely used for 111In labeling of human platelets, oxine and tropolone, were compared as to the degree of their influence on platelet function. The labelling efficiency was assessed as a function of experimental variables. A good preservation of platelet function as evaluated by ex vivo aggregation was obtained with both techniques. The extent of tracer detached from platelets was evaluated in vitro and in vivo: in normal subjects 111In was virtually all bound to platelets. A significant reduction in radiolabelling efficiency and a decreased percentage of 111In bound to platelets in vivo was observed in patients with platelet counts < 150,000/mL.

Blood Platelets↗
PubMed1995

Antiplatelet activity of synthetic and natural resveratrol in red wine.

The antiaggregating effect of the phytoalexin resveratrol (3,4,5-trihydroxystilbene), alone or associated with red wine, and polyphenol have been evaluated in vitro at different concentrations on platelet-rich plasma from healthy volunteers. Resveratrol at the concentration of 3.56 micrograms/l was able to lower platelet aggregation by 50.3% +/- 1.83. Red wine containing 1.2 mg/l of natural trans-resveratrol and 3.6 milligrams of polyphenols diluted 1000-fold (final resveratrol concentration: 1.2 micrograms/l) inhibited platelet aggregation by 41.9% +/- 2.11. By adding resveratrol to the wine up to a concentration of 1.2 micrograms/l, inhibition was raised to 78.5% +/- 4.70. These results suggest that the antiaggregating activity of resveratrol is related to its concentration in wine.

Humans↗
PubMed1995

Determination of endothelin binding sites in bovine atrium and ventricle membranes: a model for binding studies in human cardiac tissue.

The characterization of the binding sites of endothelin (ET) could constitute a useful tool to better understand its role in different pathophysiological conditions in human myocardial tissue. Crude membrane fractions were prepared from bovine atrium and ventricle for binding-assay assessment; membranes were also prepared from portions of atrium or ventricle < 100 mg each, a size comparable with human surgical fragments, and Scatchard analysis was performed from each single fragment. Portions of cardiac tissue were homogenized in 10 volumes of Tris/HCl buffer, 50 mM, pH 7.4, containing protease inhibitors; the supernatant was centrifuged at 50,000 x g for 30 min and the pellet stored at -80 degrees C. 125-I-ET-1 binding was performed by using 50 micrograms of protein and scalar concentrations of radioligand (8-200 pM), at 37 degrees C for 4 h and was stopped by filtration through a glass-fibre filter. The specific binding was saturable (at 200 pM of 125-I-ET-1 for 100 micrograms/ml of protein); the equilibrium was reached in 4 h at 37 degrees C at a radioligand concentration of 150 pM; a similar pattern, but a lower binding was obtained at 4 degrees C and 25 degrees C; the binding linearly increased with protein concentrations from 12.5 to 150 micrograms, and saturated at higher concentration. Non-specific binding was determined in presence of 0.1 microM unlabelled ET-1 and was about 2% of the total radioactivity added, for 125-I-ET-1 ranging from 8 to 200 pM, at 100 micrograms/ml of protein. By Scatchard analysis Kd proved to be 20.7 +/- 3.9 and 19.9 +/- 0.6 pM, Bmax 42.4 +/- 12.7 and 59.3 +/- 13.0 fmol/mg of protein, for atrium and ventricle respectively. Differential inhibition of binding was observed for the three ET isoforms; IC50 were similar for atrium and ventricle and proved to be 50 nM for ET-1 and ET-2 and > 200 nM for ET-3. This latter finding and the Scatchard analysis suggest the presence of a single class of binding sites in bovine cardiac membranes. No significant differences in absolute values of Kd and Bmax were found when cardiac membranes were obtained by small tissue fragments.

Animals↗
PubMed1993

n-3 fatty acids reduce proteinuria in patients with chronic glomerular disease.

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to reduce proteinuria in experimental models of renal diseases, but their potential role in the treatment of human renal disease is unknown. We administered n-3 PUFA in the form of triglycerides [with eicosapentaenoic (EPA)+docosahexaenoic (DHA) = 3 g/day into 4 patients] and of ethyl esters (EPA+DHA = 7.7 g/day) into 10 patients (one patient twice) with chronic glomerular disease (membranous glomerulonephritis and focal glomerular sclerosis), all diagnosed histologically. Serum albumin was > 2.4 g/dl and serum creatinine < 2.5 mg/dl in all patients. Treatment was given for periods of six weeks, followed by a prolonged follow-up for 27 weeks in 10 cases. Dietary supplementation with n-3 PUFA caused the expected reduction in platelet generation of thromboxane B2 (mean +/- SEM, from 490 +/- 70 ng/ml at baseline, to 342 +/- 147 ng/ml at 6 weeks, P < 0.05) of serum triglycerides (from 236 +/- 60 to 170 +/- 43, P < 0.01), and a prolongation of the bleeding time (from 5.8 +/- 0.4 min to 7.7 +/- 0.4 min, P < 0.01) in patients treated with ethyl esters. A modest but significant reduction in serum total cholesterol was noticed (from 275 +/- 27 to 252 +/- 24 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids.

It has been suggested that the induction of lipocortin-1, a phospholipase A2-inhibitory protein, may mediate the anti-inflammatory action of glucocorticoids. We assessed the production of prostaglandin E2, thromboxane B2, and leukotriene B4 and the expression of lipocortin-1 in different populations of blood leukocytes and in alveolar macrophages (obtained by bronchoalveolar lavage) from patients with inflammatory lung diseases (bronchial asthma, n = 21; interstitial lung disease, n = 6) undergoing glucocorticoid treatment at clinically effective doses. No inhibition of eicosanoid production was observed in either whole blood or single populations of blood leukocytes (granulocytes and monocytes) stimulated with ionophore A-23187, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or zymosan. Conversely, eicosanoid production from alveolar macrophages (assessed in 9 cases) was significantly inhibited by glucocorticoids. After ionophore stimulation, eicosanoid production was as follows (in ng/ml): prostaglandin E2, 0.19 +/- 0.06 and 0.06 +/- 0.01; thromboxane B2, 2.9 +/- 0.9 and 0.5 +/- 0.1; leukotriene B4, 6.6 +/- 1.1 and 3.6 +/- 1.0, before and after treatment, respectively (P < 0.05 for all differences). Lipocortin-1 expression, determined by Western blot and enzyme immunoassay, was significantly (P < 0.05) stimulated in alveolar macrophages, but not in blood leukocytes, by glucocorticoid treatment. These results indicate that alveolar macrophages, at variance from blood leukocytes, are the most likely cell target for glucocorticoid-induced eicosanoid inhibition and lipocortin expression. We suggest that cell responsiveness to glucocorticoids is acquired during differentiation from monocyte to tissue macrophage.

Adolescent↗
PubMed1993

Studies on the induction of lipocortin-1 by glucocorticoids.

Part of the anti-inflammatory efficacy of glucocorticoids has been ascribed to the inhibition of eicosanoid formation which is brought about by lipocortins (LC, phospholipase A2 inhibitory proteins) whose synthesis is induced by corticosteroids. We have investigated the effect of glucocorticoids on eicosanoid formation and lipocortin-1 induction in a human cell line in vitro and in patients with inflammatory lung disease in vivo. Human promyelocitic U-937 cell line was differentiated by 24 h incubation with phorbol myristate acetate (PMA, 6 ng/ml), then dexamethasone (1 microM) was added for further 16 h. In these conditions the steroid treatment caused both the release of lipocortin-1 in the cellular supernatant and the inhibition of eicosanoid release. These results suggest that the responsiveness of these cells to steroids is dependent on the phase of cell activation-differentiation. The selective release of the lipocortin-1 may explain the inhibition of eicosanoid formation. Patients with inflammatory lung disease underwent glucocorticoid treatment at clinically effective doses. LC-1 expression was significantly stimulated in alveolar macrophages, but not in blood-derived lympho-monocytes. These results suggest that also in vivo cell responsiveness to glucocorticoids is acquired during cell differentiation from blood monocyte to tissue macrophage.

Annexin A1↗
PubMed1993

[The use of picotamide in nephropathy with mesangial IgA deposits. The effect on thromboxane generation].

IgA nephropathy (Berger's disease) is one of the commonest forms of glomerular disease, not rarely progressing to renal failure. Hemostatic system activation may play a role in the development of glomerular injury. In a series of 12 adult patients affected with IgA nephropathy we have observed increased plasma levels of D-dimer, a stable end-product of cross-linked fibrin degradation that is considered a reliable index of blood clotting activation, as well as "in vitro" raised generation of thromboxane, the main platelet product of arachidonic acid metabolism that seems to play an important role in glomerulosclerosis. Picotamide, a novel antiplatelet drug acting as thromboxane synthase inhibitor as well as thromboxane receptor antagonist, administered for 8-12 weeks, was effective in reducing thromboxane generation. We conclude that picotamide may be useful in the management of glomerular nephropathy.

Adolescent↗
PubMed1992

The d-enantiomer form of indobufen totally accounts for the anti-cyclooxygenase and antiplatelet activity ex vivo and for the increase in bleeding time by indobufen in man.

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean +/- S.D., 58.7 +/- 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 +/- 3% for both treatments). At 12 h inhibition was 87 +/- 6% for d-indobufen and 88 +/- 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Vasoactive eicosanoids in the rat heart: clues to a contributory role of cardiac thromboxane to post-ischaemic hyperaemia.

To assess the potential role of vasoactive cardiac eicosanoids in the modulation of coronary flow, we measure thromboxane(TX)B2, 6-keto-prostaglandin(PG)F1 alpha, PGE2 and sulphido-peptide leukotrienes (LTC4, D4, E4) in the coronary effluent of isolated perfused rat heart in both baseline and post-ischaemic conditions. Leukotrienes were undetectable. The order of production rate for the other eicosanoids was 6-keto-PGF1 alpha > TXB2 > PGE2. Production of such substances was increased about seven-fold over control after 5 min. global ischaemia; experiments with hypoxia showed that this was due to an actual increase in synthesis and not to a washout effect. A platelet source for TXB2 was excluded by 111In platelet labelling experiments. We assessed relative sensitivity to inhibition of cardiac TX synthesis relative to production of 6-keto-PGF1 alpha to inhibition by aspirin, ibuprofen, diclofenac and the specific thromboxane synthase inhibitor OKY-046. Aspirin, ibuprofen and diclofenac decreased 6-keto-PGF1 alpha production at a concentration always greater than required for a similar extent of TX inhibition. On the other hand a selective inhibition (> 90%) of TX was observed in the presence of OKY-046. Regression analysis of various 6-keto-PGF1 alpha/TXB2 ratios, as obtained in these different conditions, vs coronary flow, showed no correlation in baseline conditions, but a significant positive correlation (r = 0.59, P < 0.01) for post-ischaemic values. These data suggest a role for cardiac eicosanoids, including a non-platelet, cardiac-derived TX, in modulating the hyperaemic response in the isolated rat heart.

Animals↗
PubMed1991

Benefit/risk profile of combined antiplatelet therapy with ticlopidine and aspirin.

Ticlopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 microM; adrenaline 0.75-2.5 microM; collagen 1.5-150 micrograms/ml; arachidonic acid 1 mM; PAF 1 microM; adrenaline 0.17 microM + ADP 0.62 microM; serum thromboxane [( TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p less than 0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean +/- SEM: T: 95 +/- 3; ASA: 96 +/- 5; T + ASA: 89 +/- 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗