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Biomedical subjects

W Bernini

Publications and source records attributed to W Bernini.

At least 37 records · Page 2Linked to original sources
PubMed1990

Inhibition of platelet function during in vivo infusion of isosorbide mononitrates: relationship between plasma drug concentration and hemodynamic effects.

Isosorbide monitrates (IS-2-MN and IS-5-MN), hepatic metabolites of isosorbide dinitrate, inhibit platelet function in vitro very differently, with IS-2-MN being much more potent than IS-5-MN. To assess their antiplatelet properties in vivo and to compare time and dosage requirements, we infused both IS-2-MN and IS-5-MN for 30 minutes, on 2 separate days, into nine patients with stable coronary artery disease, at rates of 4 mg/hr (n = 4) and 8 mg/hr (n = 5). Two additional patients received IS-5-MN at 16 mg/hr. Platelet aggregation and thromboxane (TX) B2 generation in response to various agonists, drug plasma concentrations, and blood pressure were monitored throughout the study. A significant decrease in platelet aggregation and TXB2 production by adenosine diphosphate and adrenaline occurred in seven of nine patients receiving IS-2-MN and in 7 of 11 patients receiving IS-5-MN. Response was dose related, with more patients responding at 8 mg/hr to IS-2-MN (five of five) than to IS-5-MN (three of five), and was maximum at the end of the infusion time, corresponding to peak plasma levels. Patients responding to drug infusions with an inhibition of platelet function were characterized by a greater vascular responsiveness compared to nonresponders, since the decrease in systolic blood pressure (mean +/- SEM) was significantly greater in the former (15.4 +/- 3.2) than in the latter (2.5 +/- 2.1, p less than 0.05). Therefore both mononitrates, when administered at infusion rates between 8 and 16 mg/hr, are accompanied by a consistent inhibition of adenosine diphosphate- and adrenaline-induced aggregation and TX generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗
PubMed1990

Vascular prostacyclin is increased in patients ingesting omega-3 polyunsaturated fatty acids before coronary artery bypass graft surgery.

Interest in the antithrombotic potential of diets enriched with fish oil-derived polyunsaturated fatty acids (omega-3 PUFAs) prompted us to examine how these fatty acids, when taken preoperatively, affect hemostasis, plasma lipid levels, and production of prostacyclin (PGI2) by vascular tissues in atherosclerotic patients undergoing coronary artery bypass graft surgery. Fifteen patients with angiographically proven coronary artery disease received 3 g/day eicosapentaenoic acid and 1.3 g/day docosahexaenoic acid as capsules of purified fish oil for 28 days before surgery. Platelet aggregation induced by low concentrations of ADP, collagen, and epinephrine decreased (p less than 0.05) and serum thromboxane B2 decreased 36% (p less than 0.01) from baseline values. Bleeding times increased 40% (p less than 0.01) from baseline. Serum triglycerides decreased 50% (p less than 0.05) without a change in total serum cholesterol. Spontaneous production of PGI2 measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), its stable hydrolytic product, by saphenous vein and aortic and atrial tissues obtained at surgery was greater in tissues from patients receiving omega-3 PUFA supplements than in tissues from matched controls (13.8 +/- 2.2 versus 8.6, 21.0 +/- 3.1 versus 11.5 +/- 2.1, and 166 +/- 13 versus 102 +/- 15 ng/g, respectively, all p less than 0.05). Arachidonate-stimulated production of PGI2, as indicated by increased levels of 6-keto-PGF1 alpha, was increased. Despite changes in platelet function, bleeding time, and vascular PGI2, the perioperative blood loss was not increased in subjects receiving fish oil supplements. Thus, omega-3 PUFAs at moderate dosages may exert antithrombotic effects by increasing prostacyclin production by vessel walls as well as by direct inhibition of platelet activity.

Aged↗
PubMed1989

In vivo actions of organic nitrates on platelet function in humans.

Nitroglycerin and isosorbide dinitrate (ISDN), the most commonly used nitrate vasodilators, have been shown to possess antiplatelet properties. It has also been shown, interestingly, that their inhibition of aggregation (mostly upon ADP and adrenaline) occurs in vivo at concentrations 1-2 log orders lower than in vitro, and in the full therapeutic range. Many different hypotheses may explain such an in vivo/in vitro difference: 1) that nitrates induce prostacyclin synthesis; 2) that they synergize prostacyclin; 3) that they give rise to more active in vivo metabolites; 4) that some other requirement for their action, such as the availability of reducing thiols, may be a limiting factor in the in vitro setting. The discrimination among such hypotheses should contribute new insights into nitrate action at the platelet level. On the basis of experiments on cultured endothelial cells and vascular fragments, we had previously concluded against prostacyclin induction by nitrates. On the other hand, ISDN may decrease the IC50 for prostacyclin in aggregation by suprathreshold doses of various aggregating agents, and therefore, be synergistic with this endogenous antiplatelet substance. Compared to ISDN, the two longer-lived metabolites isosorbide-2- and isosorbide-5-mononitrates (IS-2-MN, IS-5-MN) appear remarkably different in terms of antiplatelet potency in vitro (minimum effective concentrations 10(-7)-10(-6)M for IS-2-MN, 10(-4)M for IS-5-MN, for ADP-and adrenaline-induced aggregation and thromboxane (TX) B2 production).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1988

Organic nitrates: direct antiplatelet effects and synergism with prostacyclin. Antiplatelet effects of organic nitrates.

Isosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10(-7)-10(-6) vs. 10(-6)-10(-5) M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10(-7) M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p less than 0.05) and TX production (-36%, p less than 0.01) by ADP. At 10(-6) M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p less than 0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.

Adult↗
PubMed1988

Mechanisms for the in vivo antiplatelet effects of isosorbide dinitrate.

We investigated two possible reasons for the greater antiplatelet efficacy of isosorbide dinitrate (ISDN) in vivo as compared to in vitro. ISDN and its two main hepatic metabolites, isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were compared for their ability to inhibit platelet aggregation and thromboxane B2 generation in vitro in response to threshold concentrations of ADP, adrenaline, collagen, thrombin and arachidonic acid. We also determined the concentration of prostacyclin required to inhibit by 50% platelet aggregation (IC50) in response to supra-threshold doses of aggregating agents. Out of the three nitrates tested, IS-2-MN was more effective than ISDN in inhibition of platelet aggregation and thromboxane B2 formation after ADP (minimum effective concentration: 10(-7) M) and adrenaline (minimum effective concentration: 10(-6) M). In addition, ISDN 10(-4)-10(-6) M decreased IC50 for prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active species, IS-2-MN, and synergism with prostacyclin are novel properties of ISDN and may account for in vivo-in vitro differences in antiaggregatory properties and in vivo mechanism of action.

Adult↗
PubMed1985

Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction.

This study explores the effects on some hematological parameters of a low-dose aspirin regimen (50 mg/day) versus a conventional aspirin treatment with reported antithrombotic efficacy (324 mg/day), in patients with acute myocardial infarction. Fifteen patients were randomized into 3 equal groups receiving 50 mg or 324 mg aspirin or placebo, daily for 21 days. Compared with placebo, bleeding time was significantly and similarly prolonged with both aspirin doses (+ 71 +/- 22% and + 69 +/- 20%, mean +/- S.D.). Aspirin 50 mg/day suppressed arachidonate-induced platelet aggregation and secondary phase aggregation after ADP and adrenaline. Collagen aggregation was inhibited by 44 +/- 15%. In no case were differences in the antiplatelet effects of the two doses observed. The effects of 50 mg/day persisted without attenuation during the observation period. Platelet thromboxane B2 generation during arachidonate-induced aggregation was inhibited by 95 +/- 2 and 99 +/- 1% compared to placebo group after 50 and 324 mg/day, respectively (P between doses less than 0.05). No change was observed with any treatment in coagulation time, prothrombin time or plasma thromboplastin time. Thus, in patients with acute myocardial infarction, the antiplatelet effects of aspirin 50 mg/day are stable over time and superimposable on those of 324 mg/day. The antithrombotic efficacy of aspirin 50 mg/day remains to be tested clinically.

Administration, Oral↗
PubMed1985

Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function.

The adequacy, selectivity and long-term persistence of inhibition in cyclooxygenase-dependent platelet function by a daily low-dose (0.45 mg kg-1 day-1) aspirin treatment have been evaluated in 15 patients after a recent (less than 17 days) acute myocardial infarction. Serum thromboxane (TX) B2, an index of platelet TXA2 production, was decreased by 94-98% (P less than 0.001) by aspirin, while urinary excretion of 6-keto-prostaglandin F1 alpha, as an index of extraplatelet cyclooxygenase activity, remained unchanged. Compared to placebo, aspirin induced a persistent increase in bleeding time (% difference 45.6 +/- 21.4, mean +/- SD) and a decrease in platelet aggregation by ADP, epinephrine, collagen and arachidonic acid. No tendency towards an attenuation of the effects was apparent for the period of aspirin administration (4 weeks). Aspirin 0.45 mg kg-1 day-1 is adequate and selective in the long-term inhibition of TX-related platelet function in patients after acute myocardial infarction. The clinical effectiveness of such a regimen remains to be proven in clinical trials.

Adult↗
PubMed1984

Inhibition of platelet function by injectable isosorbide dinitrate.

The possibility that isosorbide dinitrate (ISDN) inhibits platelet function in humans has been explored in vitro and in vivo. Incubation of citrated platelet-rich plasma from healthy subjects with scalar concentrations (1.25, 12.5 and 125 micrograms/ml) of ISDN for 5 and 10 minutes resulted in a decrease in platelet aggregation after ADP, adrenaline, and arachidonic acid at the highest drug concentration (mean decrease: 72% [p less than 0.01], 56% [p less than 0.05] and 62% [p less than 0.05], respectively, with the 10-minute incubation). Also, a significant reduction (30%) in generated thromboxane (TX)B2 levels was observed after arachidonic acid (p less than 0.01). ISDN was then infused at rate of 4 mg/hour for 30 minutes in 11 patients with angina and at a rate of 30 mg/hour for 20 minutes in 8. The smaller dose, which caused minor changes in arterial pressure and heart rate, was accompanied by a marked, significant decrease in ADP- and adrenaline-induced aggregation, with a nadir at 60 minutes from the infusion stop (decreases of 40% and 51% respectively). Circulating platelet aggregates also decreased, with a minimum (-41%, p less than 0.05) at the end of the infusion. The higher infusion rate, causing marked hemodynamic effects, was not accompanied by the occurrence of clear antiplatelet effects. Thus, ISDN can affect platelet function both in vitro and in vivo. The in vivo effect occurs at lower concentrations than in vitro but is blunted when a marked hemodynamic response occurs.

Adenosine Diphosphate↗
PubMed1983

Antiplatelet effects of isosorbide dinitrate in man.

Variable antiplatelet effects have been described for various antianginal drugs, including beta-blockers, verapamil, and nifedipine. To assess and characterize a possible similar effect of nitrates, platelet-rich plasma (PRP) from 22 healthy donors was incubated with scalar concentrations (1.25, 12.5, 125 micrograms/ml) of isosorbide dinitrate (ISDN) and with the vehicle alone for periods of 5 and 10 min. Platelet aggregation was successively induced by ADP (0.4-1.2 microM), adrenaline (0.8-8 microM), collagen (16.7 micrograms/ml), arachidonic acid (AA; 1 mM) and thrombin (0.5-2 U/ml). At the end of aggregation thromboxane (TX) B2 levels in PRP were assessed by RIA. A dose-dependent decrease in both platelet aggregation and TXB2 levels by all the inducers tested was demonstrated with both incubation times. Maximum inhibition of platelet aggregation was observed with ADP and adrenaline (72.0% and 55.6% respectively with 10-min incubation and the highest ISDN concentration. P less than 0.01 and P less than 0.05 respectively). A reduction in TXB2 levels in PRP was also observed, but reached statistical significance (P less than 0.01) only for AA-induced TXB2 generation. For an in vivo study ISDN was infused for periods of 30 min at 4 mg/h in 11 angina patients, and for periods of 20 min at 30 mg/h in an other eight, under ECG and arterial blood pressure monitoring. ADP- and adrenaline-induced aggregation and TXB2 production, and determination of circulating platelet aggregates (CPA) were performed in basal conditions and at 5, 15, 30 and 90 min from infusion start in the first group, at 5, 15, and 80 min in the second group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Uric acid levels and platelet function in humans. An in-vivo ex-vivo study.

Platelet function (aggregation by ADP, adrenaline, collagen and circulating platelet aggregates) before, during and after dietary induction of hyperuricemia (ribonucleic acid, 3 g/day) was studied in five healthy volunteers to assess the relationship between uric acid level and platelet function. In the same subjects, during a second period of ribonucleic acid diet, the acute and chronic effects of a hypo-uricemizing agent, allopurinol, were assessed. No significant correlation was detected between platelet function and uricemia either in the absence or in the presence of pharmacological treatment with allopurinol. On the basis of these results, the well known relationship between uric acid levels and ischemic heart disease does not appear to be mediated by an exaggerated platelet function.

Adult↗